Hypoaldosteronism due to a novel SEC61A1 variant successfully treated with fludrocortisone

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 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.

Keywords: SEC61A1; autosomal dominant tubulo-interstitial kidney disease; kidney; renal tubular dysgenesis; renin.

Graphical Abstract

Figure 1:

Histopathological and ultramorphological findings in the patient's kidney biopsies. (A–C) Biopsy at 18 months of age. (A) A few immature glomeruli (arrow) were present but otherwise normal maturation and histological appearance, periodic acid–Schiff stain (PAS) stain. (B) Tubules with preserved brush border and basal membrane of normal thickness without atrophy or interstitial fibrosis. (C) Immunohistochemical staining for renin showing labeling in the juxtaglomerular area (arrow). (D–H) Biopsy at 9 years of age. (D) Globally sclerotic glomeruli and interstitial fibrosis were present (arrow, trichrome stain). (E) Electron microscopy showed 10%–20% foot process effacement and glomerular basement membrane thickening (arrow). (F) Mitochondria within tubular cells exhibited irregular cristae. (G) Enlarged image of the marked area in panel (F) showing irregular cristae. (H) Renin staining localized to the juxtaglomerular area. Scale bar 0.05 mm in panels (A–D) and (H) and 2 µm in panels (E–G).

Figure 2:

Uromodulin levels in the patient and controls. Serum and EDTA plasma and citrated plasma from the patient taken at three separate time points at age 9 years and from pediatric and adult controls (n = 10) were analyzed for uromodulin levels. For comparison sera from pediatric controls (n = 9, 2–13 years, median age 9 years, three females, with unrelated conditions as previously described [24]) and one female adult were analyzed. The patient had significantly lower levels (median 72; range 62–84 ng/mL) than the controls (median 168; range 74–450 ng/mL, the one adult value was 120 ng/mL). *P < .05 (two-tailed Mann–Whitney U test).

Figure 3:

SEC61A1 in patient and control blood. A SEC61A1 protein band (arrow) was visualized, by immunoblotting, in the patient's blood cell lysate at approximately 52 kDa and comparable in size to that from a normal adult male and the HeLa cell lysate.

Figure 4:

Angiotensin II levels in serum from the patient, pediatric controls, the patient's mother and adult controls. Angiotensin II levels analyzed by ELISA in serum samples from the patient at age 11 years (measured at 19 and 157 pg/mL) compared with pediatric controls (median 70; range 13–167 pg/mL; n = 9), her mother bearing the same heterozygous AGT variant (170 pg/mL) and adult controls (median 220; range 8–2430 pg/mL; n = 10).