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Table of Contents
CASE REPORT
Year : 2015  |  Volume : 9  |  Issue : 1  |  Page : 33-37

Familial renal tubular acidosis: Report of two cases from a single family


1 Department of Pediatrics, RAK College of Medical Sciences, Ras-al-Khaimah, United Arab Emirates
2 Department of Medicine, Mafraq Hospital, Abu Dhabi, United Arab Emirates
3 Department of Pediatrics, Saqr Hospital, Ras-al-Khaimah, United Arab Emirates
4 Department of Biochemistry, RAK College of Medical Sciences, Ras-al-Khaimah, United Arab Emirates

Date of Web Publication21-Aug-2015

Correspondence Address:
Subhranshu Sekhar Kar
Department of Pediatrics, Room No. 211, RAK College of Medical Sciences, Ras-al-Khaimah
United Arab Emirates
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0331-3131.163334

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   Abstract 

Renal tubular acidosis (RTA) is a disease that occurs when the kidneys fail to excrete acids into the urine, as a result of which the person's blood remains very acidic. Without proper treatment, chronic acidity of the blood leads to chronic kidney disease, kidney stones, metabolic bone disease, and growth failure. These are relatively rare inherited renal tubular disorders. We report two cases from a single family with distal RTA (dRTA) or Type 1 RTA presenting with varied clinical manifestations. Sensorineural deafness, which is rarely associated with dRTA, was present in the elder sibling.

Keywords: Acidosis, familial, nephrocalcinosis, renal, tubular


How to cite this article:
Naeem A, Kiblawi MA, Kar SS, Ahmed E, Mossad S, Manjunatha Goud B K. Familial renal tubular acidosis: Report of two cases from a single family. Ann Nigerian Med 2015;9:33-7

How to cite this URL:
Naeem A, Kiblawi MA, Kar SS, Ahmed E, Mossad S, Manjunatha Goud B K. Familial renal tubular acidosis: Report of two cases from a single family. Ann Nigerian Med [serial online] 2015 [cited 2021 Apr 18];9:33-7. Available from: https://www.anmjournal.com/text.asp?2015/9/1/33/163334


   Introduction Top


Inherited renal tubular disorders involve a variety of defects in renal tubular transport processes and their regulation. Renal tubular acidosis (RTA) is a group of syndromes due to derangements of renal tubular acid transport. The underlying abnormalities consist of an impairment of bicarbonate reabsorption or excretion of hydrogen (H + ) ions or a combination of both. Studies have shown that the disorder involves various molecular mechanisms and are transmitted as single gene defects. [1] The disorder may be inherited as autosomal dominant (AD), but rare autosomal recessive (AR) forms are also seen. [1] Certain syndromes like Lowe syndrome, Alagille syndrome, Fanconi-Bickel syndrome, Sly syndrome, Say syndrome, cystinosis, dent disease, and nephronophthisis have well-described association with RTA. [2]

Familial forms of proximal RTA (pRTA) and distal RTA (dRTA) have been reported. Recessive pRTA with ocular and central nervous system abnormalities is caused by loss-of-function mutations in basolateral membrane Na-HCO 3 - cotransporter NBCe1/SLC4A4. Recessive dRTA with deafness is caused by loss-of-function mutations in either of two subunits of the vacuolar H + -ATPase (V-ATPase) of intercalated cells; the B1 subunit of the V1 cytoplasmic ATPase complex, and the a4 subunit of the V0 transmembrane pore complex. The dominant anion exchanger 1 (AE1) dRTA mutations are accompanied by mild or asymptomatic erythroid changes, while the erythroid dyscrasias accompanying recessive AE1 dRTA mutations can be mild or severe. Recessive mixed pRTA-dRTA is caused by loss-of-function mutations of the cytoplasmic carbonic anhydrase II. [3]

dRTA is characterized by metabolic acidosis due to impairment in the tubular secretion of hydrogen (H + ) ions in the distal nephron. Due to tubular derangements it can be associated with characteristic features of hypokalemia, nephrocalcinosis, metabolic bone disease, and nerve deafness. In untreated cases, the progression of nephrocalcinosis may lead to chronic renal failure. [4],[5],[6]

A very few cases have been identified in Arab populations suffering from dRTA with hearing loss. [7] One case of dRTA with progressive nerve deafness was reported from Morocco, and four cases were reported from Saudi Arabia. All these cases were associated with consanguineous marriages. [8] Inherited combined pRTA and dRTA with osteopetrosis and pure pRTA associated with ocular abnormalities, are rare diseases which have been recently described. [9]

We report the rare occurrence of two cases of dRTA with a varied clinical presentation from a single family.


   Case Reports Top


Case 1

A 2½-year-old male child, first of the four siblings born to parents of consanguineous marriage, presented to our hospital with complaints of growth failure, language developmental delay, hearing difficulty, polydipsia, and polyuria dating back to 3 months prior to presentation. He had a history of recurrent urinary infections. On examination, his weight was 12.1 kg (35% tile); height of 89.2 cm (40% tile); and head circumference was 49 cm (50% tile). The systemic examinations were within the normal limit.

On investigation, blood pH was found to be 7.2 (Normal = 7.35-7.45). Serum sodium (Na) was 135 mEq/L (Normal = 135-145 mEq/L), serum potassium (K)-2.8 mEq/L (Normal = 3.5-5.5 mEq/L), serum bicarbonate (HCO 3 )-9 mEq/L (Normal = 22-28 mEq/L), and the serum chloride (Cl) level was 118 mEq/L (Normal = 95-105 mEq/L). Blood urea nitrogen (BUN) was 12 mEq/L and serum creatinine (Cr)-0.8 mg/dL. Antinuclear antibody, anti-ds-DNA, and hepatitis virus panel were all negative. Arterial blood gas analysis showed metabolic acidosis with normal anion gap. Urinalysis showed an alkaline pH of 7. The urinary anion gap (UAG = Na+K−Cl) is positive (20 mEq/L). Hypercalciuria (24 h calcium excretion of 60 mg), hyperphosphaturia, and hypocitraturia (24 h citrate excretion of 11 mg) were noted. Urinary ammonium (NH 4 ) excretion was low. The fractional HCO 3 excretion was found to be 3% (Normal: <5%). Abdominal ultrasound showed nephrocalcinosis Grade B, with a mild diffuse increase in echogenicity of the entire medullary pyramid [Figure 1] and [Figure 2]. Brain stem evoked audiometry showed 80 dB bilateral sensorineural hearing loss (SNHL). DNAs were extracted by the standard phenol/chloroform method. Molecular analysis was performed by polymerase chain reaction (PCR) amplification and direct sequencing which revealed V-ATPase mutations in ATP6V1B1 isoform.
Figure 1: Abdominal ultrasonographic picture of first child showing nephrocalcinosis Grade B, with mild diffuse increase in echogenicity of the entire medullary pyramid (left kidney)

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Figure 2: Abdominal ultrasonographic picture of first child showing nephrocalcinosis Grade B, with mild diffuse increase in echogenicity of the entire medullary pyramid (right kidney)

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Case 2

A 4-month-old female baby, a sibling to case number 1 above presented with poor feeding and poor weight gain while on exclusive breastfeeding. She is the fourth child, born full term but was small for gestational age (birth weight: 2.0 kg) with no history of parental or neonatal problems. On examination, her weight was 3.8 kg, height 45 cm, head circumference 36 cm (all below third centile). Systemic examination was normal, but neurological exam showed mild hypotonia. She was diagnosed to have nephrocalcinosis Grade A by abdominal ultrasound. There was also persistent fetal lobulation of both kidneys associated with tubular ectasia.

On investigation, serum Na was 134 mEq/L (Normal = 135-145 mEq/L), serum K-2.5 mEq/L, serum HCO 3 -8 mEq/L, and the serum Cl level was 116 mEq/L. BUN was 8 mEq/L and serum Cr-0.7 mg/dL. Antinuclear antibody, anti-ds-DNA, and hepatitis virus panel were all negative. Urine analysis revealed hematuria (urine: Pus cells 8-10/high-powered field [HPF], red blood cells-40-45/HPF, pH-8, specific gravity-1.015). There was no growth in urine culture. The UAG is positive (17 mEq/L). Hypercalciuria (24 h calcium excretion of 26 mg), hyperphosphaturia, and hypocitraturia (24 h citrate excretion of 4 mg) were noted. Urinary ammonium (NH 4 ) excretion was low. The fractional HCO 3 excretion was found to be 4%. Abdominal ultrasound showed nephrocalcinosis II a [Figure 3]. Brain stem evoked audiometry showed normal hearing power. Molecular analysis was performed by PCR amplification and direct sequencing which revealed mutations in V-ATPases of isoform ATP6V0A4.
Figure 3: Abdominal ultrasonographic picture of the second child showing nephrocalcinosis II a, with diffuse increase in echogenicity of the entire medullary pyramid

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On the basis of clinical presentation and investigations of both the patients, the diagnosis of familial AR dRTA was made. The parents and other two siblings (apart from these two cases) were clinically normal and genetic studies in them did not reveal any abnormality.

Both the patients were treated with bicitra (K citrate 33 g, Na citrate 30 g, citric acid 20 g, aqua 300 mL), to normalize the bicarbonate and potassium levels. They are now continuously monitored with quarterly blood studies and abdominal ultrasonography every half yearly, with proper dose adjustments of the drugs and are now thriving well.


   Discussion Top


The RTA syndromes encompass a disparate group of tubular transport defects that have in common the inability to secrete hydrogen ions (H + ), a defect that is disproportionately large in relation to any reduction in the glomerular filtration rate. [10],[11] This condition, first described in 1935, was confirmed as a disorder in 1946 and the term "RTA" was designated to the disease in 1951. [12],[13],[14] A patient with RTA usually presents with metabolic acidosis with normal plasma anion gap, normal glomerular filtration load, and hyperchloremia. Diagnosis can be established following detailed clinical history and physical examination, as well as carrying out appropriate laboratory tests. [6]

dRTA is divided into primary and secondary types. Primary dRTA is further subdivided into persistent and transient types and dRTA with sensorineural deafness is classified under the persistent type. [6],[11]

Bruce et al. demonstrated that patients with AD familial dRTA were heterozygous for mutations in their red cell HCO3 /Cl exchanger, band 3 (AE1, SLC4A1) genes, and these mutations were not found in any of the normal family members studied. [15] Karet discussed that dRTA of AR type is linked with mutations in ATP6V0A4 and the AR type with deafness is associated with mutations in ATP6V1B1 genes. In patients with recessive Type 1 RTA, many have progressive and irreversible bilateral (SNHL; Type 1 Type 1b). [1],[16] The coexistence of hearing loss with Type 1 RTA is noteworthy due to the challenges faced by the inner ear in maintaining pH homeostasis in its interior milieu. Endolymph pH is maintained near 7.4 in the cochlea, and is even lower in the endolymphatic sac (pH 6.6), indicating an active acidification process. [1],[16]

In the first case, the boy presented with features of failure to thrive and hearing loss. Further investigations showed the presence of nephrocalcinosis. Normal ultrasound of the kidney should show anechoic pyramids relative to the cortex. According to ultrasound grading, nephrocalcinosis is divided into three grades. Grade A nephrocalcinosis is identified as echogenic pyramids, Grade B signifies more marked changes apparent as rings and echogenic pyramids, and Grade C is designated for marked nephrocalcinosis. [17] The genetic analysis revealed V-ATPase mutations in ATP6V1B1 isoform. In 1999, Karet et al. first studied the genetic basis of recessive dRTA in a subset of patients with associated SNHL. [18] Through genome linkage analysis, they identified the locus of suspected mutations at chromosome 2p13 that was later identified as the ATP6V1B1 gene encoding B1 subunit. They studied 31 unrelated kindred with recessive dRTA. Twenty-seven of them had a family history of consanguineous marriage. All reported cases were diagnosed at an early age with the majority diagnosed by age 1. Nineteen cases were identified with ATP6V1B1 mutation. A total of 87% of the cases had hearing impairment.

Joshua et al. studied hearing loss in five children with dRTA from three unrelated families. [19] All families had different ATP6V1B1 mutations. Hearing loss was diagnosed between 3 months and 2 years. Audiometric and imaging techniques were used to characterize the hearing loss. The hearing loss was bilateral, asymmetrical, progressive, and sometimes had a conductive component.

In 2010, Yashima et al. reported a patient in whom renal calcification was found at the 1 st month medical screening. Further investigation had led to the diagnosis of dRTA. [20] The patient had developed bilateral hearing loss by age 3 and had started using hearing aids. Since the age of 4, he had several attacks of rotating vertigo. [20]

Many researchers have also reported RTA cases from different geographical regions. Sharifian et al., gave an account of 51 children with dRTA and sensorineural deafness in Turkey. Bajaj and Quan, reported dRTA and nerve deafness in 6 children out of 12 in a single family. Ranconi et al. reported one case, Guibaud et al. documented three cases, and Donckerwolcke et al. documented two cases of dRTA and nerve deafness in a single family. [21],[22],[23],[24],[25] Due to the rarity of this disease, the incidence by ethnicity and geographical area is still inconclusive.

Our second case has only nephrocalcinosis without hearing impairment. Genetic analysis revealed mutations in V-ATPases of isoform ATP6V0A4. Karet et al. studied a subset of recessive dRTA patients with normal hearing and identified a different locus of suspected mutation at chromosome 7q33-34. [26] Through the positional cloning approach, the ATP6V0A1 gene encoding a 4 subunit was identified at that locus. Thirteen kindred with normal hearing were studied. All except one had a family history of consanguinity. They had severe metabolic acidosis and hypokalemia with normal renal function. Urinary pH was reported to be >6.5. All had nephrocalcinosis, and with the exception of two, they all had elevated urine calcium. Rickets was present in seven of them. Audiometric evaluation revealed normal hearing Saito et al. described a 2-month-old Japanese male infant who had presented with vomiting and failure to thrive. [27] The patient had hyperchloremic metabolic acidosis, hypokalemia, a normal serum anion gap, a positive UAG, nephrocalcinosis, and high urine pH. Auditory brain stem response test also revealed normal hearing bilaterally. Stover et al. later described a several novel mutation in the ATP6V0A4 gene causing AR dRTA. [8]

Simple alkali replacement can correct the metabolic acidosis manifestations, but will not prevent occurrence or progression of hearing loss. Alkali administration will neutralize the metabolic acids and reduces urinary potassium and sodium excretion, normalizes hypokalemia, and sodium depletion. [6],[28]

Rehabilitation therapy was instituted for the sensorineural deafness. As the dRTA with hearing loss is an AR disorder, a detailed family history with analysis of pedigree chart is of paramount importance. With severe hearing loss, cochlear implantation should be considered after performing computed tomography scan to confirm the presence of cochlea and auditory canal. [29] Furthermore, speech therapy and psychology assessments are often needed for children with sensorineural deafness. When the patient is on systemic alkalizers such as bicitra and polycitra, urine pH should be monitored every 3 months with half yearly ultrasonography to monitor the progression of nephrocalcinosis. [6],[28]


   Conclusion Top


Failure of early diagnosis and treatment will adversely affect the outcome of the disease as seen in our patient and his sister. As the disorder is autosomally inherited, genetic evaluation, and genetic counseling plays an important role in its prevention.

 
   References Top

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7.
Centre for Arab Genomic Studies. The Catalogue for Transmission Genetics in Arabs CTGA Database: Renal Tubular Acidosis, Distal, with Progressive Nerve Deafness. C2005. Available from: http://www.cags.org.ae [Last accessed on 2011 Jun 02].  Back to cited text no. 7
    
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Stover EH, Borthwick KJ, Bavalia C, Eady N, Fritz DM, Rungroj N, et al. Novel ATP6V1B1 and ATP6V0A4 mutations in autosomal recessive distal renal tubular acidosis with new evidence for hearing loss. J Med Genet 2002;39:796-803.  Back to cited text no. 8
    
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Batlle D, Kurtzman NA. Distal renal tubular acidosis: Pathogenesis and classification. Am J Kidney Dis 1982;1:328-44.  Back to cited text no. 10
    
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Lightwood R. Calcium infarction of the kidneys in infants. Arch Dis Child 1935;10:205-6.  Back to cited text no. 12
    
13.
Albright F, Burnett CH, Parson W, Reifenstein EC, Roos A. Osteomalacia and late rickets: Various etiologies met on United States with emphasis on that resulting from specific forms of renal acidosis, therapeutic implications for each etiological subgroup, and relationship between osteomalacia and Milkman′s syndrome. Medicine 1946;25:399-79.  Back to cited text no. 13
    
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Pines KL, Mudge GH. Renal tubular acidosis with osteomalacia; report of 3 cases. Am J Med 1951;11:302-11.  Back to cited text no. 14
    
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Bruce LJ, Cope DL, Jones GK, Schofield AE, Burley M, Povey S, et al. Familial distal renal tubular acidosis is associated with mutations in the red cell anion exchanger (Band 3, AE1) gene. J Clin Invest 1997;100:1693-707.  Back to cited text no. 15
    
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Karet FE. Inherited distal renal tubular acidosis. J Am Soc Nephrol 2002;13:2178-84.  Back to cited text no. 16
    
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Allan PL. Parenchymal Diseases of the Kidney. In : Baxter GM, Sidhu PS, editors, eds. Ultrasound of the Urogenital System. Georg Thieme Verlag: Stuttgart, Germany; 2005. p. 33.  Back to cited text no. 17
    
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Karet FE, Finberg KE, Nelson RD, Nayir A, Mocan H, Sanjad SA, et al. Mutations in the gene encoding B1 subunit of H+−ATPase cause renal tubular acidosis with sensorineural deafness. Nat Genet 1999;21:84-90.  Back to cited text no. 18
    
19.
Joshua B, Kaplan DM, Raveh E, Lotan D, Anikster Y. Audiometric and imaging characteristics of distal renal tubular acidosis and deafness. J Laryngol Otol 2008;122:193-8.  Back to cited text no. 19
    
20.
Yashima T, Noguchi Y, Kawashima Y, Rai T, Ito T, Kitamura K. Novel ATP6V1B1 mutations in distal renal tubular acidosis and hearing loss. Acta Otolaryngol 2010;130:1002-8.  Back to cited text no. 20
    
21.
Sharifian M, Esfandiar N, Mazaheri S, Kariminejad A, Mohkam M, Dalirani R, et al. Distal renal tubular acidosis and its relationship with hearing loss in children: Preliminary report. Iran J Kidney Dis 2010;4:202-6.  Back to cited text no. 21
    
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Bajaj G, Quan A. Renal tubular acidosis and deafness: Report of a large family. Am J Kidney Dis 1996;27:880-2.  Back to cited text no. 22
    
23.
Ronconi GF, Pesenti P, Usai AE, Ronconi M, Soffiati G. Distal renal tubular acidosis with nerve deafness. Pediatr Med Chir 1984;6:549-52.  Back to cited text no. 23
    
24.
Guibaud P, Parchoux B, Langue J, Bouissou F, Barthe P, Larbre F. Distal renal tubular acidosis: Report of 3 cases. J Genet Hum 1979;27:157-66.  Back to cited text no. 24
    
25.
Donckerwolcke RA, Van Biervliet JP, Koorevaar G, Kuijten RH, Van Stekelenburg GJ. The syndrome of renal tubular acidosis with nerve deafness. Acta Paediatr Scand 1976;65:100-4.  Back to cited text no. 25
    
26.
Karet FE, Finberg KE, Nayir A, Bakkaloglu A, Ozen S, Hulton SA, et al. Localization of a gene for autosomal recessive distal renal tubular acidosis with normal hearing (rdRTA2) to 7q33-34. Am J Hum Genet 1999;65:1656-65.  Back to cited text no. 26
    
27.
Saito T, Hayashi D, Shibata S, Jogamoto M, Kamoda T. Novel compound heterozygous ATP6V0A4 mutations in an infant with distal renal tubular acidosis. Eur J Pediatr 2010;169:1271-3.  Back to cited text no. 27
    
28.
Habbig S, Hoppe B. Treatment of nephrocalcinosis in children: A review. Eur Pediatr 2009;3:71-5.  Back to cited text no. 28
    
29.
National Institute for Health and Clinical Excellence. Cochlear implants for children and adults with severe to profound deafness. NICE technology appraisal guidance 166. 2011. p. 1-41. Available from: http://www.nice.org.uk [Last accessed on 2011 Feb 06].  Back to cited text no. 29
    


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