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Pseudohypoaldosteronism Workup

  • Author: Alicia Diaz-Thomas, MD, MPH; Chief Editor: Stephen Kemp, MD, PhD  more...
 
Updated: Apr 30, 2014
 

Laboratory Studies

Renal pseudohypoaldosteronism type I

The clinical characteristics of pseudohypoaldosteronism (PHA) type I (PHA-I) are those of hypoaldosteronism (ie, hyponatremia, hyperkalemic metabolic acidosis, hyperreninemia, and renal salt wasting) despite normal or elevated aldosterone levels. Overall renal function is normal. The condition does not respond to the administration of exogenous mineralocorticoids.

Although hyponatremia is usually present, it may be masked by hemoconcentration. Hyperkalemia and metabolic acidosis are typically present despite a normal glomerular filtration rate (GFR). The plasma potassium concentration ranges from moderately to greatly increased values. Occasionally, hypercalciuria and nephrocalcinosis have also been described.

The diagnosis is made by demonstrating inappropriately high urinary sodium losses in the presence of hyponatremia, decreased urinary potassium excretion, a normal GFR, normal adrenal function, and increased levels of aldosterone and renin. Plasma aldosterone concentration, urinary aldosterone excretion, and plasma renin activity (PRA) are all usually elevated. Sweat and salivary sodium and chloride determinations are characteristicallynormal.

Plasma deoxycorticosterone and corticosterone concentrations are within the reference range. The ratio of plasma 18-hydroxycorticosterone to aldosterone is within the reference range. The ratio of urinary excretion of tetrahydroaldosterone to 18-hydroxytetrahydro-compound A is within the reference range in contrast to primary hypoaldosteronism.

Children with the early childhood hyperkalemia variant of renal PHA-I (renal tubular acidosis [RTA] type IV subtype 5) have consistently normal or elevated PRA and 24-hour urinary aldosterone excretion. The only biochemical abnormality in these patients is the presence of hyperkalemia and hyperchloremic (non–anion gap) metabolic acidosis. Azotemia and sodium chloride wasting are notably absent.

Functional evaluation reveals a normal ability to acidify urine, low ammonium and potassium excretion, and a mild defect in bicarbonate reabsorption (ie, functional markers of RTA type IV). Renal bicarbonate wasting can be observed with high-dose alkali therapy, but unlike proximal RTA type II, early childhood hyperkalemia is not associated with kaliuria. Unlike RTA type I and II, this subtype is not characterized by hypercalciuria but, rather, by relative hyperreabsorption of calcium and high urinary citrate excretion; thus, nephrocalcinosis is absent.

Multiple target organ defects pseudohypoaldosteronism type I

Like renal PHA-I, multiple target organ defects (MTOD) PHA-I is characterized by urinary salt wastage, which can occur from the salivary glands, sweat glands, respiratory tract, and colon. A variant of MTOD PHA-I has been described in which salt wastage is limited to sweat and salivary glands, without associated renal salt wasting. Urinary sodium is typically elevated, sweat and salivary sodium concentrations are elevated, and active sodium transport in the rectal mucosa is impaired.

Pseudohypoaldosteronism type II

Hyperkalemia, hyperchloremic metabolic acidosis, and a normal GFR are present. Renin and aldosterone levels are low to normal; renin and aldosterone levels increase if volume expansion is corrected by diuretics or salt restriction. Although aldosterone levels may be within the reference range in some cases, they are probably not appropriately elevated for the degree of hyperkalemia.

Sodium wasting is absent, in contrast to renal PHA-I and mineralocorticoid deficient states.

Patients with PHA have hyperkalemia and decreased renal potassium excretion in the absence of glomerular insufficiency. Children with the chloride shunt syndrome (Spitzer-Weinstein syndrome) are typically hyperkalemic at presentation. Potassium excretion responds to sodium sulfate infusion but not to sodium chloride infusion.

Serum bicarbonate concentration is typically low, but this is a more variable finding in children and is observed in only one half of cases. Fractional excretion of bicarbonate is normal.

Hypercalciuria[14] has usually been overlooked as a biochemical feature of this disorder, although its presence has occasionally been recognized. Nephrolithiasis is unusual.

Renal concentration and dilution are normal. Urinary acidification after an ammonium chloride load is normal; however, most patients have a marked reduction in urinary acid excretion and in net acid excretion.

Secondary pseudohypoaldosteronism

The clinical presentation of secondary PHA in children is that of renal tubular resistance to aldosterone (ie, hyponatremia, hyperkalemia, and metabolic acidosis). The plasma aldosterone concentration is elevated, and fractional sodium excretion may be inappropriately high.

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Other Tests

Chest radiography may reveal an increased volume of liquid in the airways in patients with MTOD PHA-I, secondary to failure to absorb liquid from airway surfaces. These findings mimic cystic fibrosis.

Renal ultrasonography may show nephrocalcinosis in patients with PHA-I and nephrolithiasis in patients with PHA-II.

Renal biopsy findings in PHA-I are usually normal; however, hypertrophy of the juxtaglomerular apparatus has occasionally been reported.

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Contributor Information and Disclosures
Author

Alicia Diaz-Thomas, MD, MPH Assistant Professor of Pediatrics, University of Tennessee Health Science Center

Alicia Diaz-Thomas, MD, MPH is a member of the following medical societies: American Association of Clinical Endocrinologists, Endocrine Society, Pediatric Endocrine Society, Tennessee Medical Association

Disclosure: Nothing to disclose.

Coauthor(s)

Jose F Pascual-Y-Baralt, MD Chief, Division of Pediatric Nephrology, San Antonio Military Pediatric Center; Clinical Professor, Department of Pediatrics, University of Texas School of Medicine at San Antonio

Jose F Pascual-Y-Baralt, MD is a member of the following medical societies: American Academy of Pediatrics, American Society of Nephrology, American Society of Pediatric Nephrology, Association of Military Surgeons of the US, International Society of Nephrology

Disclosure: Nothing to disclose.

Chief Editor

Stephen Kemp, MD, PhD Former Professor, Department of Pediatrics, Section of Pediatric Endocrinology, University of Arkansas for Medical Sciences College of Medicine, Arkansas Children's Hospital

Stephen Kemp, MD, PhD is a member of the following medical societies: American Academy of Pediatrics, American Association of Clinical Endocrinologists, American Pediatric Society, Endocrine Society, Phi Beta Kappa, Southern Medical Association, Southern Society for Pediatric Research

Disclosure: Nothing to disclose.

Acknowledgements

Robert J Ferry Jr, MD Le Bonheur Chair of Excellence in Endocrinology, Professor and Chief, Division of Pediatric Endocrinology and Metabolism, Department of Pediatrics, University of Tennessee Health Science Center

Robert J Ferry Jr, MD is a member of the following medical societies: American Academy of Pediatrics, American Diabetes Association, American Medical Association, Endocrine Society, Pediatric Endocrine Society, Society for Pediatric Research, and Texas Pediatric Society

Disclosure: Eli Lilly & Co Grant/research funds Investigator; MacroGenics, Inc Grant/research funds Investigator; Ipsen, SA (formerly Tercica, Inc) Grant/research funds Investigator; NovoNordisk SA Grant/research funds Investigator; Diamyd Grant/research funds Investigator; Bristol-Myers-Squibb Grant/research funds Other; Amylin Other; Pfizer Grant/research funds Other; Takeda Grant/research funds Other

Lynne Lipton Levitsky, MD Chief, Pediatric Endocrine Unit, Massachusetts General Hospital; Associate Professor of Pediatrics, Harvard Medical School

Lynne Lipton Levitsky, MD is a member of the following medical societies: Alpha Omega Alpha, American Academy of Pediatrics, American Diabetes Association, American Pediatric Society, Endocrine Society, Pediatric Endocrine Society, and Society for Pediatric Research

Disclosure: Pfizer Grant/research funds P.I.; Tercica Grant/research funds Other; Eli Lily Grant/research funds PI; NovoNordisk Grant/research funds PI

Arlan L Rosenbloom, MD Adjunct Distinguished Service Professor Emeritus of Pediatrics, University of Florida College of Medicine; Fellow of the American Academy of Pediatrics; Fellow of the American College of Epidemiology

Arlan L Rosenbloom, MD is a member of the following medical societies: American Academy of Pediatrics, American College of Epidemiology, American Pediatric Society, Endocrine Society, Florida Pediatric Society, Pediatric Endocrine Society, and Society for Pediatric Research

Disclosure: Nothing to disclose.

Mary L Windle, PharmD Adjunct Associate Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Nothing to disclose.

References
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  2. Geller DS, Zhang J, Zennaro MC, et al. Autosomal dominant pseudohypoaldosteronism type 1: mechanisms, evidence for neonatal lethality, and phenotypic expression in adults. J Am Soc Nephrol. 2006. 17:1429-1436. [Medline].

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  4. Hogg R, Marks J, Marver D, Frolich J. Long-term observation in a patient with pseudohypoaldosteronism. Pediatr Nephrol. 1991. 5:205-210. [Medline].

  5. Huang CL, Cha SK, Wang HR, Xie J, Cobb MH. WNKs: protein kinases with a unique kinase domain. Exp Mol Med. 2007. 39:565-73. [Medline].

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  8. Sheridan MB, Fong P, Groman JD, et al. Mutations in the beta-subunit of the epithelial Na+ channel in patients with a cystic fibrosis-like syndrome. Hum Mol Genet. 2005. 14:3493-3498. [Medline].

  9. Adachi M, Asakura Y, Muroya K, Tajima T, Fujieda K, Kuribayashi E, et al. Increased Na reabsorption via the Na-Cl cotransporter in autosomal recessive pseudohypoaldosteronism. Clin Exp Nephrol. 2010 Apr 8. [Medline].

  10. Sartorato P, Lapeyraque AL, Armanini D, et al. Different inactivating mutations of the mineralocorticoid receptor in fourteen families affected by type I pseudohypoaldosteronism. J Clin Endocrinol Metab. 2003 Jun. 88(6):2508-17. [Medline].

  11. Boyden LM, Choi M, Choate KA, et al. Mutations in kelch-like 3 and cullin 3 cause hypertension and electrolyte abnormalities. Nature. 2012 Jan 22. 482(7383):98-102. [Medline]. [Full Text].

  12. Chang SS, Grunder S, Hanukoglu A, et al. Mutations in subunits of the epithelial sodium channel cause salt wasting with hyperkalaemic acidosis, pseudohypoaldosteronism type 1. Nat Genet. 1996 Mar. 12(3):248-53. [Medline].

  13. Mastrandrea LD, Martin DJ, Springate JE. Clinical and biochemical similarities between reflux/obstructive uropathy and salt-wasting congenital adrenal hyperplasia. Clin Pediatr (Phila). 2005. 44:809-812. [Medline].

  14. Perimenis P, Wemeau JL, Vantyghem MC. Hypercalciuria [French]. Ann Endocrinol (Paris). 2005. 66:532-539. [Medline].

 
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Renin angiotensin aldosterone system
Table. Characteristics of Primary Pseudohypoaldosteronism (Types I and II)
Details PHA Type I PHA Type II
Renal PHA-I MTOD PHA-I Early Childhood Hyperkalemia PHA-II
Synonyms Classic PHA of infancy, Cheek and Perry syndrome, autosomal dominant PHA-I, subtype 4 RTA IV Autosomal recessive PHA-I Subtype 5 RTA IV Adolescent hyperkalemic syndrome, Spitzer-Weinstein syndrome, subtype 3 RTA IV Gordon syndrome, mineralocorticoid-resistant hyperkalemia, chloride shunt syndrome
Age Newborn period, infancy Newborn period, infancy Infancy, childhood Childhood Adulthood
Organs Kidney Kidney, sweat glands, salivary glands, colon Kidney Kidney Kidney
Genetics Autosomal dominant, sporadic Autosomal recessive, sporadic Unknown Unknown Autosomal dominant, sporadic
Mechanism Heterozygous MLR mutations (possible) Defective Na transport in organs that contain ENaC Maturation disorder in the number or function of aldosterone receptors Chloride shunt Chloride shunt
Serum potassium High High High High High
Acidosis Present Present Present Present Present
Serum sodium Normal or low Normal or low Normal Normal Normal
PRA* High High Normal or high Normal or low Low
Aldosterone High High Normal or high Normal or low Low
Blood volume Normovolemia, hypovolemia Normovolemia, hypovolemia Normovolemia Hypervolemia Hypervolemia
Blood pressure Normal or low Normal or low Normal or low Normal or low Normal or low
GFR Normal Normal Normal Normal Normal
Salt wasting Renal Renal, sweat or salivary glands, colon Absent Absent Absent
Hypercalciuria Present or absent Absent Absent Present Present
Therapy Na supplementation, K-binding resins High-Na, low-K diet, K-binding resins, hydrochlorothiazide Na bicarbonate, K-binding resins Dietary Na restriction, hydrochlorothiazide Dietary Na restriction, hydrochlorothiazide
Prognosis Outgrow by age 2 y Lifelong therapy Outgrow by age 5 y Lifelong therapy Lifelong therapy
*Plasma renin activity.



ENaC = epithelial sodium channel; GFR = glomerular filtration rate; MLR = mineralocorticoid receptor gene; PHA = pseudohypoaldosteronism; RTA = renal tubular acidosis.



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