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Hypoaldosteronism due to a novel SEC61A1 variant successfully treated with fludrocortisone

Karpman, Diana LU orcid ; Lindström, Martin L. ; Möller, Mattias LU orcid ; Ivarsson, Sofie ; Kristoffersson, Ann Charlotte LU ; Bekassy, Zivile LU ; Fogo, Agnes B. and Elfving, Maria LU (2024) In Clinical Kidney Journal 17(8).
Abstract

Background: Genetic variants in SEC61A1 are associated with autosomal dominant tubulointerstitial kidney disease. SEC61A1 is a translocon in the endoplasmic reticulum membrane and variants affect biosynthesis of renin and uromodulin. Methods: A patient is described that presented at 1 year of age with failure-to-thrive, kidney failure (glomerular filtration rate, GFR, 18 ml/min/1.73m2), hyperkalemia and acidosis. Genetic evaluation was performed by whole genome sequencing. Results: The patient has a novel de novo heterozygous SEC61A1 variant, Phe458Val. Plasma renin was low or normal, aldosterone was low or undetectable and uromodulin was low. Kidney biopsy at 2 years exhibited subtle changes suggestive of tubular dysgenesis... (More)

Background: Genetic variants in SEC61A1 are associated with autosomal dominant tubulointerstitial kidney disease. SEC61A1 is a translocon in the endoplasmic reticulum membrane and variants affect biosynthesis of renin and uromodulin. Methods: A patient is described that presented at 1 year of age with failure-to-thrive, kidney failure (glomerular filtration rate, GFR, 18 ml/min/1.73m2), hyperkalemia and acidosis. Genetic evaluation was performed by whole genome sequencing. Results: The patient has a novel de novo heterozygous SEC61A1 variant, Phe458Val. Plasma renin was low or normal, aldosterone was low or undetectable and uromodulin was low. Kidney biopsy at 2 years exhibited subtle changes suggestive of tubular dysgenesis without tubulocystic or glomerulocystic lesions and with renin staining of the juxtaglomerular cells. The patient experienced extreme fatigue due to severe hypotension attributed to hypoaldosteronism and at 8 years of age fludrocortisone treatment was initiated with marked improvement in her well-being. Blood pressure and potassium normalized. Biopsy at 9 years showed extensive glomerulosclerosis and mild tubulointerstitial fibrosis, as well as tubular mitochondrial abnormalities, without specific diagnostic changes. Her GFR improved to 54 ml/min/1.73m2. Conclusions: As the renin-angiotensin system promotes aldosterone release, and the patient had repeatedly undetectable aldosterone levels, the SEC61A1 variant presumably contributed to severe hypotension. Treatment with a mineralocorticoid had a beneficial effect and corrected the electrolyte and acid-base disorder. We suggest that the increased blood pressure hemodynamically improved the patient's kidney function.

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author
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organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
autosomal dominant tubulo-interstitial kidney disease, kidney, renal tubular dysgenesis, renin, SEC61A1
in
Clinical Kidney Journal
volume
17
issue
8
article number
sfae213
publisher
Oxford University Press
external identifiers
  • pmid:39135939
  • scopus:85201188287
ISSN
2048-8505
DOI
10.1093/ckj/sfae213
language
English
LU publication?
yes
id
76099b92-bc96-4a8a-bd00-b0dd291ded15
date added to LUP
2025-01-09 13:24:07
date last changed
2025-07-11 04:43:19
@article{76099b92-bc96-4a8a-bd00-b0dd291ded15,
  abstract     = {{<p>Background: Genetic variants in SEC61A1 are associated with autosomal dominant tubulointerstitial kidney disease. SEC61A1 is a translocon in the endoplasmic reticulum membrane and variants affect biosynthesis of renin and uromodulin. Methods: A patient is described that presented at 1 year of age with failure-to-thrive, kidney failure (glomerular filtration rate, GFR, 18 ml/min/1.73m<sup>2</sup>), hyperkalemia and acidosis. Genetic evaluation was performed by whole genome sequencing. Results: The patient has a novel de novo heterozygous SEC61A1 variant, Phe458Val. Plasma renin was low or normal, aldosterone was low or undetectable and uromodulin was low. Kidney biopsy at 2 years exhibited subtle changes suggestive of tubular dysgenesis without tubulocystic or glomerulocystic lesions and with renin staining of the juxtaglomerular cells. The patient experienced extreme fatigue due to severe hypotension attributed to hypoaldosteronism and at 8 years of age fludrocortisone treatment was initiated with marked improvement in her well-being. Blood pressure and potassium normalized. Biopsy at 9 years showed extensive glomerulosclerosis and mild tubulointerstitial fibrosis, as well as tubular mitochondrial abnormalities, without specific diagnostic changes. Her GFR improved to 54 ml/min/1.73m<sup>2</sup>. Conclusions: As the renin-angiotensin system promotes aldosterone release, and the patient had repeatedly undetectable aldosterone levels, the SEC61A1 variant presumably contributed to severe hypotension. Treatment with a mineralocorticoid had a beneficial effect and corrected the electrolyte and acid-base disorder. We suggest that the increased blood pressure hemodynamically improved the patient's kidney function.</p>}},
  author       = {{Karpman, Diana and Lindström, Martin L. and Möller, Mattias and Ivarsson, Sofie and Kristoffersson, Ann Charlotte and Bekassy, Zivile and Fogo, Agnes B. and Elfving, Maria}},
  issn         = {{2048-8505}},
  keywords     = {{autosomal dominant tubulo-interstitial kidney disease; kidney; renal tubular dysgenesis; renin; SEC61A1}},
  language     = {{eng}},
  number       = {{8}},
  publisher    = {{Oxford University Press}},
  series       = {{Clinical Kidney Journal}},
  title        = {{Hypoaldosteronism due to a novel SEC61A1 variant successfully treated with fludrocortisone}},
  url          = {{http://dx.doi.org/10.1093/ckj/sfae213}},
  doi          = {{10.1093/ckj/sfae213}},
  volume       = {{17}},
  year         = {{2024}},
}