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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. [ABSTRACT FROM AUTHOR]

Abstract 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.

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.

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Abstract 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.

Abstract 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.

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. [ABSTRACT FROM PUBLISHER]

Proteinuria is occasionally detected on "routine" examination (not done for a suspected renal or urinary tract problem) and often presents a diagnostic problem. Even mild proteinuria is abnormal and needs an explanation. Its degree and persistence should be ascertained and associated hematuria looked for. Nonpathological (including orthostatic) proteinuria and renal tubular disorders should be excluded. Persistent proteinuria is mostly due to a primary or secondary (eg hepatitis B) glomerular condition, which requires expert evaluation of renal biopsy. Aggressive therapy may be needed in some cases. The intensity of proteinuria can be decreased with ACE inhibitors. Long-term observation is essential. [ABSTRACT FROM AUTHOR]