**5. Conclusions**

98 Basic Nephrology and Acute Kidney Injury

excess, chronic liquorice ingestion and carbenoxolone therapy. Treatment of Liddle's syndrome consists of sodium restriction and potassium-sparing diuretics, like amiloride and triamterene, which directly inhibit the ENaC. There is no benefit of using mineralocorticoid antagonists, such as spironololactone, as in this syndrome the up

This autosomal recessive syndrome is characterised by hypertension, hypokalemia, metabolic alkalosis, with suppressed renin and aldosterone levels. Hypercalciuria and nephrocalcinosis may occur. Typically, an affected child will have polyuria and polydipsia, low birth weight and faltering growth. The molecular basis for this syndrome is secondary to mutations in the *HSD11B2* gene encoding the enzyme 11-betahydroxysteroid dehydrogenase 2 (Wilson, et al., 1995). This enzyme normally inactivates cortisol to cortisone, preventing overstimulation of the mineralocorticoid receptor (MR). Mutations lead to an excess of cortisol which is able to have a mineralocorticoid–like affect and stimulate sodium retention, volume expansion and renin and aldosterone

This syndrome may be mimicked by licorice ingestion (Walker &Edwards, 1994). Licorice contains glycyrrhizinic acid, which inhibits 11-beta-HSD2. Carbenoxolone also inhibits this enzyme. The treatment of choice for AME is a mineralocorticoid receptor blocker such as

In a family with familial hypertension, hypokalemia and suppressed aldosterone levels, heterozygous mutations were identified in the NR3C2 gene encoding the mineralocorticoid receptor (MR), resulting in a gain of function (Geller, et al., 2000). Additionally, the specificity of the MR was altered such that progesterone was able to bind to it and activate it. Thus pregnant females in this family presented with severe

Glucocorticoid remediable hypertension (also known as familial hyperaldosteronism type I) is characterised by autosomal dominant hypertension, low plasma renin levels, normal plasma aldosterone levels and hypokalemia (McMahon &Dluhy, 2004). The age of onset of hypertension is usually in teenage years, but may be in adulthood. Hypertension is typically refractory to treatment. The molecular basis for disease is secondary to a chimeric gene, involving CYP11B1, encoding 11-beta-hydroxylase and CYP11B2, encoding aldosterone synthase. The chimeric gene results in aldosterone synthesis under the regulatory control of ACTH, resulting in hyperaldosteronism (Lifton, et al., 1992). Thus, the causative mutation affects the cortical collecting duct indirectly, and therefore this is not a "tubulopathy". Traditionally, diagnosis has been made by a dexamathasone suppression test, which results in reduced plasma aldosterone levels. A specific urinary profile of 18 oxotetrahydrocortisol and 18 hydrocortisol may be sought, but molecular genetic testing also allows a definitive diagnosis. Treatment with glucocorticoids (using shorter acting agents prednisone or hydrocortisone) is often effective, but additional antihypertensives may be needed

regulation of ENaC is not mediated by aldosterone.

suppression.

hypertension.

as adjuncts.

spironolactone or epleronone.

**4.6 Syndrome of Apparent Mineralocorticoid Excess (AME)** 

**4.7 Activating mutations of the mineralocorticoid receptor** 

**4.8 Glucocorticoid remediable hypertension** 

The ability to provide a definitive molecular genetic diagnosis to a patient with an inherited tubulopathy allows a confidence in the diagnosis, despite phenotypic variabilities (which may be intrafamilial). A molecular genetic diagnosis also allows the targeted pharmacology to be employed to achieve normalization / improvement in symptoms, serum biochemistry and blood pressure. The discovery of renal tubular transporters and channels has allowed significant gains in our understanding of this group of renal diseases, with families with inherited tubulopathies providing the ultimate "animal model". Although perhaps uncommon, the discovery of the molecular players of salt and water handling within the nephron has allowed applications to be made to sufferers of "essential hypertension".

It is certainly true that a patient with hypokalemia / metabolic alkalosis, no matter how mild, warrants further evaluation to determine the underlying cause.
