All in the Genes: Chronic Benign Proteinuria Due to CUBN Mutations

Introduction: Proteinuria is common in primary care patients. It can have transient causes such as UTI and heavy exercise or can be persistent. Most forms of persistent proteinuria are caused by damage to the kidney which can be intrinsic as in glomerular diseases or secondary to conditions such as CHF, hypertension, or diabetes. Persistent forms including protein receptor deficiencies can also cause chronic benign proteinuria and do not require treatment. The CUBN gene encodes the cubilin protein which forms a receptor in the proximal renal tubule that plays a key role in blocking excessive protein excretion. Deficiency in the cubilin protein can lead to non-nephrotic range proteinuria without decreased renal function given the lack of associated glomerular disease. We present a case of a patient with chronic, non-nephrotic range proteinuria with normal renal function, found to have the CUBN mutation. Case Description: A 33-year-old male with a history of mild hypertension treated with 2.5mg lisinopril presented to the nephrology office for evaluation of persistent proteinuria. He had a renal biopsy 15 years prior which showed normal renal cortex by light and electron microscopy. No diagnosis was made or treatment started at that time. His only symptom was slightly foamy urine. Creatinine was 0.99 mg/dl and a 24-hour urine protein collection was significantly elevated at 945 mg/24h, but not nephrotic range. Hepatitis, HIV, and rheumatic disease workup was negative. The patient was started on dapagliflozin for renal protection. At his follow-up visit, a genetic panel showed two very rare heterozygous mutations to the CUBN gene. He was diagnosed with chronic benign proteinuria. Given the low risk for progression to CKD, dapagliflozin and lisinopril were discontinued with plans for one-year follow up. Discussion: CUBN gene mutations that cause chronic benign proteinuria have been shown to be nondetrimental to kidney function with limited progression to CKD. This case shows the benefit of early genetic testing in cases with isolated, non-nephrotic range proteinuria with normal kidney function through early diagnosis and avoidance of unnecessary treatments or invasive tests such as biopsies. While unlikely, these patients should be followed routinely to screen for worsening renal function.