Tubulopathy: the clinical and genetic approach in diagnosis

Article information

Child Kidney Dis. 2023;27(1):11-18

Publication date (electronic) : 2023 May 16

doi : https://doi.org/10.3339/ckd.23.001

Jinwoon Joung¹, Heeyeon Cho¹

¹Department of Pediatrics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea

Correspondence to Heeyeon Cho Department of Pediatrics, Samsung Medical Center, Sungkyunkwan University School of Medicine, 81 Irwon-ro, Gangnam-gu, Seoul 06351, Republic of Korea E-mail: choheeyeon@gmail.com

Received 2023 January 31; Revised 2023 March 7; Accepted 2023 March 13.

Abstract

Introduction

Nephron, a microscopic structural and functional unit of kidney, is composed of glomerulus, vasculature, tubules, and interstitium. Renal tubules are responsible for homeostasis of body fluid, electrolyte, and acid-base conditions [1,2]. The tubules modulate reabsorption and secretion of fluid and solutes by passive or active mechanisms [1-3].

Renal tubules consist of four main segments with different anatomies and functions: proximal convoluted tubule (PCT), thick ascending limb of Henle’s loop (TAL), distal convoluted tubule (DCT), and collecting duct (CD). Each segments perform distinct functions with specific transporters. Dysfunctions of these tubular transports are called tubulopathies [1-3].

Tubulopathies have either inherited or acquired etiologies [3,4]. This review focused on inherited tubulopathies that generally manifest in pediatric period. Mutant variants encoding transporters in any tubular segments can cause inherited tubulopathies and determine their distinguishing clinical features [2]. Remarkable advances in genetic diagnosis have expanded our knowledge of inherited tubulopathies.

This review tries to present clinical clues to approach and diagnose inherited tubulopathies. Simplification of categorizing the tubular diseases could allow clear diagnosis and prompt management. Moreover, present review clarifies the recently defined concept of autosomal dominant tubulointerstitial disease (ADTKD) and introduces a few novel therapies for tubulopathies updated lately.

Clinical and genetic approach to tubulopathies

Inherited tubulopathies are commonly discussed in academic sessions with details of a particular disease. However, there are numerous diseases associated with various transporters and tubular segments and the incidence of tubular diseases is relatively low comparing with the other glomerular diseases. Due to the diversity and rarity, diagnosing the inherited tubulopathies remains challenging.

In the practical field, distinct clinical presentations are substantial for diagnosing tubulopathies. Nephrologists should focus on manifestations identifying affected segments and transporters other than the common features of polyuria, polydipsia, and growth failure. Part I and II describe functions of different tubular segments and categorize tubular diseases according to the key features.

Part I. Principal functions of the tubular segments

Table 1 describes the functions of each tubular segment. PCT plays a major role in reabsorbing most of water and solutes. These solutes include glucose, bicarbonate, amino acids, low-molecular-weight proteins, calcium, phosphate, and citrate. Na⁺-K⁺-ATPase, the main transporter of PCT, has high energy requirement. Thus, PCT segment is vulnerable to hypoxic conditions and impairment of energy supply such as mitochondrial cytopathies and inborn error of metabolism [2-5].

Table 1.

Principal functions of tubular segments

TAL and DCT can regulate urinary concentration by reabsorbing sodium and chloride via Na⁺-K⁺-2Cl^– cotransporter (NKCC2) and Na⁺-Cl^– cotransporter (NCC), respectively. These two segments also contribute to calcium and magnesium homeostasis via paracellular and transcellular mechanisms [2,3,5].

CD consists of two cell types: principal cells and α-intercalated cells. In principal cells, the epithelial sodium channel (ENaC) modulated by aldosterone, can reabsorb Na⁺ and secrete K⁺ while arginine vasopressin receptor 2 (AVPR2) and aquaporin 2 (AQP2), controlled by antidiuretic hormone (ADH) can reabsorb free water. Acid or bicarbonate is excreted through α-intercalated cells [2,3,5].

Part II. Clinical approach to inherited tubulopathies

When evaluating patients clinically suspicious of underlying inherited tubulopathies, it is important to differentiate clinical conditions with simple categorizations before localizing the affected tubular segment. Patients with inherited tubulopathies can be classified according to (1) the volume of body fluid and (2) acid-base status. Fig. 1 describes early differential diagnosis based on volume and acid-base status sequentially. Although some patients show hypertension, most with tubulopathy show volume depletion due to the malabsorption. Activation of renin-angiotensin-aldosterone system (RAAS) then causes hypokalemia. Metabolic acidosis is accompanied by defect of urine acidification in which PCT and α-intercalated cells of CD play a major role. Meanwhile, abnormal urine concentration can lead to metabolic alkalosis in TAL and DCT, target segments of diuretics [3].

Fig. 1.

Clinical approach to inherited tubulopathies. RAAS, renin-angiotensin-aldosterone system; HTN, hypertension; PCT, proximal convoluted tubule; CD, collecting duct; TAL, thick ascending limb of Henle’s loop; DCT, distal convoluted tubule; pRTA, proximal renal tubular acidosis; dRTA, distal renal tubular acidosis; NBCe, electrogenic sodium bicarbonate cotransporter 1; NC, nephrocalcinosis; vH-ATPase, vacuolar type (H+)-ATPase; SNHL, sensorineural hearing loss; AE1, anion exchanger 1; NKCC2, Na⁺-K⁺-2Cl^– cotransporter; ROMK, renal outer medullary potassium; CIC-Kb, chloride channel-Kb; CIC-Ka, chloride channel-Ka; CaSR, calcium sensing receptor; UTI, urinary tract infection; CKD, chronic kidney disease; NCC, Na⁺-Cl^– cotransporter; PHA1, pseudohypoaldosteronism (PHA) type 1; PHA2, PHA type 2; ENaC, epithelial sodium channel; RTA, renal tubular acidosis; DI, diabetes insipidus; AVPR2, arginine vasopressin receptor 2; AQP2, aquaporin 2. ^a)Tubulopathy with ocular involvement. ^b)Tubulopathy with nephrocalcinosis. ^c)Tubulopathy with sensorineural hearing loss.

Hypertension presents in a few types of tubulopathies characterized by mineralocorticoid excess or activation of aldosterone-sensitive ENaC in the CD. Sodium and water retention can result in excretion of potassium and hydrogen ion [3,6].

Part III. ADTKD and whole exome sequencing as a diagnostic tool

Unexplained familial clustering, which implicates the underlying genetic kidney disease, has been detected among CKD patients. With increasing knowledge about inherited kidney disorders, monogenic causes have been identified in a few patients. Although the etiology is still not established for most cases, monogenic disorders were diagnosed in about 10% of CKD patients [17,18]. Autosomal dominant polycystic kidney disease (ADPKD) is the most common genetic kidney disease, followed by type IV collagen disorder [17,18]. ADTKD, a recently defined disease entity, has also been suggested as one of the common monogenic kidney diseases [19].

Different from ADPKD and type IV collagen disorder, some patients show characteristic features of tubulointerstitium-limited involvements with definite familial histories and gradual progression to end-stage kidney disease. From these nonglomerular autosomal dominant kidney diseases, genetic mutations of UMOD, REN, HNF1β, and MUC1 have been detected [17,18]. Additional identifications are in progress.

Various terms have been used over the years to describe this disease group. However, old terms including medullary cystic kidney disease and familial juvenile hyperuricemic nephropathy did not point out nor correspond to overall characteristics of the disease. Establishing uniform diagnostic criteria and nomenclature was unavoidable. Therefore, in 2015, Kidney Disease Improving Global Outcomes standardized the term as ADTKD. According to the affected gene, the ADTKD is specified into ADTKD-UMOD, -MUC1, -REN, -HNF1β, and -NOS (not otherwise specified) [17].

Clinical findings of ADTKD correspond to the following diagnostic criteria: (1) autosomal dominant inheritance; (2) progressive loss of kidney function; and (3) bland urinary sediment (normal or mild microscopic hematuria). Glomerular function remains intact so that proteinuria should be absent or mild. Renal histology reveals degenerative changes involving only tubules and interstitium. Sonographic findings including small-sized kidney and renal cysts are not pathognomonic signs. Confirmative diagnosis is made with compatible familial history of CKD and fulfilling clinical characteristics or with demonstration of a mutation for one of the four known genes [17].

Table 2 describes the specific features of each subtype of ADTKD [19]. ADTKD-UMOD is the most common subtype. Accumulation of abnormal uromodulin in TAL can inhibit NKCC2 resulting in decreased reabsorption of sodium. Compensatory increase in reabsorption of PCT can reduce urinary secretion of uric acid and cause the typical symptoms of hyperuricemia and early gout. ADTKD-MUC1 also deposits abnormal mucin 1 in TAL. However, the pathophysiology is incompletely known. Unique features have not been noted except gout. For ADTKD-HNF1β, renal manifestations may present early in childhood as congenital anomalies of kidney and urinary tract. Since hepatocyte nuclear factor 1β is involved in fetal development of multi-organs, patients might have numerous extra-renal manifestations such as genital abnormalities, abnormal liver function, diabetes mellitus, and autism spectrum disorder. Interestingly, de novo mutation is estimated to account for up to 50% cases of ADTKD-HNF1β. Incomplete penetrance is also common. These are the factors interrupting the diagnosis of ADTKD-HNF1β with confusing pedigree. Hyporeninemic hypoaldosteronism of ADTKD-REN can result in childhood anemia, hypotension, and hyperkalemia.

Table 2.

Specific features of ADTKD subtypes

Genetic diagnosis is generally recommended for certain diseases. It can benefit diagnosis considering cost and ethical issue. Genetic analysis is currently the only way to definitively prove ADTKD, although disease-specific therapies are currently unavailable [17]. Still, children with subtypes of REN and HNF1β might benefit from early conservative management of anemia, hypotension, and other extra-renal symptoms, although UMOD and MUC1 related ADTKD have no distinct symptoms requiring interventions except gout [20]. Of diverse types of genetic testing, whole exome sequencing (WES) is an adequate diagnostic tool for ADTKD due to the incomplete recognition of the disease entity. It is impractical to clinically differentiate the subtypes of ADTKD so far. Moreover, only 50% to 60% of suspected ADTKD patients show the discovered mutations of four genes, indicating that a negative genetic testing result does not exclude the diagnosis [17,18]. Therefore, applying WES for diagnosis ADTKD would be more appropriate than sequencing gene panels.

Sinha et al. [21] performed research on the utility of WES for confirming other inherited tubular disorders in addition to ADTKD. WES was performed for 77 pediatric patients who were clinically diagnosed renal tubular diseases at median age of 48 months. Overall diagnostic yield was 70%. Revision of clinical diagnosis was made in 18%, higher comparing a rate of 4% in previous research of Ashton et al. by Sanger sequencing [22]. WES also directly impacted the clinical management for 31% of the cohort and helped reveal other associated pathologies such as SNHL [21].

Apparently, WES performs efficient verifications of inherited tubulopathies especially ADTKD. However, gene panels still could be a good option for patients with distinctive and typical manifestations of particular tubulopathies. Further discussion is needed to suggest more suitable types of genetic testing for inherited tubulopathies considering the cost and ethical issues such as undesirable reveal of private information including secondary findings or familial histories.

Part IV. Gene therapy in tubulopathies

Multiple genes have been implicated as causes of genetic kidney disease including tubulopathies recently. The necessity of disease-specific therapy targeting the causative gene is emerging along with the acceleration of genetic diagnosis in CKD patients [23]. Undoubtedly, the field of gene therapy has markedly improved recently. For kidney diseases, however, relatively little progress has been made toward gene therapy due to several reasons: (1) given the complex structure and over 20 different cell types, it is difficult to optimally target the affected cell type; (2) causative genes of most prevalent genetic kidney diseases are larger than the capacity of adeno-associated vector (AAV) which is the most common vector used for in vivo strategies; and (3) with the most favored intravenous route, most vectors get lost in the liver and 26 nm-sized AAV can hardly pass through the 10 nm-sized slit diaphragm of glomerulus [24].

Consistent and vigorous attempts are being continued to overcome the points that are currently limiting gene therapy in kidney diseases. As the size of genes packed in AAV and an efficient delivery are the crucial points to modify, studies focusing on utilizing smaller genes essential for modifying target genes and alternative delivery strategies such as subcapsular direct injection or retro-ureteral route are in progress [18,24,25].

Despite the difficulties mentioned above, novel therapies for inherited tubulopathies are actively investigated. Here we introduce on-going research on cystinosis and Lowe syndrome.

Cystinosis is an autosomal recessive lysosomal storage disease caused by CTNS variants. Affected patients are characterized by lysosomal accumulation of cystine crystal in multiple organs including kidney, eye, pancreas, and muscles. Current conservative treatment is the use of drug cysteamine which is expensive, inconvenient to take, and not for cure. Cherqui et al. [26,27] have tried ex vivo cell therapy using hematopoietic stem and progenitor cells (HSPC). In phase I/II clinical trial starting from July 2019, autologous HSPCs were gene-modified ex vivo with CTNS-loaded lentivirus vectors and transplanted to patients. The research team of Cherqui [27] provided a recent update in September 2022. Their results revealed significant longitudinal decrease in leukocyte cystine level and corneal cystine crystals in patients treated with the cell therapy. Lowe syndrome, another proximal tubulopathy, is a X-linked multisystemic disorder caused by OCRL gene mutation. Deposits of phosphatidylinositol 4,5-bisphosphate (PI(4,5)P₂) can produce excessive actin which blocks endosomal trafficking and result in congenital cataract, intellectual disability, and proximal renal tubular dysfunction [10]. Berquez et al. [28] have focused on rebalancing phosphoinositide signals by phosphoinositide 3-kinase (PI3K) inhibitor. The team performed mouse model research of alpelisib which was conventionally used to treat breast cancer but lately known as PI3K inhibitor. When administered to mice model of Lowe syndrome, alpelisib alleviated actin organizational defect and improved kidney function. Likewise, numerous studies are actively in progress to establish novel therapies not only for the proximal tubular disease but also for other inherited tubular diseases including ADTKD.

Conclusion

Distinct transporters exist in each of four tubular segments. In patients with inherited tubular disorders, phenotypes are determined by affected transporters. Interpreting the status of volume and acid-base will help physicians localize the affected segment. ADTKD, a recently defined disease entity, is one of more common genetic kidney disease. Since much about ADTKD have remained unknown, WES can be a suitable tool for discovering both known and unknown genetic information. Along with advances in genetic diagnosis, disease-specific novel therapies for tubulopathies are currently under development.

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