Presentation Summary

Written by Jasna Trbojevic-Stankovic
Reviewed by Francesca Becherucci

Inherited tubulopathies are rare mono- or oligogenic disorders
Inherited tubulopathies represent a cluster of specific disorders caused by the genetic dysfunction of specialized transporters and channels expressed in the renal tubule. Inherited tubulopathies are rare diseases usually following Mendelian patterns of inheritance. Many are mono- or oligogenic disorders affecting children, but cases are not restricted to pediatrics and diagnosis may be delayed until adulthood. According to the main clinical picture, inherited tubulopathies can be classified in proximal tubule diseases; sodium and water reabsorption disorders (i.e. salt-losing tubulopathies); and renal tubular acidosis.
The main disorder of the proximal tubule is Fanconi syndrome which can occurs either isolated (e.g. caused by the mutations in SLC34A1 gene), or secondary to other tubular disorders, including Dent disease and Lowe syndrome, or systemic diseases, such as cystinosis or Wilson disease [1]. Salt-losing tubulopathies are disorders of the distal part of the renal tubule, mainly affecting the reabsorption of sodium and water mediated by endocrine signals such as renin-angiotensin-aldosterone system (RAAS) and vasopressin [1]. These disorders can present with a wide range of clinical pictures, including hypo- or hyperkalemic metabolic acidosis or alkalosis and nephrogenic diabetes insipidus. Each clinical phenotype can be due to a variety of specific diseases. As an example, Bartter and Gitelman or Liddle syndrome can present with hypokalemic metabolic alkalosis [1]. Moreover, many of these diseases can be caused by mutations in more than one gene, representing the most relevant example of oligogenicity among inherited tubulopathies [1]. Renal tubular acidosis are disorders caused by the genetic impairment of the mechanisms responsible for the maintenance of acid-base homeostasis, in the absence of glomerular filtration abnormalities. We can distinguish four different types (I-IV) of renal tubular acidosis, according to the clinical phenotype (hypo-/hyperkaliemia, accompanying features) and the segment of the tubule where the dysfunctional transporter/channel is expressed.

Next-generation sequencing for personalized diagnosis of inherited tubulopathies
Personalized or precision medicine represents an “emerging approach for disease treatment and prevention that takes into account individual variability in genes, environment and lifestyle”, at a single-patient level [2]. The goal of personalized medicine is to determine the right drug for the right patient at the right time [3]. In rare diseases, such as inherited tubulopathies, personalized medicine is expected to provide the patient and the family with the right diagnosis, the right prognosis prediction and the right genetic counseling.
Next-generation sequencing (NGS) technologies were first introduced at the beginning of 2000s. They enable the simultaneous sequencing of multiple genes, and soon after their advent, they became commercially available for diagnostics and research [4]. Following NGS spreading, in the near future genetic testing will probably move from genetics departments and will be initiated by clinicians in the relevant specialty [5].
NSG has already markedly improved our understanding of the mechanisms responsible for the development of inherited tubulopathies, including distal renal tubular acidosis (dRTA). In a recent study, NGS made possible to obtain a conclusive genetic diagnosis in about 72% of patients with dRTA. Moreover, genotype-phenotype correlation analysis confirmed some previous findings, but brought new and unexpected observations [6]. According to the literature, patients with mutations in SLC4A1 gene had a significantly higher age of clinical onset in comparison to patients with mutations in ATP6V1B1 or ATP6V0A4 [6]. On the other hand, the association between sensorineural hearing loss (SNHL) and mutations in ATP6V1B1, previously reported to be as highly specific, was questioned by the finding of a high frequency of SNHL also in patients with mutations in ATP6V0A4 [6].
In summary, genetic testing performed with NGS can personalize the medical management of patients with inherited tubulopathies by: 1. Confirming the clinical diagnosis of or shortening the time necessary to obtain it; 2. Guiding the differential diagnosis by identifying phenocopies; 3. Initiating additional work-up and surveillance of extra-renal complications; 4. Establishing genotype-phenotype correlations, including prognosis; 5. Guiding genetic counseling, cascade screening of family members and donor selection for kidney transplantation; 6. Inform therapy and the clinical management of patients [7]. However, the spread of NGS raises some questions and new challenges in the research of inherited tubulopathies. Indeed, a conclusive molecular diagnosis is identified in only 40-50% of patients with inherited tubulopathies, leading to a significant frequency of “missing genotypes”. In addition, we have to deal with a high phenotypic heterogeneity, that can be caused by heterogeneity of genetic loci (e.g. in Bartter syndrome), allelism (e.g. in infantile and juvenile cystinosis), di-/oligogenic inheritance, modifiers or epigenetic factors. Finally, the advent of NGS claimed for a revision of the ontology of inherited tubulopathies, since diseases with very different long-term prognosis are still classified into the same nosologic group.

Inherited tubulopathies may cause chronic kidney disease
Chronic kidney disease (CKD) affects about 10% of adult population worldwide, with substantial mortality and morbidity, leading to high healthcare costs. Similar data are reported in the pediatric population [8]. In children and adolescents, CKD frequently shows genetic etiology, and about 500 genes have been reported as monogenic causes of CKD. However, monogenic cause of CKD are increasingly recognized also in adults. Indeed, inherited tubulopathies represent a small but detectable fraction of monogenic causes of CKD in cohorts of adults, including patients with CKD of unknown origin [9,10]. Although inherited tubulopathies are usually considered as benign diseases due to the long-term preservation of renal function, about 2% of early-onset CKD is caused by inherited tubulopathies. Therefore, 30 genes related to inherited tubulopathies are included in gene panels for the screening of genetic forms of CKD [11].

Figure 1. Monogenic causes of CKD in adults. Specific mutation category identified by whole exome sequencing (Slide 38 [12])

While it is known that cystinosis, Dent disease and Lowe syndrome have unfavorable renal prognosis, the long-term outcome of other inherited tubulopathies is still far to be fully elucidated. As an example, dRTA has long been considered as a benign disease, but two recent studies clearly showed that about 30% of patients with dRTA patients develops CKD [6,13]. CKD mostly occurs in patients with a long history of the disease, although kidney damage probably develops in childhood [6,13].

In conclusion, the use of personalized medicine in inherited tubulopathies could improve our understanding of the genetic background, could help in identifying new potential therapeutic targets and in collecting data on long-term outcome, thus informing and tailoring prognosis and clinical management. Personalized medicine may contribute to a revision of the current classification of inherited tubulopathies, challenging the border between common and rare diseases, potentially leading to a new definition of inherited tubulopathies as a collection of rare diseases with different mechanisms, but sharing a common phenotype. Importantly, integrating information coming from genetics into clinical practice is a crucial and delicate process that has to be led by expert clinicians, in order to allow precise medicine to be actually precise in daily clinical practice, and thus change the way we take care of our patients.



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12. Francesca Becherucci. Personalized diagnosis and CKD prediction in genetic tubular disorders. 56th ERA-EDTA Congress; June 14, 2019; Budapest, Hungary. View the Webcast on ERA-EDTA Virtual Meeting

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