Renal biopsy should not always be considered indispensable for the workup of proteinuria in a young patient.
We present the case of a 17-year-old male patient with a history of asthma and allergic rhinitis, who initially presented with nonspecific urinary discomfort along the urethral tract. Although urine cultures were negative and the urinary sediment was normal, laboratory workup revealed proteinuria with a protein-to-creatinine ratio of 0.41 mg/mg. The patient was an athlete who regularly engaged in high-intensity exercise. At specialized nephrology evaluation, normal renal function was confirmed (creatinine 0.9 mg/dL), along with persistent 24-h urine proteinuria of 0.7 g and a negative autoimmune workup and serum protein electrophoresis. Renal ultrasound showed no structural abnormalities.
Initially, cessation of exercise was advised for two weeks. As proteinuria persisted at the same level, treatment with candesartan (16 mg/day) was initiated without response after two months. In the absence of etiological clarification, rather than proceeding to renal biopsy, a genetic study was performed using a next-generation sequencing (NGS) panel.
The study identified two variants in the CUBN gene: a pathogenic variant (c.7906C>T; p.Arg2636Ter) and a likely pathogenic variant (c.8755+1G>A). This finding confirmed a diagnosis of tubular albuminuria with autosomal recessive inheritance, allowing immediate discontinuation of ARB therapy. Regarding the family workup, a decision was made not to perform genetic screening for the younger sibling (age 12) since urine analyses showed no proteinuria; however, he remains under close clinical surveillance. With regard to the parents, given the recessive nature of the disease and the patient’s compound heterozygosity, they were assumed to be obligate carriers, and additional molecular confirmation was not considered necessary since there was no doubt regarding segregation.
Some methodological clarifications regarding the initial management are necessary. We acknowledge that a formal fractioned urine collection maneuver to exclude orthostatic proteinuria was not performed. This condition is extremely common in adolescence and should be part of the systematic differential diagnosis.
The CUBN gene encodes cubilin, a protein that lacks a transmembrane domain and requires the protein amnionless (AMN) for proper assembly and transport to the apical membrane of the proximal tubule, forming the CUBAM complex.1 This complex works in close collaboration with megalin (LRP2), which acts as the essential endocytic motor for the reabsorption of physiologically filtered albumin.2 Classically, CUBN mutations were associated with Imerslund-Gräsbeck syndrome (proteinuria and megaloblastic anemia due to vitamin B12 deficiency)3; however, when the involvement is limited to isolated albuminuria without other systemic deficits, the condition is defined as PROCHOB syndrome (Proteinuria, Chronic, Benign).4–6
One aspect that warrants clarification is the heterogeneity of CUBN gene variants. While biallelic variants located at the C-terminus of the gene (such as those detected in our case) are associated with chronic benign proteinuria and preserved renal function, they must be distinguished from certain common polymorphisms (such as rs1801239, rs7918972 or rs141640975). These common variants, in specific epidemiological contexts such as diabetes mellitus or certain ethnic cohorts, have been associated with greater susceptibility to developing CKD or more accelerated progression.7,8 Therefore, the benign nature of PROCHOB syndrome cannot be extended to all variations of the gene, underscoring the importance of precise genomic interpretation.
The identification of this syndrome challenges the nephrological dogma that ‘all proteinuria is toxic.’ In glomerular diseases, protein overload in the tubule activates inflammatory cascades. In PROCHOB syndrome, albumin does not enter the tubular cell due to the receptor defect, so it is excreted inertly without activating cellular toxicity. This explains why these patients typically maintain a stable glomerular filtration rate for decades. However, the recent description of cases with focal segmental glomerulosclerosis (FSGS) lesions on renal biopsies of patients with pathogenic CUBN variants introduces a degree of uncertainty that warrants cautious longitudinal follow-up.9,10
From a therapeutic standpoint, this diagnosis is disruptive in that it avoids overmedication. The use of ACEi, ARBs, or SGLT2i aims to reduce intraglomerular pressure, but in this case the proteinuria is of tubular origin, which explains the lack of pharmacological response observed in these patients. Immunosuppressants obviously have no indication either.
In conclusion, in a young patient with non-nephrotic proteinuria, inactive urinary sediment, and preserved renal function, ‘liquid biopsy’ via NGS is positioned as a first-line tool. The primary value of this case does not lie in displacing renal biopsy as the historical standard, but rather in demonstrating that adequate phenotypic characterization allows for the early incorporation of high-yield genetic testing in carefully selected patients, thereby avoiding aggressive interventions and ineffective treatments.
