Results of a Gene Panel Approach in a Cohort of Patients with Incomplete Distal Renal Tubular Acidosis and Nephrolithiasis

Abstract

<b><i>Background:</i></b> Distal renal tubular acidosis (dRTA) is characterized by an impairment of urinary acidification resulting in metabolic acidosis, hypokalemia, and inappropriately elevated urine pH. If not treated, this chronic condition eventually leads to nephrocalcinosis, nephrolithiasis, impaired renal function, and bone demineralization. dRTA is a well-defined entity that can be diagnosed by genetic testing of 5 genes known to be disease-causative. Incomplete dRTA (idRTA) is defined as impaired urinary acidification that does not lead to overt metabolic acidosis and therefore can be diagnosed if patients fail to adequately acidify urine after an ammonium chloride (NH<sub>4</sub>Cl) challenge or furosemide and fludrocortisone test. It is still uncertain whether idRTA represents a distinct entity or is part of the dRTA spectrum and whether it is caused by mutations in the same genes of overt dRTA. <b><i>Methods:</i></b> In this cross-sectional study, we investigated a group of 22 stone formers whose clinical features were suspicious of idRTA. They underwent an NH<sub>4</sub>Cl challenge and were found to have impaired urinary acidification ability. These patients were then analyzed by genetic testing with sequencing of 5 genes: <i>SLC4A1</i>, <i>ATP6V1B1</i>, <i>ATP6V0A4</i>, <i>FOXI1</i>, and <i>WDR72</i>. <b><i>Results:</i></b> Two unrelated individuals were found to have two different variants in <i>SLC4A1</i> that had never been described before. <b><i>Conclusions:</i></b> Our results suggest the involvement of other genes or nongenetic tubular dysfunction in the pathogenesis of idRTA in stone formers. However, genetic testing may represent a cost-effective tool to recognize, treat, and prevent complications in these patients.

Prospective long-term evaluation of incomplete distal renal tubular acidosis in idiopathic calcium nephrolithiasis diagnosed by low-dose NH4CL loading – gender prevalences and impact of alkali treatment

“…The abnormality might be either acquired or genetic [ 28 ]. Evidence for the latter, however, was only found in 10% of idRTA patients with positive family history for stones in a recent genetic study [ 13 ].…”

“…For more equilibrated comparisons due to the strong female preponderance among idRTA patients (results), we formed 62 pairs of idiopathic calcium stone formers (ICSF) with and without idRTA, matched for gender, age, BMI and serum creatinine. Eleven idiopathic calcium stone formers (ICSF) with idRTA and positive family history for nephrolithiasis were also part of a recent genetic study [ 13 ].…”

A Genetic Polymorphism in the WDR72 Gene is Associated With Calcium Nephrolithiasis in the Chinese Han Population

“…dRTA is characterized by an impairment of urinary acidification resulting in metabolic acidosis, hypokalemia, and inappropriately elevated urine pH. If not treated, this chronic condition eventually leads to nephrocalcinosis, nephrolithiasis and impaired renal function ( D'Ambrosio et al, 2021 ). Recently, a trans-ethnic GWAS in British and Japanese populations identified that rs578595, an intronic variant in WDR72 , was significantly associated with nephrolithiasis ( Howles et al, 2019 ).…”

Renal tubular acidosis as one of the causes of urolithiasis.

“…ПКА характеризуется нарушением экскреции нелетучих кислот почками при сохраненной скорости клубочковой фильтрации (СКФ) [14]. При ПКА в сыворотке крови прослеживается или нормальный анионный провал (то есть разница между содержанием катионов и анионов в плазме крови составляет 12 мэкв/л) или гиперхлоремический метаболический ацидоз, вызванный неспособностью почечных канальцев удерживать бикарбонат НСО3 − или секретировать ионы водорода Н + при нормальной или умеренно нарушенной функции почек [15].…”

“…Авторы исследовали биоматериал 22 пациентов с семейным анамнезом МКБ и подтвержденной неполной формой дистального ПКА. В процессе работы были выполнены генетические тестирования с секвенированием 5 генов: SLC4A1 (OMIM 109270), ATP6V1B1 (OMIM 192132), ATP6V0A4 (OMIM 605239), FOXI1 (OMIM 601093) и WDR72 (OMIM 613214) и были обнаружены 2 гетерозиготные мутации в гене SLC4A1 у 2 исследуемых пациентов [14].…”