Advertisment

Indian Journal of Nephrology About us |  Subscription |  e-Alerts  | Feedback | Login   
  Print this page Email this page   Small font sizeDefault font sizeIncrease font size
 Home | Current Issue | Archives| Ahead of print | Search |Instructions |  Editorial Board  

Users Online:1477

Official publication of the Indian Society of Nephrology

Ahead of print articles
CASE REPORT
Ahead of print publication  

Late-onset bartter's syndrome Type II with end-stage renal disease due to a novel mutation in KCNJ1 gene in an Indian adult male – A case report


 Department of Nephrology, Nizam's Institute of Medical Sciences, Punjagutta, Hyderabad, Telangana, India

Date of Submission07-Sep-2021
Date of Acceptance06-Oct-2021
Date of Web Publication29-Sep-2022

Correspondence Address:
Sree Bhushan Raju D,
Department of Nephrology, First Floor, Near ARCU, Nizam's Institute of Medical Sciences, Punjagutta, Hyderabad - 500 082, Telangana
India
Login to access the Email id

Source of Support: None, Conflict of Interest: None

DOI: 10.4103/ijn.ijn_383_21

  Abstract 


Mutations in ROMK1 potassium channel gene (KCNJ1) causes antenatal/neonatal Bartter's syndrome type II, which presents with renal salt wasting, hypokalemic metabolic alkalosis, secondary hyperaldosteronism, hypercalciuria, and nephrocalcinosis. We herein describe a case of late-onset Bartter's syndrome type II with progressive renal failure requiring renal replacement therapy secondary to a novel homozygous missense mutation in Exon 2 of KCNJ1 gene (c.500G>A). With this case, we aim to highlight the need for a high index of suspicion and the role of genetic evaluation to diagnose clinically unclassified cases of nephrocalcinosis with renal electrolyte abnormalities more so in late and atypical presentations.

Keywords: Bartter's syndrome, KCNJ1, late-onset, ROMK



How to cite this URL:
Gaggar P, Raju D SB, Tej M R, Pragna P. Late-onset bartter's syndrome Type II with end-stage renal disease due to a novel mutation in KCNJ1 gene in an Indian adult male – A case report. Indian J Nephrol [Epub ahead of print] [cited 2022 Dec 10]. Available from: https://www.indianjnephrol.org/preprintarticle.asp?id=357226


  Introduction Top


Bartter's syndrome is an autosomal recessive disorder affecting the function of the thick ascending limb of the loop of Henle giving a clinical picture of salt wasting and hypokalemic metabolic alkalosis. Most cases present antenatally or in neonates, and it has an estimated prevalence of 1 pmp.[1] Bartter's syndrome is classified as type 1–type 6, which reflects the gene affected. Type 1 is caused by mutations in SLC12A1, type 2 by a mutation in KCNJ1, type 3 by CLC-Kb mutation, type 4 by BSND mutation, type 5 by activating mutation in CaSR, and type 6 by mutations in both CLC- Ka and CLC-Kb.[2] [Figure 1] We report a case of late-onset Bartter's syndrome type II due to a novel mutation in KCNJ1 gene with progressive renal failure.
Figure 1: Schematic representation of transport proteins involved in Bartter's syndrome. An epithelial cell of the thick ascending limb of the Loop of Henle with Na+–K+–2Cl cotransporter and renal outer medullary potassium channel (ROMK) at the apical side. Chloride channel ClC-Ka and ClC-Kb with its Barttin subunit, calcium-sensing receptor (CaSR), and Na+–K+ ATPase channel at the basolateral side

Click here to view



  Case Details Top


A 34-year-old gentleman came with chief complains of nausea, vomiting, and decreased appetite for 10 days. On probing further, he revealed that he had history of polydipsia, polyuria, nocturia, and repeated episodes of carpopedal spasms in his childhood. He was born via normal vaginal delivery at full term with an uneventful antenatal or neonatal period. The patient denied history of paralysis/paresis of limbs, recurrent urinary tract infections, fractures, hearing disturbances, and visual loss. There was no history of renal diseases in the family. He was found to have a creatinine of 2 mg% 4 years back and was under follow-up of a nephrologist at a local hospital.

On physical examination, the patient was moderately built and well-nourished with short stature (height: 140 cm) and no other obvious deformities or skeletal dysmorphic facies. He was normotensive (120/80 mm Hg) with normal ECG and 2D Echo. Laboratory tests revealed severe azotemia (urea: 139 mg%, creatinine: 10 mg%). There was hypokalemia (3.28 meq/L), hypocalcemia (5.0 mg%), and hyperphosphatemia (7.0 mg%) with normal sodium (140 meq/L) and chloride (96 meq/L) levels. Vitamin D levels were low (20 ng/ml) with inappropriately normal PTH levels (90 pg/ml). In arterial blood gas analysis, pH was normal and bicarbonate was low with respiratory compensation (pH = 7.41, serum bicarbonate = 18 mmol/l). The evaluation of 24-hour urinary examination was hampered in view of decreased residual renal function with a urine output of approximately 100 ml/day. His immunological profile (ANA, dsDNA, Anti Sm, and Anti Ro/La) and viral markers (HIV, HbsAg, and HCV) were negative. X-ray of the lumbosacral spine and hands were unremarkable other than for mild changes of renal osteodystrophy.

Ultrasound abdomen was suggestive of medullary nephrocalcinosis with normal-sized kidneys, which was confirmed by computed tomography scan. [Figure 2]. A percutaneous kidney biopsy was performed from the lower pole of the left kidney, which revealed 1/6 glomeruli showing segmental sclerosis, a large area of interstitial fibrosis, and diffuse dense infiltration of lymphocytes and plasma cells in the interstitium. Tubules showing intraluminal calcification [Figure 3] along with the destruction of tubules and unremarkable vessels.
Figure 2: CT scan of the abdomen showing medullary nephrocalcinosis

Click here to view
Figure 3: Interstitial inflammation comprising of lymphocytes and plasma cells with multiple foci of intratubular calcification (Hematoxylin and Eosin stain, magnification: ×100)

Click here to view


The patient was initiated on hemodialysis via a temporary right internal jugular venous catheter, and transplant evaluation was initiated. After informed consent, genomic DNA was extracted from peripheral blood leukocytes and clinical exome sequencing was performed. The analysis revealed a homozygous missense variation in exon 2 of KCNJ1 gene in the chromosome 11 that results in the amino-acid substitution of glutamic acid for glycine at codon 167. {c.500 G>A, homozygous, exon 2, codon 167, p.Gly167Glu}.


  Discussion Top


Inactivating loss of function mutations in the KCNJ1 gene encoding the apical potassium inwardly rectifying outer medullary potassium channel (ROMK) in the thick ascending limb of Henle is classically associated with antenatal/neonatal Bartter's syndrome type II. The ROMK (Kir 1.1) channel generates the lumen positive potential, which is critical for transepithelial Na+- Cl- transport via the NKCC2 channel in the thick ascending limb.[3]

More than 40 cases of KCNJ1 mutations have been described so far. Most of the mutations are missense/nonsense mutations substituting conserved amino acid residues, predominantly within coding exon 2, the most influential putative functional domain of ROMK.[4] In our case, a novel homozygous missense mutation in the codon 167 of exon 2 of the KCNJ1 gene was found, which is known to result in defective potassium conductance due to a conformational change in the ROMK channel,[5] which impairs the function of NKCC2 and leads to salt wasting tubulopathy.

However, the KCNJ1 mutation in the present case could represent a mild phenotype considering the lack of classical antenatal/neonatal onset of the disease. [Table 1] lists the various novel mutations seen in similar case reports of late-onset Bartter's syndrome. The present case had a short stature, probably indicating the tubular loss of salts and calcium since adolescence. The growth retardation in Bartter's syndrome has been attributed to many causes such as hypokalemia, depletion of extracellular fluid volume, malnutrition, polydipsia, polyuria, salt wasting, hypercalciuria, and growth hormone deficiency.[9] Progressive renal failure in Bartter syndrome is extraordinarily rare. Lin et al.[10] described a case of chronic renal failure in a 17-year-old Chinese boy with classical Bartter's syndrome due to a novel mutation in CLC-Kb coding for the chloride channel.
Table 1: List of previously reported cases of late-onset Bartter's syndrome type II

Click here to view


Possible mechanisms of renal failure in Bartter's syndrome are 1) chronic hypokalemic nephropathy, which is associated with impaired renal angiogenesis;[11] 2) volume depletion activating the renin–angiotensin aldosterone system (RAAS); 3) renin–angiotensin–II, aldosterone system contributing to renal fibrosis by triggering the proliferation of transforming growth factor-beta (TGF-β) and plasminogen activator inhibitor-1 gene expression and accelerate renal damage by induction of reactive oxygen species.[12] The presence of chronic interstitial fibrosis in the renal biopsy of the patient probably suggests an interplay of the various abovementioned mechanisms leading to progressive renal failure and the intratubular calcification seen in the biopsy may also have contributed to progressive renal damage[13] in the present case.

Based on the above mentioned mechanisms, Walsh et al.[14] suggested that long-term blockade of mineralocorticoid receptor in BS with spironolactone or eplerenone (or perhaps even direct renin inhibition or angiotensin-converting enzyme inhibitors) may be justified more for renal protection in Bartter's patients than for trying to correct hypokalemia per se.

To the best of our knowledge, this is the first case of late-onset Bartter's syndrome type II with progressive renal failure secondary to a novel KCNJ1 mutation being reported in the Indian literature.


  Conclusion Top


With this case, we aimed to highlight the need for a high index of suspicion and the role of genetic evaluation in diagnosing clinically unclassified cases of nephrocalcinosis with renal electrolyte abnormalities, more so in atypical and late presentations. The evaluation of different pathogenic mechanisms of ROMK mutation will also help in tailoring distinct rescue mechanisms according to the underlying genetic defect.[15]

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form, the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

1.
Ji W, Foo JN, O'Roak BJ, Zhao H, Larson MG, Simon DB, et al. Rare independent mutations in renal salt handling genes contribute to blood pressure variation. Nat Genet 2008;40:592-9.  Back to cited text no. 1
    
2.
Bichet DG, Fujiwara TM. Reabsorption of sodium chloride- Lessons from the chloride channels. N Engl J Med 2004;350:1281-3.  Back to cited text no. 2
    
3.
Greger R, Schlatter E. Presence of luminal K+, a prerequisite for active NaCl transport in the cortical thick ascending limb of Henle's loop of rabbit kidney. Pflugers Arch 1981;392:92-4.  Back to cited text no. 3
    
4.
Fretzayas A, Gole E, Attilakos A, Daskalaki A, Nicolaidou P, Papadopoulou A. Expanding the spectrum of genetic mutations in antenatal bartter syndrome type II. Pediatr Int 2013;55:371-73.  Back to cited text no. 4
    
5.
Derst C, Konrad M, Köckerling A, Károlyi L, Deschenes G, Daut J, et al. Mutations in the ROMK gene in antenatal Bartter syndrome are associated with impaired K+channel function. Biochem Biophys Res Common 1997;230:641-5.  Back to cited text no. 5
    
6.
Gollasch B, Aniston Y-M, Canaan-Kühl S, Gollasch M. Late-onset Bartter syndrome type II. Clin Kidney J 2017;10:594-9.  Back to cited text no. 6
    
7.
Huang L, Luiken GPM, van Riemsdijk IC, Petrij F, Zandbergen AAM, Dees A. Nephrocalcinosis as adult presentation of Bartter syndrome type II. Neth J Med 2014;72(2):91-3.  Back to cited text no. 7
    
8.
Khandelwal P, Sabanadesan J, Sinha A, Hari P, Bagga A. Isolated nephrocalcinosis due to compound heterozygous mutations in renal outer medullary potassium channel. CEN Case Rep 2020;9:232-6.  Back to cited text no. 8
    
9.
Spector-Cohen I, Koren A, Sakran W, Tenenbaum-Rakover Y, Halevy R. Growth hormone deficiency in children with antenatal bartter syndrome. J Pediatr Endocrinol Metab 2019;32:225-31.  Back to cited text no. 9
    
10.
Lin C-M, Tsai J-D, Lo Y-F, Yan M-T, Yang S-S, Lin S-H. Chronic renal failure in a boy with classic Bartter's syndrome due to a novel mutation in CLCNKB coding for the chloride channel. Eur J Pediatr 2009;168:1129-33.  Back to cited text no. 10
    
11.
Reungjui S, Roncal CA, Sato W, Glushakova OY, Croker BP, Suga S-I, et al. Hypokalemic nephropathy is associated with impaired angiogenesis. J Am Soc Nephrol 2008;19:125-34.  Back to cited text no. 11
    
12.
Sun Y, Zhang JQ, Ramires FJ. Local angiotension II and transforming growth factor beta-1 in renal fibrosis in rats. Hypertension 2000;35:1078-84.  Back to cited text no. 12
    
13.
Sayer JA, Carr G, Simmons NL. Nephrocalcinosis: Molecular insights into calcium precipitation within the kidney. Clin Sci (Lond) 2004;106:546-61.  Back to cited text no. 13
    
14.
Walsh SB, Unwin E, Vargas-Poussou R, Houillier P, Unwin R. Does hypokalemia cause nephropathy? An observational study of renal function in patients with Bartter or Gitelmann syndrome. QJM 2011;104:939-44.  Back to cited text no. 14
    
15.
Peters M, Ermert S, Jeck N, Derst C, Pechmann U, Weber S, et al. Classification and rescue of ROMK mutations underlying hyperprostaglandin E syndrome/antenatal Bartter syndrome. Kidney Int 2003;64:923-32.  Back to cited text no. 15
    


    Figures

  [Figure 1], [Figure 2], [Figure 3]
 
 
    Tables

  [Table 1]



 

 
Top
 
 
  Search
 
  

 
  In this article
   Abstract
  Introduction
  Case Details
  Discussion
  Conclusion
   References
   Article Figures
   Article Tables

 Article Access Statistics
    Viewed227    
    PDF Downloaded6    

Recommend this journal

Indian Journal of Nephrology
Published by Wolters Kluwer - Medknow
Online since 20th Sept '07