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BACKGROUND: Proteinuria is a prevalent symptom of pediatric nephrology, while kidney biopsy remains the gold standard for kidney tissue analysis, and it is currently controversial. We report the rare case that the mutation in the AMN gene was considered to cause chronically isolated proteinuria and also suggest that renal biopsy should be chosen with caution in children with chronic isolated non-nephrotic levels of proteinuria and that genetic testing may be feasible for the early precise diagnosis. CASE PRESENTATION: A 35-month-old boy presented with excessive urine foaming for more than half a month; his proteinuria was considered non-nephrotic range and urine protein electrophoresis was suggestive of mixed proteinuria; other than that, the investigations are non-specific. Given the child's chronic isolated proteinuria and good renal function, we chose to refine the genetic test rather than a renal biopsy; a compound heterozygous variant was found in the AMN gene of this child which was caused by a point mutation in the father, and a partial chromosomal deletion in the mother. CONCLUSIONS: Cubilin(encoded by CUBN), amnionless(encoded by AMN), and megalin form a multiligand receptor complex; CUBN or AMN gene variants have been implicated as a hereditary cause of megaloblastic anemia, proteinuria, and neurological impairment. In the past few decades, chronic isolated proteinuria caused by CUBN gene variants is benign, non-progressive, and has normal renal function. However, the child is the first reported case of isolated proteinuria of AMN gene mutation, indicating that the earlier diagnostic genetic sequencing in an otherwise well, not nephrotic proteinuria child may be a convenient, cost-effective, and harmless option, challenging the traditional paradigm.

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BACKGROUND: Although proteinuria is long recognized as an independent risk factor for progressive chronic kidney diseases, not all forms of proteinuria are detrimental to kidney function, one of which is isolated proteinuria caused by cubilin (CUBN)-specific mutations. CUBN encodes an endocytic receptor, initially found to be responsible for the Imerslund-Gräsbeck syndrome (IGS; OMIM #261100) characterized by a combined phenotype of megaloblastic anemia and proteinuria. METHODS: After analyzing their clinical and pathological characterizations, next-generation sequencing for renal disease genes or whole-exome sequencing (WES) was performed on four patients with non-progressive isolated proteinuria. CUBN biallelic pathogenic variants were identified and further analyzed by cDNA-PCR sequencing, immunohistochemistry, minigene assay, and multiple in silico prediction tools, including 3D protein modeling. RESULTS: Here, we present four patients with isolated proteinuria caused by CUBN C-terminal biallelic pathogenic variants, all of which showed no typical IGS symptoms, such as anemia and vitamin B12 deficiency. Their urine protein levels fluctuated between +~++ and estimated glomerular filtration rate (eGFR) were normal or slightly higher. Mild mesangial hypercellularity was found in three children's renal biopsies. A homozygous splice-site variant of CUBN (c.6821+3 (IVS44) A>G) was proven to result in the exon 44 skipping and premature translation termination by cDNA sequencing and immunohistochemistry. Compound heterozygous mutations were identified among the other three children, including another novel splice-site variant (c.10764+1 (IVS66) G>A) causing the retention of first 4 nucleotides in intron 66 by minigene assay, two unreported missense mutations (c.4907G>A (p.R1636Q); c. 9095 A>G (p.Y3032C)), and two reported missense mutations in China (c.8938G>A (p.D2980N); c. 9287T>C (p.L3096P)), locating behind the vitamin B12-binding domain, affecting CUB11, CUB16, CUB22, CUB23, and CUB27 domains, respectively. CONCLUSION: These results demonstrate that above CUBN mutations may cause non-progressive and isolated proteinuria, expanding the variant spectrum of CUBN and benefiting our understanding of proteinuria and renal function.

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Mutations in the cubilin (CUBN) gene commonly cause Imerslund-Gräsbeck syndrome, while isolated proteinuria as a result of CUBN variations is rarely reported. The clinical manifestation is mainly chronic isolated proteinuria in the non-nephrotic range. However, findings to date suggest that isolated proteinuria associated with abnormalities in the CUBN gene is benign and does not affect long-term prognosis of kidney function. We identified 2 patients with isolated proteinuria triggered by compound heterozygous CUBN mutations. Renal functions of both patients remained normal over a 10-year follow-up period, supporting the benign nature of proteinuria caused by CUBN gene variations. Two novel mutation sites were detected, expanding the genotypic spectrum of CUBN variations. In addition, etiology, pathogenesis, clinical manifestations, auxiliary examination, and treatment of the condition were reviewed, with the aim of providing further guidance for clinical management.

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We experienced a case of preeclampsia in which massive ascites became apparent in the postpartum period. The patient had isolated proteinuria without hypertension before delivery. The infant had fatal growth restriction and neonatal distress. Massive ascites and isolated proteinuria are important symptoms for predicting the aggravation of PE.

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BACKGROUND: Herein, a 3-year-old boy presented with hidden-onset isolated proteinuria was reported. The disease was induced by COQ8B (previously termed ADCK4) compound heterozygous variants, including c.[271C > T] and c.[737G > A], which were inherited from his father and mother, respectively. CASE PRESENTATION: The patient visited our clinic due to non-nephrotic range proteinuria for 3 months, but no obvious abnormality was detected in the vital signs or laboratory test results. Renal histopathology revealed mitochondrial nephropathy, which manifested as mild glomerular abnormalities under light microscope, together with mitochondrial proliferation and hypertrophy and crowded arrangement under electron microscope. As suggested by whole exome sequencing, the patient inherited the COQ8B compound heterozygous variants from both of his parents who showed normal phenotype. After literature review, it was confirmed that one of the variant site (c.[271C > T]) had not been reported among the East Asian populations so far. CONCLUSIONS: Steroid-resistant nephrotic syndrome and focal segmental glomerulosclerosis are the most common phenotypes and renal histopathological manifestations of COQ8B variant. Nonetheless, our case shows that such variant may have hidden and mild clinical manifestations at the early onset. Therefore, early diagnosis will help to identify children at the early disease stage who have opportunity to benefit from oral coenzyme Q10 supplementation.

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OBJECTIVE: The present study aimed to investigate perinatal outcomes and to describe antenatal factors for development of preeclampsia (PE) in patients with isolated proteinuria in pregnancy. METHODS: This retrospective case control study consisted of patients with isolated proteinuria between 2009 and 2014. The patients were considered as gestational proteinuria (GP) (group 1, n: 35) if they remain normotensive. Patients who develop PE after onset of proteinuria were allocated into group 2 (n: 19). Perinatal outcomes of patients in each group were compared. Logistic regression analysis was performed to detect antenatal risk factors for PE. RESULTS: The rate of small for gestational age (SGA) fetuses was higher in patients with isolated proteinuria than control group. In the logistic regression model, maternal age and completed gestational weeks at onset of proteinuria decreased the risk of PE in multivariate analysis (OR: 0.849 (95% CI: 0.731-0.986), OR: 0.732 (95% CI: 0.594-0.902) respectively). Systolic BP at onset of proteinuria, however, was associated with an independently increased risk of PE (OR: 1.181 (95% CI: 1.046-1.333)). CONCLUSION: Maternal clinical characteristics, but not laboratory features may help to predict development of PE.

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PURPOSE: The urinary mass screening program for the detection of urinary abnormalities in school aged population has been performed in Seoul since 1981. Nation-wide urinary mass screening program was also performed since 1998. The aim of this study was to analyze the cause and nature of isolated proteinuria detected by chance on the urinary mass screening test in Busan and Kyungsangnam-do Province. METHODS: The medical records of 44 cases of isolated proteinuria detected by chance on the urinary mass screening test in Busan and Kyungsangnam-do Province, and evaluated for urinary abnormalities at the pediatrics outpatients renal clinics of Busan Paik Hospital from April 2002 to August 2003 were reviewed prospectively. RESULTS: The cause and incidence of isolated proteinuria were as follows; transient proteinuria 4 cases(9.1%), orthostatic proteinuria 36 cases(81.8%) and persistent proteinuria 4 cases (9.1%). The total protein amount of the 24 hour urine were 121.0+/-136.4 mg in transient proteinuria, 179.1+/-130.0 mg in orthostatic proteinuria and 1532.8+/-982.5 mg in persistent proteinuria. In the orthostatic proteinuria group, the total protein amount of the 24 hour urine was in the range of 40-616 mg. Spot urine protein/creatinine ratio(PCR) were 0.10+/-0.01 in transient proteinuria, 0.61+/-0.61 in orthostatic proteinuria and 4.35+/-4.04 in persistent proteinuria. In the orthostatic proteinuria group, spot urine PCR was in the range of 0.09-2.32. Renal biopsy was performed in 4 children of the persisitent proteinuria group. They showed minimal change in 1 case, membranoproliferative glomerulonephritis in 2 cases and secondary renal amyloidosis in 1 case. CONCLUSION: The majority of isolated proteinuria which was detected by chance on school urinary mass screening were transient or orthostatic proteinuria. Even though the incidence of persistent proteinuria was much lower, it is necessary to take care of these children regularly and continuously, because persistent proteinuria itself is a useful marker of the progressive renal problems.

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PURPOSE: The urinary mass screening program for the detection of urinary abnormalities in school aged population has been performed in Seoul since 1981. Nation-wide urinary mass screening program was also performed since 1998. The aim of this study was to analyze the cause and nature of isolated proteinuria detected by chance on the urinary mass screening test in Busan and Kyungsangnam-do Province. METHODS: The medical records of 44 cases of isolated proteinuria detected by chance on the urinary mass screening test in Busan and Kyungsangnam-do Province, and evaluated for urinary abnormalities at the pediatrics outpatients renal clinics of Busan Paik Hospital from April 2002 to August 2003 were reviewed prospectively. RESULTS: The cause and incidence of isolated proteinuria were as follows; transient proteinuria 4 cases(9.1%), orthostatic proteinuria 36 cases(81.8%) and persistent proteinuria 4 cases (9.1%). The total protein amount of the 24 hour urine were 121.0+/-136.4 mg in transient proteinuria, 179.1+/-130.0 mg in orthostatic proteinuria and 1532.8+/-982.5 mg in persistent proteinuria. In the orthostatic proteinuria group, the total protein amount of the 24 hour urine was in the range of 40-616 mg. Spot urine protein/creatinine ratio(PCR) were 0.10+/-0.01 in transient proteinuria, 0.61+/-0.61 in orthostatic proteinuria and 4.35+/-4.04 in persistent proteinuria. In the orthostatic proteinuria group, spot urine PCR was in the range of 0.09-2.32. Renal biopsy was performed in 4 children of the persisitent proteinuria group. They showed minimal change in 1 case, membranoproliferative glomerulonephritis in 2 cases and secondary renal amyloidosis in 1 case. CONCLUSION: The majority of isolated proteinuria which was detected by chance on school urinary mass screening were transient or orthostatic proteinuria. Even though the incidence of persistent proteinuria was much lower, it is necessary to take care of these children regularly and continuously, because persistent proteinuria itself is a useful marker of the progressive renal problems.

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PURPOSE: The urinary mass screening program in school aged population has been performed since 1981, but the consensus on the follow-up schedule and the management of isolated proteinuria has not been reached yet. The aim of this study was to investigate the cause of isolated proteinuria and to propose a guideline for the treatment and follow-up afterwards. Methods: The medical records of 114 cases of isolated proteinuria detected through the analysis of urinary mass screening and evaluated at the pediatric outpatient clinic of Asan Medical Center from January 1990 to July 2001 have been reviewed. RESULTS: The classification of isolated proteinuria was as follows. Transient proteinuria 32%, orthostatic proteinuria 65%, persistent proteinuria 3%. In orthostatic proteinuria group, daytime and nighttime proteinuria were 319.2+/-89.1 mg/dL and 56.5+/-6.1 mg/dL. In persistent proteinuria group, daytime and nighttime proteinuria were 1140+/-40.5 mg/dL and 289+/-8 mg/dL. After 30 month follow-up, 2 cases of persistent proteinuria were needed renal biopsy and 1 case revealed focal segmental glomerular sclerosis. In all cases, serum creatinine, albumin and complements levels were normal. In the orthostatic proteinuria group, no significant renal diseases were detected. CONCLUSION: Since most of the isolated proteinuria detected through the school urinary mass screening were orthostatic proteinuria or transient proteinuria, initially aggressive diagnostic method such as renal biopsy is not needed and regular follow-up with quantitation of proteinuria is warranted.

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Asymptomatic urinary abnormalities are one of the most frequent abnormalities in clinical nephrology. Between April 1981 and February 1999, we conducted retrospective follow-up studies of 159 patients with asymptomatic urinary abnormality that was proven by kidney biopsy, and evaluated their histologic findings and natural course. Mean age was 34.7 years old and sex ratio of male to female was 78: 81. They were divided into three groups according to the initial urinalysis findings' six patients with isolated hematuria, 33 patients with isolated proteinuria, and 120 patients with concomitant hematuria and proteinuria. The mean follow-up period was 35.5+/-30.5 months. In pathologic findings, 95 cases(59.3%) had IgA nephropathy, 27 cases(17.5%) had minor lesion, 12 cases(7.5%) showed focal and segmental glomerulo- sclerosis, 10 cases(6.3%) had membrannvs glomer-ulonephritis, 9 cases(5.6%) had mesangial prolifera- tive glomerulonephritis. Amyloidosis and thin base-ment membrane disease were seen in two cases, respectively. There were no specific correlations between morphologic patterns and degree of proteinuria. During the mean follow-up period, hematuria or proteinuria disppeared in 14%, persisted in 49%, and developed renal insufficiency in 21%. During the mean follow-up period, isolated proteinuria disappeared in 24%, persisted in 36%, and developed renal insufficiency in 21%. We conclude that the most common cause of asymptomatic urinary abnormalities was IgA nephropathy and early diagnosis through renal biopsy and management is needed to prevent or slow the progression to chronic renal failure.

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