Chronic Benign Tubular Albuminuria From Compound Heterozygous Variants in CUBN : A Case Report

Introduction

Albuminuria is a ubiquitously employed clinical parameter for predicting risk of kidney function decline. ¹ Strategies to reduce albuminuria, such as with angiotensin-converting enzyme (ACE) inhibitors, angiotensin-II receptor blockers (ARB), and sodium-glucose cotransporter-2 (SGLT2) inhibitors prevent progression to end-stage kidney disease on a population level. ² While these medications are designed to reduce albuminuria of glomerular etiology, albumin excretion may arise from other origins, such as tubular or urologic.

Cubilin, encoded by the gene CUBN, is a critical protein involved in low molecular weight protein reabsorption in the proximal tubule. Along with its binding partners amnionless (AMN) and megalin (LRP2), cubilin orchestrates receptor-mediated endocytosis, which is the primary mechanism for albumin reabsorption in the proximal tubule. ³ Cubilin has an additional role in the small intestine and enables vitamin B12 absorption via binding to the intrinsic factor-vitamin B12 (IF-B12) complex. ⁴

Variants in the CUBN gene are classically described to cause Imerslund-Gräsbeck syndrome (IGS). ⁵ This disorder is characterized by vitamin B12 deficiency (and consequences related to that, such as megaloblastic anemia and growth delay) with or without proteinuria.

Recently, a cross-sectional cohort study demonstrated that biallelic variants in CUBN downstream of the IF-B12 binding domain (ie, closer to the C-terminus) leads to isolated proteinuria without other features of IGS. ⁶ A subsequent cohort study reproduced these findings, while also observing stability in estimated glomerular filtration rate (eGFR) over an average follow-up of 7 years. ⁷ It remains an important question whether eGFR stability persists longitudinally and later into adulthood.

Presenting Concerns

We present the case of a 52-year-old East Asian male with longstanding albuminuria yet preserved eGFR. He self-reported albuminuria since his late teenage years, although formally our records document albuminuria since the age of 38. His proteinuria is albumin-predominant (50%-60% of his proteinuria) and has remained within the subnephrotic range with urine albumin to creatine ratio of 50 to 100 mg/mmol (Figure 1).

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Figure 1.

Measured values of patient (A) serum creatinine and (B) urine albumin to creatinine ratio (ACR) across age. Timing of intervention with therapeutics is indicated. Best fit by linear regression is shown with a dotted line.

Clinical Findings

The patient did not smoke and his comorbidities include dyslipidemia, hypertension, and gout, all of which developed in his late 40s. He had a normal serum albumin (47 g/L) and no edema. He was briefly treated with ramipril and demonstrated no appreciable change in his albuminuria; this was discontinued after a few months due to development of an ACE inhibitor-induced cough. He was subsequently trialed on candesartan but discontinued after 1 week due to dizziness and hypotension. Several years later, he developed hypertension and was restarted on candesartan, which has controlled his blood pressure yet has not affected his albuminuria. Over the years, he exhibited intermittent microscopic hematuria (maximum of 1-3 erythrocytes per high power field), without evidence of acanthocytes or erythrocyte casts. Kidney ultrasound and cystoscopy were both normal.

Timeline

A timeline of his pertinent lab values and interventions are provided in Figure 1.

Diagnostic Focus and Assessment

The etiology of his albuminuria remained unexplained for decades. Given the stability of his eGFR and absence of disease progression, a kidney biopsy was never pursued. He was eventually referred to our center for genetic testing. A specimen was analyzed with the Blueprint Nephrotic Syndrome gene panel (Helsinki, Finland, https://blueprintgenetics.com/tests/panels/nephrology/nephrotic-syndrome-panel/), which tests for variants in 96 genes implicated in proteinuria and nephrotic syndrome. The patient was found to have 3 variants in the CUBN gene that were deemed pathogenic or likely pathogenic by American College of Medical Genetics and Genomics (ACMG) classification (Figure 2). The first variant, 10:16961959A>G (c.6821+3A>G, splice variant), is a splice variant of likely pathogenicity and was paternally inherited. The other 2 variants, 10:16975122C>T (c.6088C>T, p.Arg2030*) and 10:16982151C>T (c.5428C>T, p.Arg1810*), confer premature stop codons which exist in cis and were maternally inherited. Segregation analysis with the unaffected parents confirmed these were germline-inherited variants; of note, his mother possessed 2 variants in cis, thus maintaining an unaffected copy of the gene.

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Figure 2.

(A) Schematic representation of CUBN protein structure and binding regions, along with location of this patient’s variants. (B) Summary of patient genetic variants. (*) indicates nonsense mutation.

Interestingly, all variants were downstream of the IF-B12 binding domain of cubilin (Figure 2). The patient did not have a history of growth delay or congenital anomalies. Furthermore, he had normal vitamin B12 levels (249 pg/mL) and never exhibited evidence of megaloblastic anemia (hemoglobin 157 g/L). Consequentially, he was not diagnosed with IGS.

Therapeutic Focus and Assessment

After the identification of the CUBN variants, the patient was provided with a diagnosis of chronic benign albuminuria. He was advised that he did not require specific treatment with proteinuria-reducing therapy. A kidney biopsy was also not pursued, as his diagnosis was achieved non-invasively via genetic testing. He was advised that his risk of kidney decline most likely mirrors that of the general population.

Follow-up and Outcomes

The patient continues to be monitored with quarterly lab work. His albuminuria and eGFR remain unchanged. No further invasive work-up as been initiated.

Discussion

This case report adds to a growing chorus of studies that show biallelic inactivating variants in CUBN leads to chronic benign tubular albuminuria without decline in kidney filtration function.^6,7 We extend previous findings by reporting longitudinal data in an older adult patient, proving stability in eGFR persists with age. It has been previously postulated that proteinuria can confer direct nephrotoxicity via re-uptake of excessive amounts of filtered protein in the proximal tubule. ⁸ As our patient cannot effectively resorb protein, the absence of accelerated kidney decline is consistent with such a mechanism. Indeed, in a rat model of adriamycin-induced proteinuria, CUBN knockdown reduced tubulointerstitial damage, suggesting a potential protective role cubilin loss. ⁹ This case argues that tubular albuminuria does not exhibit the same toxicity profile as glomerular albuminuria.

For this patient, the variants in CUBN are downstream of IF-B12 binding domain; consequently, this patient did not exhibit vitamin B12 deficiency or megaloblastic anemia. This report is consistent with prior findings of allelism of the CUBN gene, whereby N-terminal variants lead to IGS while C-terminal variants lead to isolated albuminuria. ⁶ Of note, our case report rejects the possibility of haploinsufficiency, as both parents remained unaffected while possessing only 1 wildtype allele. Segregation analysis was critical for determining these variants to be in trans, which lead to the phenotype observed in our patient.

An interesting finding is the intermittent microscopic hematuria, despite normal cystoscopy and kidney ultrasound imaging. A prior study has also reported a subset of patients with CUBN variants exhibit microscopic hematuria. ⁶ Mechanistically, it is not clear how CUBN variants would confer such a phenotype, as expression is restricted the proximal tubule in the kidney ¹⁰ where no known appreciable exchange of red blood cells occurs. It is possible this hematuria is unrelated to the CUBN disease phenotype.

As expected, we show that this tubular albuminuria does not respond to ACE inhibitors or ARBs. Furthermore, the need for kidney biopsy was obviated as a diagnosis was reached using genetic tools alone. This approach highlights the utility of genetic testing early in the diagnostic work-up, thereby avoiding ineffective interventions and unnecessary invasive procedures.