Clinical and molecular aspects of distal renal tubular acidosis in children

Besouw, Martine; Bienias, Marc; Walsh, Patrick R.; Kleta, Robert; Hoff, William G. van’t; Ashton, Emma; Jenkins, Lucy; Böckenhauer, Detlef

doi:10.1007/s00467-016-3573-4

Cited by 84 publications

(107 citation statements)

References 25 publications

(28 reference statements)

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“…However, the clinical courses and the long-term prognosis showed no difference between the two groups. These findings were consistent with those of previously reported studies [10, 13, 15]. …”

Section: Discussionsupporting

confidence: 83%

“…Several comprehensive genotype–phenotype correlation studies of patients with dRTA have been published worldwide [10, 13, 15]. In this Korean cohort study of pediatric patients with dRTA, the most distinctive finding compared to other studies was the high incidence (58.8%) of patients with SLC4A1 mutations (Table 3).…”

Section: Discussionmentioning

confidence: 51%

“…A large cohort study showed CKD in 32.3% of all patients (31.3% patients with pathogenic mutations) [15], and another study observed CKD in 37.5% of all patients (36.8% patients with pathogenic mutations) [10]. Most of the patients with CKD in these studies were followed up with for at least 15 years or longer.…”

Section: Discussionmentioning

confidence: 99%

“…In this Korean cohort study of pediatric patients with dRTA, the most distinctive finding compared to other studies was the high incidence (58.8%) of patients with SLC4A1 mutations (Table 3). In one previous study [10] including eight Asian patients, only one Asian patient had compound heterozygous SLC4A1 mutations. All of the 10 patients with SLC4A1 mutations in our study had the AD form of dRTA, which is different from the AR dRTA that is prevalent in Southeast Asian countries [7, 8].…”

Section: Discussionmentioning

confidence: 99%

“…Several genotype–phenotype correlation studies in patients with primary dRTA have been reported, although the results from these studies vary [10-15]. …”

Section: Introductionmentioning

confidence: 99%

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Genotype–Phenotype Analysis in Pediatric Patients with Distal Renal Tubular Acidosis

Park

Cho

Hyun

et al. 2018

Kidney Blood Press Res

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Background/Aims: Primary distal renal tubular acidosis (dRTA) in children is a rare genetic disorder, and three causative mutated genes have been identified: SLC4A1, ATP6V1B1, and ATP6V0A4. We analyzed the prevalence and phenotypic differences of genetic mutations in children with dRTA. Methods: A total of 17 children with dRTA were enrolled in the study. All patients underwent genetic testing for all three candidate genes. Results: Pathogenic mutations, including six novel mutations, were detected in 15 (88.2%) patients: dominant SLC4A1 mutations in ten (58.8%) patients, recessive ATP6V0A4 mutations in three (17.6%) patients, and recessive ATP6V1B1 mutations in two (11.8%) patients. Compared to other patients, patients with SLC4A1 mutations showed an older age of onset (3.7 ± 2.6 years) and less severe metabolic acidosis at initial presentation. All patients developed nephrocalcinosis, and sensorineural hearing loss was observed in two patients with ATP6V1B1 mutations. Three (17.6%) patients had decreased renal function (chronic kidney disease stage 2), and five (29.4%) patients had persistent growth retardation at the last follow-up. Long-term prognosis showed no genotype–phenotype correlation. Conclusions: SLC4A1 is the most common defective gene in Korean children with dRTA. Patients with SLC4A1 mutations show later onset and milder disease severity. Long-term follow-up of hearing ability, renal function, and growth is necessary for patients with dRTA.

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Section: Discussionsupporting

confidence: 83%

Section: Discussionmentioning

confidence: 51%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

“…Several genotype–phenotype correlation studies in patients with primary dRTA have been reported, although the results from these studies vary [10-15]. …”

Section: Introductionmentioning

confidence: 99%

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Genotype–Phenotype Analysis in Pediatric Patients with Distal Renal Tubular Acidosis

Park

Cho

Hyun

et al. 2018

Kidney Blood Press Res

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Overactivity or blockade of transforming growth factor‐β each generate a specific ureter malformation

Lopes

Roberts

Zeef

et al. 2019

The Journal of Pathology

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Transforming growth factor- (TGF) has been reported to be dysregulated in malformed ureters. There exists, however, little information on whether altered TGF levels actually perturb ureter development. We therefore hypothesised that TGF has functional effects on ureter morphogenesis. Tgfb1, Tgfb2 and Tgfb3 transcripts coding for TGF ligands, as well as Tgfbr1 and Tgfbr2 coding for TGF receptors, were detected by quantitative polymerase chain reaction in embryonic mouse ureters collected over a wide range of stages. As assessed by in situ hybridisation and immunohistochemistry, the two receptors were detected in embryonic urothelia. Next, TGF1 was added to serum-free cultures of embryonic day 15 mouse ureters. These organs contain immature smooth muscle and urothelial layers and their in vivo potential to grow and acquire peristaltic function can be replicated in serum-free organ culture. Such organs therefore constitute a suitable developmental stage with which to define roles of factors that affect ureter growth and functional differentiation. Exogenous TGF1 inhibited growth of the ureter tube and generated cocoon-like dysmorphogenesis. RNA sequencing suggested that altered levels of transcripts encoding certain fibroblast growth factors (FGFs) followed exposure to TGF. In serum-free organ culture exogenous FGF10 but not FGF18 abrogated certain dysmorphic effects mediated by exogenous TGF1. To assess whether an endogenous TGF axis functions in developing ureters, embryonic day 15 explants were exposed to TGF receptor chemical blockade; growth of the ureter was enhanced, and aberrant bud-like structures arose from the urothelial tube. The muscle layer was attenuated around these buds, and peristalsis was compromised. To determine whether TGF effects were limited to one stage, explants of mouse embryonic day 13 ureters, more primitive organs, were exposed to exogenous TGF1, again generating cocoon-like structures, and to TGF receptor blockade, again generating ectopic buds. As for the mouse studies, immunostaining of normal embryonic human ureters detected TGFRI and TGFRII in urothelia. Collectively, these observations reveal unsuspected regulatory roles for endogenous TGF in embryonic ureters, fine-tuning morphogenesis and functional differentiation. Our results also support the hypothesis that the TGF up-regulation reported in ureter malformations impacts on pathobiology. Further experiments are needed to unravel the intracellular signalling mechanisms involved in these dysmorphic responses.

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Renal Tubular Acidosis

Böckenhauer

Lopez-Garcia

Walsh

2022

Pediatric Nephrology

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Clinical and molecular aspects of distal renal tubular acidosis in children

Abstract: In general, the prognosis of dRTA is good in children treated with alkali.

Cited by 84 publications

References 25 publications

Genotype–Phenotype Analysis in Pediatric Patients with Distal Renal Tubular Acidosis

Genotype–Phenotype Analysis in Pediatric Patients with Distal Renal Tubular Acidosis

Overactivity or blockade of transforming growth factor‐β each generate a specific ureter malformation

Renal Tubular Acidosis

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