A critical re-analysis of cases of post-transplantation recurrence in genetic nephrotic syndrome

Abstract Background Genetic defects in podocyte proteins account for up to 30% of steroid-resistant nephrotic syndrome (SRNS) in the paediatric population. Most children with genetic SRNS are resistant to immunosuppression and at high risk of progression to stage 5 chronic kidney disease. Kidney transplantation is often the treatment of choice. The possibility of post-transplantation disease recurrence in genetic SRNS remains controversial, and poses fundamental questions about disease biology. Methods We critically evaluated the published cases of post-transplantation recurrence in genetic patients, particularly testing ‘mutations’ against the most recent population variant databases, in order to clarify the diagnoses, and compare the clinical courses and responses to therapy. Results Biallelic pathogenic variants in NPHS1 leading to a complete absence of nephrin were the most commonly reported and best understood instance of nephrotic syndrome occurring post-transplantation. This is an immune-mediated process driven by antibody production against the novel nephrin protein in the allograft. We also identified a number of plausible reported cases of post-transplantation recurrence involving pathogenic variants in NPHS2 (8 patients, biallelic), one in WT1 (monoallelic) and one in NUP93 (biallelic). However, the mechanism for recurrence in these cases remains unclear. Other instances of recurrence in genetic disease were difficult to interpret due to differing clinical criteria, inclusion of patients without true pathogenic variants or the influence of other factors on renal outcome. Conclusions Overall, post-transplantation recurrence remains very rare in patients with genetic SRNS. It appears to occur later after transplantation than in other patients and usually responds well to plasmapheresis with a good renal outcome.

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Diagnostic difficulties and possibilities of NF1-like syndromes in childhood

BMC Pediatrics ◽

10.1186/s12887-021-02791-0 ◽

2021 ◽

Vol 21 (1) ◽

Author(s):

Eva Pinti ◽

Krisztina Nemeth ◽

Krisztina Staub ◽

Anna Lengyel ◽

Gyorgy Fekete ◽

...

Keyword(s):

Diagnostic Criteria ◽

Neurofibromatosis Type ◽

Early Years ◽

Diagnostic Efficiency ◽

Clinical Criteria ◽

Pathogenic Variants ◽

Clinical Diagnostic ◽

Long Time ◽

Diagnostic Difficulties ◽

Clinical Diagnostic Criteria

Abstract Background Neurofibromatosis type 1 (NF1), which is caused by heterozygous inactivating pathogenic variants in the NF1, has poor phenotypic expressivity in the early years of life and there are numerous conditions, including many other tumor predisposition syndromes, that can mimic its appearance. These are collectively termed NF1-like syndromes and are also connected by their genetic background. Therefore, the NF1’s clinical diagnostic efficiency in childhood could be difficult and commonly should be completed with genetic testing. Methods To estimate the number of syndromes/conditions that could mimic NF1, we compiled them through an extensive search of the scientific literature. To test the utility of NF1’s National Institutes of Health (NIH) clinical diagnostic criteria, which have been in use for a long time, we analyzed the data of a 40-member pediatric cohort with symptoms of the NF1-like syndromes’ overlapping phenotype and performed NF1 genetic test, and established the average age when diagnostic suspicion arises. To facilitate timely identification, we compiled strongly suggestive phenotypic features and anamnestic data. Results In our cohort the utility of NF1’s clinical diagnostic criteria were very limited (sensitivity: 80%, specificity: 30%). Only 53% of children with clinically diagnosed NF1 had a detectable NF1 pathogenic variation, whereas 40% of patients without fulfilled clinical criteria tested positive. The average age at first genetic counseling was 9 years, and 40% of children were referred after at least one tumor had already been diagnosed. These results highlight the need to improve NF1-like syndromes’ diagnostic efficiency in childhood. We collected the most extensive spectrum of NF1-like syndromes to help the physicians in differential diagnosis. We recommend the detailed, non-invasive clinical evaluation of patients before referring them to a clinical geneticist. Conclusions Early diagnosis of NF1-like syndromes can help to prevent severe complications by appropriate monitoring and management. We propose a potential screening, diagnostic and management strategy based on our findings and recent scientific knowledge.

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Pathogenic variants in GNPTAB and GNPTG encoding distinct subunits of GlcNAc-1-phosphotransferase differentially impact bone resorption in patients with mucolipidosis type II and III

Genetics in Medicine ◽

10.1038/s41436-021-01285-9 ◽

2021 ◽

Author(s):

Giorgia Di Lorenzo ◽

Lena M. Westermann ◽

Timur A. Yorgan ◽

Julian Stürznickel ◽

Nataniel F. Ludwig ◽

...

Keyword(s):

Bone Resorption ◽

Bone Remodeling ◽

Bone Cells ◽

Collagen Crosslinks ◽

Clinical Criteria ◽

Pathogenic Variants ◽

Bone Biopsies ◽

Appropriate Therapy ◽

Alpha Beta ◽

Deficient Mice

Abstract Purpose Pathogenic variants in GNPTAB and GNPTG, encoding different subunits of GlcNAc-1-phosphotransferase, cause mucolipidosis (ML) II, MLIII alpha/beta, and MLIII gamma. This study aimed to investigate the cellular and molecular bases underlying skeletal abnormalities in patients with MLII and MLIII. Methods We analyzed bone biopsies from patients with MLIII alpha/beta or MLIII gamma by undecalcified histology and histomorphometry. The skeletal status of Gnptgkoand Gnptab-deficient mice was determined and complemented by biochemical analysis of primary Gnptgko bone cells. The clinical relevance of the mouse data was underscored by systematic urinary collagen crosslinks quantification in patients with MLII, MLIII alpha/beta, and MLIII gamma. Results The analysis of iliac crest biopsies revealed that bone remodeling is impaired in patients with GNPTAB-associated MLIII alpha/beta but not with GNPTG-associated MLIII gamma. Opposed to Gnptab-deficient mice, skeletal remodeling is not affected in Gnptgko mice. Most importantly, patients with variants in GNPTAB but not in GNPTG exhibited increased bone resorption. Conclusion The gene-specific impact on bone remodeling in human individuals and in mice proposes distinct molecular functions of the GlcNAc-1-phosphotransferase subunits in bone cells. We therefore appeal for the necessity to classify MLIII based on genetic in addition to clinical criteria to ensure appropriate therapy.

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MO1027EFFICACY OF CALCINEURIN INHIBITORS IN CHILDREN WITH MONOGENIC STEROID-RESISTANT NEPHROTIC SYNDROME

Nephrology Dialysis Transplantation ◽

10.1093/ndt/gfab108.0024 ◽

2021 ◽

Vol 36 (Supplement_1) ◽

Author(s):

Larisa Prikhodina ◽

Svetlana Papizh ◽

Inna Povolotskaya

Keyword(s):

Nephrotic Syndrome ◽

Calcineurin Inhibitors ◽

Compound Heterozygous ◽

Target Level ◽

Steroid Resistant ◽

Steroid Resistant Nephrotic Syndrome ◽

Pathogenic Variants ◽

Nail Patella Syndrome

Abstract Background and Aims Monogenic causes of steroid-resistant nephrotic syndrome (SRNS) have been reported for up to one-third of children depending on age of the disease onset. Immunosuppressive treatment of genetic SRNS with calcineurin inhibitors (CNIs) is still controversial. The aim of the study was to investigate the efficacy of CNIs with focus on inducing remission and long-term kidney function in children with monogenic SRNS. Method Retrospective analysis of efficacy CNIs in five children (2M/3F) with monogenic SRNS was performed. Kidney biopsy prior CNIs revealed FSGS (n=4) and MCD (n=1). The initial cyclosporine (CsA) dose was 5 mg/kg/24h to keep a target level of 80-150 ng/ml and tacrolimus (TAC) - 0.1 mg/kg/24h to achieve a target level of 5-10 ng/ml. CsA took all 5 patients with subsequent switching to TAC in 2 children due to cosmetic side effects. The median follow-up period was 165.0 (IQR: 59.0; 185.5) months. Next generation sequencing (NGS) was used for identification of pathogenic variants in all patients. Results The median age at onset of monogenic SRNS was 33.0 (IQR: 16.5; 63.0) months. 2/5 (40%) patients presented with acute SRNS, 1/5 (20%) child with infantile NS, 1/5 (20%) - with isolated nephrotic range proteinuria with hypoalbuminemia and 1/5 (20%) - with NS and extrarenal features of Nail-Patella syndrome. NGS identified previously described pathogenic variants in all 5 children, including NPHS2 homozygous c.28dup (p.Glu87Ter) (n=1), NPHS2 compound heterozygous c.868G>A (p.Val290Met) in combination with c.686G>A (p.Arg229Gln) (n=1), LMX1B heterozygous c.788T>G (p.Val263Gly) (n=1), LMX1B heterozygous c.737G>A (p.Arg246Gln) (n=1), and COL4A3 heterozygous c.2962G>A (p.Gly988Arg) variant (n=1). The median time from diagnosis to initiation of CNIs treatment was 72.0 (IQR: 33.0; 93.0) months. CNIs induced complete remission in 2/5 (40%) patients, presented with acute SRNS, including one girl with MCD due to NPHS2 compound heterozygous variants with mutation-dependent pathogenicity of one (p.R229Q) of them and one boy with FSGS due to COL4A3 heterozygous variant (n=1). Partial remission was induced by CNIs in 2/5 (40%) girls with FSGS due to LMX1B heterozygous variants with isolated SRNS (n=1) and Nail-Patella syndrome (n=1). The median duration of CNIs treatment to obtain complete or partial remission was 13.5 (IQR: 6.8; 15.8) months. Acute CNIs-associated nephrotoxicity had 2 patients with LMX1B variants. At the last follow up full and partial responders to CNIs treatment aged of 16.5 (IQR: 11.8; 17.5) years had CKD-1 (n=3) and CKD-2 (n=1). 1/5 (20%) boy with NPHS2-associated infantile NS was CNI resistant and developed CKD-5 at the age of 6.5 years with subsequent living related kidney transplantation. Conclusion We found that 4/5 (80%) children with monogenic SRNS demonstrated partial or full response to CNIs treatment with stable long-term kidney function. We assume that CNIs might improve podocyte function by stabilization of their cytoskeleton disrupted in patients with monogenic SRNS.

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Immunosuppression and Renal Outcome in Congenital and Pediatric Steroid-Resistant Nephrotic Syndrome

Clinical Journal of the American Society of Nephrology ◽

10.2215/cjn.01190210 ◽

2010 ◽

Vol 5 (11) ◽

pp. 2075-2084 ◽

Cited By ~ 114

Author(s):

Anja K. Büscher ◽

Birgitta Kranz ◽

Rainer Büscher ◽

Friedhelm Hildebrandt ◽

Bernd Dworniczak ◽

...

Keyword(s):

Nephrotic Syndrome ◽

Renal Outcome ◽

Steroid Resistant ◽

Steroid Resistant Nephrotic Syndrome

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Reverse Phenotyping after Whole-Exome Sequencing in Steroid-Resistant Nephrotic Syndrome

Clinical Journal of the American Society of Nephrology ◽

10.2215/cjn.06060519 ◽

2019 ◽

Vol 15 (1) ◽

pp. 89-100 ◽

Cited By ~ 15

Author(s):

Samuela Landini ◽

Benedetta Mazzinghi ◽

Francesca Becherucci ◽

Marco Allinovi ◽

Aldesia Provenzano ◽

...

Keyword(s):

Nephrotic Syndrome ◽

Exome Sequencing ◽

Whole Exome Sequencing ◽

Clinical Signs ◽

Long Term Outcome ◽

Steroid Resistant ◽

Steroid Resistant Nephrotic Syndrome ◽

Pathogenic Variants ◽

Whole Exome ◽

Steroid Sensitive

Background and objectivesNephrotic syndrome is a typical presentation of genetic podocytopathies but occasionally other genetic nephropathies can present as clinically indistinguishable phenocopies. We hypothesized that extended genetic testing followed by reverse phenotyping would increase the diagnostic rate for these patients.Design, setting, participants, & measurementsAll patients diagnosed with nephrotic syndrome and referred to our center between 2000 and 2018 were assessed in this retrospective study. When indicated, whole-exome sequencing and in silico filtering of 298 genes related to CKD were combined with subsequent reverse phenotyping in patients and families. Pathogenic variants were defined according to current guidelines of the American College of Medical Genetics.ResultsA total of 111 patients (64 steroid-resistant and 47 steroid-sensitive) were included in the study. Not a single pathogenic variant was detected in the steroid-sensitive group. Overall, 30% (19 out of 64) of steroid-resistant patients had pathogenic variants in podocytopathy genes, whereas a substantial number of variants were identified in other genes, not commonly associated with isolated nephrotic syndrome. Reverse phenotyping, on the basis of a personalized diagnostic workflow, permitted to identify previously unrecognized clinical signs of an unexpected underlying genetic nephropathy in a further 28% (18 out of 64) of patients. These patients showed similar multidrug resistance, but different long-term outcome, when compared with genetic podocytopathies.ConclusionsReverse phenotyping increased the diagnostic accuracy in patients referred with the diagnosis of steroid-resistant nephrotic syndrome.

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In-silico Analysis of NF1 Missense Variants in ClinVar: Translating Variant Predictions into Variant Interpretation and Classification

International Journal of Molecular Sciences ◽

10.3390/ijms21030721 ◽

2020 ◽

Vol 21 (3) ◽

pp. 721 ◽

Cited By ~ 1

Author(s):

Matteo Accetturo ◽

Nicola Bartolomeo ◽

Alessandro Stella

Keyword(s):

Genetic Diseases ◽

In Silico Analysis ◽

Neurofibromatosis Type ◽

Fine Tuning ◽

Variant Interpretation ◽

Score Distribution ◽

Clinical Criteria ◽

Missense Variants ◽

Pathogenic Variants ◽

Criteria For Diagnosis

Background: With the advent of next-generation sequencing in genetic testing, predicting the pathogenicity of missense variants represents a major challenge potentially leading to misdiagnoses in the clinical setting. In neurofibromatosis type 1 (NF1), where clinical criteria for diagnosis may not be fully present until late infancy, correct assessment of variant pathogenicity is fundamental for appropriate patients’ management. Methods: Here, we analyzed three different computational methods, VEST3, REVEL and ClinPred, and after extracting predictions scores for 1585 NF1 missense variants listed in ClinVar, evaluated their performances and the score distribution throughout the neurofibromin protein. Results: For all the three methods, no significant differences were present between the scores of “likely benign”, “benign”, and “likely pathogenic”, “pathogenic” variants that were consequently collapsed into a single category. The cutoff values for pathogenicity were significantly different for the three methods and among benign and pathogenic variants for all methods. After training five different models with a subset of benign and pathogenic variants, we could reclassify variants in three sharply separated categories. Conclusions: The recently developed metapredictors, which integrate information from multiple components, after gene-specific fine-tuning, could represent useful tools for variant interpretation, particularly in genetic diseases where a clinical diagnosis can be difficult.

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P0508NEPHROTIC SYNDROME DUE TO HEAVY AND LIGHT CHAIN (AHL) AMYLOIDOSIS

Nephrology Dialysis Transplantation ◽

10.1093/ndt/gfaa142.p0508 ◽

2020 ◽

Vol 35 (Supplement_3) ◽

Author(s):

Csilla Markóth ◽

László Bidiga ◽

Piroska Pettendi ◽

Éva Rékasi ◽

László Ujhelyi ◽

...

Keyword(s):

Bone Marrow ◽

Nephrotic Syndrome ◽

Plasma Cell ◽

Heavy Chain ◽

Light Chain ◽

Kidney Biopsy ◽

Kidney Diseases ◽

Screening Tests ◽

Renal Outcome ◽

Plasma Cell Dyscrasia

Abstract Background and Aims Kidney diseases with heavy chain deposition are rare, including AHL amyloidosis also. The mutation/deletion of the constant domain (CH1/CH2) of the heavy chain causing high tissue affinity seems most likely in its pathogenesis. The very low serum level is responsible for the difficult diagnosis, which is often based on kidney biopsy or laser microdissection / mass spectrometry. Method Case study of a 76-year-old male patient, examined in January, 2019. Results Besides treatment for Ménière syndrome and benign prostatic hyperplasia there was no other important event in patient’s history. Significant proteinuria and microscopic haematuria were observed from May 2016, but eGFR was 70 ml/min/1,73 m2 at that time. By April, 2018 nephrotic range proteinuria (10 g/day) with full nephrotic syndrome developed. Screening tests for cancer were negative. Despite symptomatic treatment, half year later eGFR decreased to 27 ml/min/1,73 m2, therefore he was referred to nephrology. Serum protein electrophoresis verified IgG lambda (8,1 g/l) and free lambda (0,5 g/l) monoclonal light chains, and in addition the possibility of IgG heavy chain accumulation. Urine electrophoresis showed also IgG lambda (1720,1 mg/l), and free lambda light chain (552,1 mg/l) monoclonality. Serum free lambda and kappa light chain ratio was 0,06, complement serology was normal. Kidney biopsy was done, which showed IgG heavy and light chain restriction, Congo red stain positivity and apple green birefringence under the polarized microscope in the expanded mesangium, in the interstitium and along the tubular basement membrane and the blood vessels. The electron microscope detected fibrillary deposits (10 nm) in the same structures, therefore diagnosis of AHL amyloidosis was established. He had no extrarenal symptoms. Bone marrow aspiration flow cytometry verified 1,11% plasma cell accumulation, 93% of them had pathological immunphenotype. Bone marrow morphology assay showed 30-40% plasma cell infiltration, and chromosome assay detected monoallelic deletion of IgH and MAF and gains of 1q region, suggesting myeloma multiplex in the background of AHL amyloidosis. VCD (bortezomib-cyclophosphamide-dexamethason) treatment was started, so far he has received 8 cycles. He is asymptomatic, proteinuria decreased, kidney function stabilized, eGFR 23 ml/min/1,73 m2. Conclusion only about 20 cases of AHL amyloidosis have been reported in the literature so far. In the context of longstanding kidney failure with nephrotic syndrome, we should consider renal disease associated with plasma cell dyscrasia also. If case of an AHL amyloidosis caused by myeloma multiplex, effective anti-plasma cell therapy can improve the hematological and the renal outcome.

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Clear evidence of LAMA5 gene biallelic truncating variants causing infantile nephrotic syndrome

Kidney360 ◽

10.34067/kid.0004952021 ◽

2021 ◽

pp. 10.34067/KID.0004952021

Author(s):

Yukimasa Taniguchi ◽

China Nagano ◽

Kiyotoshi Sekiguchi ◽

Atsushi Tashiro ◽

Noriko Sugawara ◽

...

Keyword(s):

Nephrotic Syndrome ◽

Splice Site ◽

Japanese Patients ◽

Compound Heterozygous ◽

Missense Variants ◽

Targeted Next Generation Sequencing ◽

Pathogenic Variants ◽

Infantile Nephrotic Syndrome ◽

Splice Site Variant

Background: Pathogenic variants in single genes encoding podocyte-associated proteins have been implicated in about 30% of steroid resistant nephrotic syndrome (SRNS) patients in children. However, LAMA5 gene biallelic variants have been identified in only 7 patients so far, and most are missense variants of unknown significance. Furthermore, no functional analysis had been conducted for all but one of these variants. Here, we report three patients with LAMA5 gene biallelic truncating variants manifesting infantile nephrotic syndrome and one SRNS case with biallelic LAMA5 missense variants. Methods: We conducted comprehensive gene screening of Japanese patients with severe proteinuria. Using targeted next-generation sequencing, 62 podocyte-related genes were screened in 407 unrelated patients with proteinuria. For the newly discovered LAMA5 variants, we conducted in vitro heterotrimer formation assays. Results: Biallelic truncating variants in the LAMA5 gene (NM_005560) were detected in 3 patients from 2 families. All patients presented with proteinuria within 6 months of age. Patients 1 and 2 were siblings possessing a nonsense variant (c.9232C>T, p.(Arg3078*)) and a splice site variant (c.1282+1G>A) that led to exon 9 skipping and a frameshift. Patient 3 had a remarkable irregular contour of the glomerular basement membrane. She was subsequently found to have a nonsense variant (c.8185C>T, p.(Arg2720*)) and the same splice site variant in patients 1 and 2. By in vitro heterotrimer formation assays, both truncating variants produced smaller laminin α5 proteins that nevertheless formed trimers with laminin β1 and γ1 chains. Patient 4 showed SRNS at the age of eight and carried compound heterozygous missense variants (c.1493C>T, p.(Ala498Val) and c.8399G>A, p.(Arg2800His)). Conclusions: Our patients showed clear evidence of biallelic LAMA5 truncating variants causing infantile nephrotic syndrome. We also discerned the clinical and pathological characteristics observed in LAMA5-related nephropathy. LAMA5 variant screening should be performed in congenital/infantile nephrotic syndrome patients.

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Prevalence of hereditary tubulointerstitial kidney diseases in the German Chronic Kidney Disease study

10.1101/2021.09.29.21264100 ◽

2021 ◽

Author(s):

Bernt Popp ◽

Arif B. Ekici ◽

Karl X. Knaup ◽

Karen Schneider ◽

Steffen Uebe ◽

...

Keyword(s):

Chronic Kidney Disease ◽

Kidney Disease ◽

Kidney Diseases ◽

Diagnostic Yield ◽

Genetic Disorder ◽

Clinical Criteria ◽

Pathogenic Variants ◽

Increased Risk ◽

Monogenic Diseases ◽

Disease Study

ABSTRACTExome sequencing (ES) studies in chronic kidney disease (CKD) cohorts could identify pathogenic variants in ∼10% of patients. This implies underdiagnosis of hereditary CKD. Tubulointerstitial kidney diseases, showing no typical clinical/histologic finding but tubulointerstitial fibrosis, are particularly difficult to diagnose.We used a custom designed targeted panel (29 genes) and MUC1-SNaPshot to sequence 271 DNA samples, selected by clinical criteria from 5,217 individuals in the German Chronic Kidney Disease (GCKD) cohort.We identified 33 pathogenic small variants. Of these 27 (81.8%) were in COL4-genes, the largest group being 15 COL4A5-variants with nine unrelated individuals carrying c.1871G>A, p.(Gly624Asp). We found three cysteine variants in UMOD, a novel missense, and a novel splice variant in HNF1B and the homoplastic MTTF variant m.616T>C. Copy-number analysis identified a heterozygous COL4A5-deletion, and a HNF1B-duplication/-deletion, respectively. Overall, pathogenic variants were present in 12.5% (34/271) and variants of unknown significance in 9.6% (26/271) of selected individuals. Bioinformatic predictions paired with gold standard diagnostics for MUC1 (SNaPshot) could not identify the typical cytosine duplication (“c.428dupC”) in any individual, implying that ADTKD-MUC1 is rare.Our study shows that >10% of individuals with certain clinical features carry disease variants in genes associated with tubulointerstitial kidney diseases. COL4-genes constitute the largest fraction, implying they are overlooked using clinical Alport-syndrome criteria. We also identified variants easily missed by some ES pipelines. Finally, our results indicate that the filtering criteria applied enrich for an underlying genetic disorder.SIGNIFICANCE STATEMENTCKD affects >10% of the global population and recent studies imply that a considerable portion can be attributed to monogenic diseases, which are likely underappreciated in the clinical routine. Tubulointerstitial kidney diseases are a particularly difficult group of hereditary kidney diseases to diagnose both clinically and genetically. To investigate the prevalence of these disorders in a large CKD cohort we established a set of clinical criteria and designed a custom panel sequencing pipeline. Based on the diagnostic yield of 12.5%, we recommend an algorithm to clinically select and genetically evaluate patients with increased risk for a hereditary tubulointerstitial kidney disease.

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COQ8B nephropathy: early detection and optimal treatment

10.21203/rs.3.rs-16568/v1 ◽

2020 ◽

Author(s):

Xiaoxiang Song ◽

Xiaoyan Fang ◽

Xiaoshan Tang ◽

Qi Cao ◽

Yihui Zhai ◽

...

Keyword(s):

Renal Transplantation ◽

Early Detection ◽

Unknown Origin ◽

Deceased Donor ◽

Chinese Children ◽

Renal Outcome ◽

Rank Test ◽

Unknown Etiology ◽

Post Transplantation ◽

Genetic Detection

Abstract Background Mutations in COQ8B as a defect of coenzyme Q10 (CoQ10) cause steroid resistant nephrotic syndrome (SRNS). Methods To define the clinical course and prognosis of COQ8B nephropathy, we retrospective assessed the genotype, phenotype in patients with COQ8B mutations from Chinese Children Genetic Kidney Disease Database. We performed the comparing study of renal outcome following CoQ10 treatment and renal transplantation between early genetic detection and delay genetic detection group. Results We identified 20 (5.8%) patients with bi-allelic mutations of COQ8B screening from patients with SRNS, non-nephrotic proteinuria, or CKD of unknown origin. Patients with COQ8B mutations showed a largely renal-limited phenotype presenting with proteinuria and/or advanced CKD at time of diagnosis. Renal biopsy uniformly showed FSGS. Proteinuria was decreased, whereas the renal function was preserved in five patients following CoQ10 administration combined with angiotensin-converting enzyme (ACE) inhibitor. The renal survival analysis disclosed a significantly better outcome in early genetic detection group than in delay genetic detection group (Kaplan-Meier plot and log rank test, p=0.037). Seven patients underwent deceased donor renal transplantation without recurrence of proteinuria or graft failure. Blood pressure showed decreased significantly during 6 to 12 months post transplantation. Conclusions COQ8B mutations are one of the most common causes of adolescent-onset proteinuria and/or CKD of unknown etiology in the Chinese children. Early detection of COQ8B nephropathy following CoQ10 supplementation combined with ACEI could slow the progression of renal dysfunction. Renal transplantation in patients with COQ8B nephropathy showed no recurrence of proteinuria.

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