Kidney Week

Abstract: FR-PO556

Familial Autosomal Dominant Hyponatremia With Reset Osmostat

Session Information

• Fluid, Electrolyte, and Acid-Base Disorders: Clinical
  November 04, 2022 | Location: Exhibit Hall, Orange County Convention Center‚ West Building
  Abstract Time: 10:00 AM - 12:00 PM

Category: Fluid‚ Electrolyte‚ and Acid-Base Disorders

• 1002 Fluid‚ Electrolyte‚ and Acid-Base Disorders: Clinical

Authors

• Zitt, Emanuel, Academic Teaching Hospital Feldkirch, Department of Internal Medicine 3 (Nephrology and Dialysis), Feldkirch, Vorarlberg, Austria

Emanuel Zitt,

• Lines, Kate E., University of Oxford Radcliffe Department of Medicine, Oxford, Oxfordshire, United Kingdom

Kate E. Lines,

• Hannan, Fadil, University of Oxford Nuffield Department of Women's & Reproductive Health, Oxford, Oxfordshire, United Kingdom

Fadil Hannan,

• Pagnamenta, Alistair T., University of Oxford Wellcome Centre for Human Genetics, Oxford, United Kingdom

Alistair T. Pagnamenta,

• Giacopuzzi, Edoardo, University of Oxford Wellcome Centre for Human Genetics, Oxford, United Kingdom

Edoardo Giacopuzzi,

• Taylor, Jenny C., University of Oxford Wellcome Centre for Human Genetics, Oxford, United Kingdom

Jenny C. Taylor,

• Lhotta, Karl, Academic Teaching Hospital Feldkirch, Department of Internal Medicine 3 (Nephrology and Dialysis), Feldkirch, Vorarlberg, Austria

Karl Lhotta,

• Thakker, Rajesh V., University of Oxford Radcliffe Department of Medicine, Oxford, Oxfordshire, United Kingdom

Rajesh V. Thakker,

Background

Hyponatremia is frequent and we report a four-generation family with autosomal dominant hyponatremia due to reset osmostat, characterised by: reduced Na⁺ set-point for arginine vasopressin (AVP) secretion; linear relationship between serum Na⁺ and urine osmolality; and normal water load excretion.

Methods

Sixteen of 19 living family members (9 males and 7 females, mean±SD age 46±18 years) consented for clinical and genetic studies.

Results

The index patient (male aged 59 years) presented with severe resistant hypertension and longstanding hyponatremia (<135 mmol/l). His hypertension eventually responded to amiloride (-20 to -30 mmHg). Similar findings in his 56-year-old brother suggested a hereditary condition. Investigation of family members revealed 10 (62.5%) to have hyponatremia, consistent with autosomal dominant inheritance. Overall, mean±SD serum Na⁺ differed significantly between affected (133±5.1 mmol/l) and unaffected individuals (141±1.5 mmol/l; p<0.001), with affected individuals having inappropriately normal plasma copeptin concentrations, when compared to unaffected relatives (4.9±3.1 vs 2.5±2.0 pmol/l, p=0.08). All individuals had normal kidney function, and serum Na⁺ and urine osmolality showed a significant positive correlation, but with a set-point shift towards lower Na⁺ values in affected individuals. Water loading led to brisk excretion of diluted urine in the index patient and his affected brother, consistent with reset osmostat. Renal response to tolvaptan was normal, which excluded nephrogenic syndrome of inappropriate antidiuresis. Plasma renin concentrations were lower in affected individuals compared to unaffected relatives (3.3±2.2 ng/l vs 12.8±6.7 ng/l, p<0.05). DNA sequence analysis did not reveal abnormalities of candidate genes such as AVP, AVPR2, ENaC subunits (SCNN1A, SCNN1B, SCNN1G, and SCNN1D), and TRPV4.

Conclusion

We describe a family with autosomal dominant hyponatremia due to reset osmostat, which is likely caused by a novel gene mutation.