Chapter 474. Renal Tubular Disorders

The glomeruli filter approximately 150 liters of ultrafiltrate daily that are delivered to the renal tubules. The renal tubules reabsorb organic solutes, salt, and water to maintain a constant extracellular fluid volume and composition. In addition, organic anions and cations, which are protein bound and not filtered by the glomerulus, are secreted by the proximal tubule. The final urine contains about one hundredth of the volume and sodium as that in the original glomerular filtrate, but contains all waste products. There are 12 nephron segments that have different transport properties to perform this task. Disorders of tubular function can be due to inherited defects in transporters or mutations in factors that regulate transport, or result from inherited or acquired disorders that cause tubular injury. Renal transport disorders can be mild with little to no clinical consequences, or life threatening, depending on the transporters and nephron segments affected.

Fanconi syndrome is a generalized proximal tubule transport disorder.1 The proximal tubule is responsible for the reabsorption of all filtered glucose and amino acids, and 80% of the filtered bicarbonate and phosphate. Patients with Fanconi syndrome have hypophosphatemia, hypokalemia, and hyperchloremic metabolic acidosis.

Pathophysiology

The luminal fluid entering the proximal tubule is an ultrafiltrate of plasma. Most solutes are transported across the apical membrane in conjunction with sodium. The driving force for solute transport is the low intracellular sodium generated by the basolateral Na+-K+-ATPase. A generalized decrease in proximal tubular transport could result from a primary injury to the Na+-K+-ATPase pump or a decrease in intracellular adenosine triphosphate (ATP) that fuels the pump. Theoretically, an increase in the permeability of the proximal tubule paracellular pathway could result in Fanconi syndrome, but this theory has been discounted. Although the cellular basis for most causes of Fanconi syndrome has not been determined, most studies have demonstrated that the proximal tubule transport defect in Fanconi syndrome is the result of a decrease in intracellular ATP.

Differential Diagnosis

The causes for Fanconi syndrome are listed in Table 474-1. Diagnosis of Fanconi syndrome is usually made due to the presence of symptoms, including failure to thrive, severe rickets, and sometimes bouts of polydipsia, polyuria, and dehydration. Laboratory findings include hypophosphatemia, hypokalemia, and acidosis.2 Evaluation of the urine reveals glucosuria, generalized aminoaciduria, and hyperphosphaturia, despite the hypophosphatemia, a stimulus that increases proximal tubule phosphate absorption.

Among the causes of Fanconi syndrome, cystinosis, an autosomal-recessive disorder, is the most common inherited cause of Fanconi syndrome in children.3 Further discussion of this disorder is provided in Chapter 143. Children with cystinosis are usually well for the first 6 months of life. Shortly thereafter, they develop polydipsia, polyuria, constipation, unexplained fevers, and failure to thrive. Patients with cystinosis have hypophosphatemic rickets due to renal phosphate waisting. These early signs and symptoms are the result of Fanconi syndrome. Patients with cystinosis develop a progressive decrease in renal function and end-stage renal disease by 10 years of age unless treated with cysteamine.4 Endocrine disorders, including hypothyroidism and diabetes mellitus, can be seen in older children. Cystine accumulates in the cornea, leading to photophobia and painful corneal ulcerations. Older patients with cystinosis who receive a renal transplant can develop retinopathy, cerebral atrophy, central nervous system dysfunction, myopathy, and respiratory dysfunction. Gastrointestinal disturbances, including swallowing difficulties, are also common in older children and adults.

Two milder forms of cystinosis have been described. In the late onset form of the disease, patients present in adolescence and have a slower rate of progression of renal disease. There is also a benign form of cystinosis, which presents with cystine crystals in the cornea seen on slit lamp exam, but none of the other manifestations of cystinosis exist.

Treatment of Cystinosis

Cysteamine therapy has proven to be very effective in slowing or preventing the deterioration in renal function in cystinosis. Cysteamine also improves the growth in patients with cystinosis. Cysteamine enters the lysosome, where it forms a mixed disulfide and the cysteine-cysteamine complex exits across the lysosomal membrane via the lysine carrier. Cysteamine eye drops effectively dissolve corneal cystine crystals. However, cysteamine does not prevent or affect the severity of Fanconi syndrome. Cysteamine also appears to be effective in treating many of the late manifestations of the disease.

Treatment of Fanconi Syndrome

Treatment of Fanconi syndrome is focused at the treatment of the primary disease. In patients with hereditary fructose intolerance, galactosemia, or tyrosinemi, removal of the nonmetabolized sugar or amino acid from the diet ameliorates the proximal tubular transport disorder. Patients with a toxin-induced form of the disease should avoid the offending agent. If Fanconi syndrome is secondary to heavy metal toxicity or Wilson disease, chelation therapy should be initiated. If this approach is unsuccessful, therapy consists of replacement of urinary solute losses. Hypophosphatemia and rickets can be successfully treated with oral phosphate supplements and 1,25-dihydroxycholecalciferol. Treatment of the proximal renal tubular acidosis (RTA) is discussed later in the chapter. The amount of solute replacement is dependent on the extent of the proximal tubular injury and the filtered load presented to the proximal tubule. In some patients with severe proximal tubule injury, reducing the filtered solute load by decreasing the glomerular filtration rate with indomethacin makes oral replacement more tolerable.

The kidney serves two functions to maintain acid-base balance. The first is to reclaim the filtered load of bicarbonate, and the second is to excrete the acid that is generated from metabolism (see Chapter 466).

Pathophysiology

In growing children, the kidney must also excrete the acid generated from new bone formation. Renal tubular acidosis (RTA) is due to impaired renal acidification and results in a hyperchloremic metabolic acidosis.5 The proximal tubule reabsorbs most of the filtered load of bicarbonate. Proximal tubule luminal proton secretion is predominantly via an apical membrane Na+/H+ exchanger. One third of proton secretion is via an apical membrane H+-ATPase. The conversion of CO2 and H2O to H2CO3 is facilitated by carbonic anhydrase, which is found on the luminal and basolateral membrane as well as in the cytoplasm. Bicarbonate exits the cell via a sodium-dependent transporter designated NBC for sodium bicarbonate cotransporter.

The serum bicarbonate concentration is maintained at a constant level, which is set by the bicarbonate reabsorptive capacity of the kidney. Ingestion or infusion of bicarbonate will only transiently increase the serum bicarbonate concentration above this threshold. The serum bicarbonate will quickly fall back to its original level as the excess bicarbonate is excreted in the urine. Because the proximal tubule is responsible for the reabsorption of 80% of the filtered bicarbonate, it plays a major role in setting the bicarbonate threshold and serum bicarbonate level.

Diagnosis

In proximal renal tubular acidosis (RTA), there is a decrease in proximal tubule bicarbonate reabsorptive capacity, resulting in a low bicarbonate threshold.5 Because the serum bicarbonate concentration is lower than normal, the concentration of bicarbonate in the glomerular ultrafiltrate delivered to the tubules will also be lower. Thus, patients with proximal RTA can reabsorb the filtered bicarbonate, albeit at a lower serum bicarbonate level than normal. Patients with proximal RTA maintain constant serum bicarbonate and do not have bicarbonaturia unless bicarbonate is administered. At their respective bicarbonate thresholds, both normal individuals and patients with proximal RTA have no bicarbonate in the tubular fluid delivered to the distal nephron. Because the distal tubule is intact, patients with proximal RTA can excrete urine with a pH less than 5.5. Hypokalemia often occurs in proximal RTA and results from the decrease in potassium reabsorption seen with metabolic acidosis.

Isolated proximal RTA can be due to an autosomal-recessive mutation in the basolateral sodium bicarbonate cotransporter. Patients with this disorder usually have visual problems, including glaucoma, band keratopathy, and cataracts, as well as short stature and intellectual impairment. Proximal tubular acidosis usually occurs in conjunction with Fanconi syndrome. As with Fanconi syndrome, patients with isolated proximal RTA present with failure to thrive.

Treatment

Therapy of proximal renal tubular acidosis (RTA) is quite difficult. More than 10 to 15 mEq/kg/d of alkali may need to be administered, which may only result in a modest improvement in the serum bicarbonate concentration. In addition, sodium bicarbonate or citrate will result in delivery of bicarbonate or citrate to the distal nephron, resulting in an increase in urinary potassium excretion. Bicarbonate or citrate should be administered as a mixture of sodium and potassium salts, and the serum potassium needs to be monitored closely. Reducing the glomerular filtration rate with indomethacin will decrease the filtered load of bicarbonate delivered to the tubules and may make alkali therapy more successful.

The distal nephron is responsible for secreting the acid generated from metabolism and during bone formation in growing children. Proton secretion across the luminal membrane is via an H+-ATPase, and under some circumstances, an H+-K+-ATPase, which secretes a proton and simultaneously reabsorbs a potassium ion. The intracellular bicarbonate formed with the aid of carbonic anhydrase exits the cell via a Cl-/HCO-3 exchanger on the basolateral membrane. Distal renal tubular acidosis (RTA) is due to a failure of normal distal tubule function.

Pathophysiology

Primary distal renal tubular acidosis (RTA) can be due to an autosomal-dominant or -recessive mutation in the basolateral Cl-/HCO-3 exchanger that is responsible for bicarbonate exit from the cell.6,7 The autosomal-recessive form is more severe and can be associated with a hemolytic anemia. Autosomal-recessive distal RTA can be the result of a mutation in apical membrane the H+-ATPase. Because the H+-ATPase is responsible for acidification of the cochlear endolymph, these patients have hearing loss. Distal RTA can also be secondary to collagen vascular diseases such as Sjögren syndrome or drugs like amphotericin B, as listed in Table 474-2. In amphotericin B therapy-induced distal RTA, proton secretion is intact, but the secreted protons diffuse back into cells through a channel created by the drug. A combined proximal and distal RTA can be seen in patients with osteopetrosis due to a mutation in carbonic anhydrase, which is necessary for both proximal and distal acidification.

Diagnosis

Children with distal renal tubular acidosis (RTA) present with short stature and can have rickets and nephrocalcinosis. Laboratory evaluation reveals a hyperchloremic metabolic acidosis and hypokalemia. The hypokalemia can be severe enough to cause muscle weakness, cramps, and paralysis. The chronic metabolic acidosis results in bone demineralization and hypercalciuria. Citrate is an important factor increasing the solubility of urinary calcium, and citrate absorption by the proximal tubule increases in response to the acidosis and hypokalemia. This results in decreased calcium solubility in the filtrate and nephrocalcinosis. Because the distal nephron is the segment responsible for final urinary acidification, patients with distal RTA are unable to excrete urine with a pH less than 5.5.

Treatment

Distal renal tubular acidosis (RTA) is treated by providing alkali in an amount equivalent to the protons normally secreted by the distal nephron. A combination of sodium and potassium citrate or bicarbonate of 3 to 5 mEq/kg/d in three to four divided doses in children and 1 mEq/kg/d in adults is sufficient to normalize the serum bicarbonate levels and prevent hypocitraturia. Children with primary distal RTA who are treated with alkali grow normally. Untreated patients develop progressive nephrocalcinosis and renal insufficiency. In children with distal RTA who present with severe hypokalemia and acidosis, potassium must be corrected prior to the initiation of alkali therapy to prevent a further decrease in the serum potassium levels, which can be life threatening.

Renal tubular acidosis (RTA) associated with hyperkalemia has been designated type 4 RTA.

Pathophysiology

The cortical collecting duct has apical sodium and potassium channels and an H+-ATPase. The driving force for sodium absorption across the sodium channel is generated by the Na+-K+-ATPase on the basolateral membrane. Sodium absorption results in a lumen-negative transepithelial potential difference and provides a driving force for luminal potassium secretion by the principal cell and proton secretion by the neighboring intercalated cell. The reabsorption of both sodium and secretion of potassium and protons are stimulated by mineralocorticoids. Mineralocorticoid deficiency results in hyperkalemia and hyperchloremic metabolic acidosis. Hyperkalemia results in lower ammonia production by the proximal tubule, which exacerbates the metabolic acidosis by limiting urinary buffer excretion.

Diagnosis

The most common causes for type 4 renal tubular acidosis (RTA) are obstructive uropathy and interstitial renal disease. In these disorders, aldosterone secretion is normal, but there is damage to the cortical collecting tubule and resistance to the action of aldosterone. In these disorders, the hyperkalemia is out of proportion to the severity of the renal insufficiency.

Several disorders associated with either mineralocorticoid deficiency or a resistance to the action of mineralocorticoids may cause type 4 RTA. These are discussed further in Chapter 534; and include Addison disease and decreases in mineral corticoid deficiency, such as seen with 21-hydroxylase deficiency, the most common form of adrenogenital syndrome. Males with 21-hydroxylase deficiency do not have ambiguous genitalia and can present with dehydration resulting from renal salt wasting in the first 2 months of life. Laboratory evaluation reveals hyponatremia, hyperkalemia, and metabolic acidosis. Converting enzyme inhibitors and chronic heparin administration can result in hypoaldosteronism. Hyporeninemic hypoaldosteronism in children can be the result of drugs such as cyclosporin, nonsteroidal anti-inflammatory agents, and tubulointerstitial disease. Adults can develop hyporeninemic hypoaldosteronism as a consequence of chronic diabetes mellitus.

Type 4 RTA is also seen in patients with type 1 pseudohypoaldosteronism. There are two forms of type 1 pseudohypoaldosteronism. Both are characterized by unresponsiveness of the collecting tubule to aldosterone.8 In the more severe autosomal-recessive form, there is a mutation of the amiloride-sensitive sodium channel in the cortical collecting tubule causing loss of channel activity. The disease presents in neonates with salt wasting and volume depletion. Children with this disorder fail to thrive and have numerous pulmonary infections. The sweat chloride levels are elevated, and this disorder has been mistaken for cystic fibrosis. The autosomal-dominant or sporadic form is due to a mutation in the mineralocorticoid receptor gene. The dominant form is milder and presents later in life. In both forms of type 1 pseudohypoaldosteronism, the serum aldosterone levels and plasma renin activities are elevated. Drugs can also cause type 4 RTA. Amiloride and triamterene block the apical sodium channel on the cortical collecting tubule, and spironolactone is an aldosterone receptor antagonist.

Type 2 pseudohypoaldosteronism, or Gordon syndrome, is an autosomal-dominant disorder characterized by hyperkalemia, RTA, and hypertension. In Gordon syndrome, there is a mutation in either WNK1 or 4, which are intracellular kinases that regulate the distal convoluted tubule thiazide sensitive NaCl cotransporter and the distal tubule apical potassium channel.9,10 WNK 1 and 4 mutations increase NaCl cotransporter activity and inhibit potassium secretion leading to increased sodium transport and decreased delivery of sodium to the cortical collecting tubule, where sodium transport is necessary to generate the electrochemical gradient for potassium and proton secretion. There is evidence that WNK1 and 4 regulate other transporters as well as transport across the paracellular pathway.

Treatment

Treatment of type 4 renal tubular acidosis (RTA) is focused at finding the cause and treating primary disease. Patients with glucocorticoid and mineralocorticoid deficiency must receive replacement therapy. Most cases of type 4 RTA are due to obstructive uropathy. Sodium bicarbonate therapy at 3 to 5 mEq/kg in children and 1 mEq/kg in adults corrects the acidosis and improves the hyperkalemia. Dietary potassium restriction is often required. Patients with type 1 pseudohypoaldosteronism should be treated with salt supplements in addition to treatment of hyperkalemia and metabolic acidosis. Gordon syndrome is treated with sodium restriction and thiazide diuretics.

Glucose is reabsorbed across the apical membrane of the proximal tubule via a Na+-glucose cotransporter and exits across the basolateral membrane by facilitated diffusion through a Na+-independent transporter. There are two Na+-glucose cotransporters on the apical membrane of the proximal tubule. The Na+-glucose cotransporter in the early proximal tubule is a low-affinity, high-capacity transporter that reabsorbs one sodium for every glucose molecule. This transporter has been designated SGLT2. In contrast, SGLT1 is a high-affinity, low-capacity transporter that transports two sodium ions for each glucose molecule. It is located in the late proximal tubule and in the intestine, where it transports both glucose and galactose.

Primary renal glucosuria is a benign autosomal-recessive condition due to a mutation in SGLT2, which is usually detected on a routine urinalysis, where there is glucosuria in the absence of hyperglycemia.11 People with this condition do not have polyuria, polydipsia, or hypoglycemia. No therapy is indicated, and there is not an increased risk of developing diabetes mellitus. Glucose-galactose malabsorption results from a mutation in SGLT1. In this autosomal-recessive disorder, patients present with watery diarrhea due to the inability to transport dietary glucose and galactose (see Chapter 408). The stools are acidic and contain sugar. The patients may also have glucosuria because this transporter is in the late proximal tubule. The diarrhea disappears when the infants are fed a glucose and galactosefree diet.

Amino acids are filtered by the glomerulus and reabsorbed by the proximal tubule. As with glucose, amino acid uptake across the apical membrane is sodium dependent, and amino acids exit the cell by facilitated diffusion. Aminoaciduria can result from an increase in the filtered load of amino acids presented to the proximal tubule, as can occur after a large protein meal, or from an inherited metabolic defect that increases the serum concentration of specific amino acids. These are discussed in detail in Chapter 143. Cystinuria is an autosomal-recessive disorder, which is the most common inherited defect in renal tubular amino acid transport, resulting in increased excretion of lysine, arginine, ornithine, and cystine.12 The limited solubility of cystine in urine results in renal calculi. Stones can form at any age but are most prevalent in the second and third decade of life. Recurrent stones produce progressive renal damage. Hartnup disorder is an autosomal-recessive disorder of neutral amino acid transport in both the intestine and kidney. Plasma levels of neutral amino acids are either normal or low. Most patients with Hartnup disorder are asymptomatic; however, some patients develop pelagralike symptoms, including a “sunburnlike” rash on exposed skin surfaces, ataxia, and behavioral and/or psychologic disturbances.

Dent disease is an X-linked recessive disorder characterized by low-molecular-weight proteinuria, nephrocalcinosis, recurrent renal stones, and progressive renal insufficiency.13,14 Some patients with Dent disease have rickets, phosphaturia, glucosuria, and aminoaciduria. Dent disease is due to a defect in a renal chloride channel designated as CLC-5. CLC-5 is expressed in endosomes, where it mediates chloride entry to dissipate the positive charge caused by H+-ATPase–mediated endosomal acification. A defect in CLC-5 impairs endosomal acidification, which inhibits proximal tubule transport by affecting membrane trafficking and protein absorption. Patients with Dent disease have low-molecular-weight proteinuria and thus excrete high levels of β-2 microglobulin, α-1 microglobulin, and retinol-binding protein. Treatment is directed at preventing renal calculi. Patients should have adequate fluid intake and eat a low sodium diet. A thiazide diuretic may be helpful in decreasing renal calcium excretion.

X-linked hypophosphatemia (XLH) is a sex-linked dominant disorder of proximal tubule phosphate transport and abnormal 1,25-dihydroxy vitamin D metabolism. XLH is the most common inherited cause of rickets.15

Pathophysiology

Hypophosphatemia stimulates proximal tubule phosphate reabsorption by increasing the number of Na+-dependent phosphate transporters on the proximal tubule. In X-linked hypophosphatemia (XLH), there is impaired proximal tubule phosphate transport despite the hypophosphatemia.15,16 The phosphate transporter is normal, but there is impaired trafficking of the transporter to the apical membrane. Clues to the pathogenesis of X-linked hypophosphatemia have come from the Hyp mouse, which has the same abnormalities in vitamin D metabolism and phosphate transport as patients with X-linked hypophosphatemia. Transplantation of a Hyp mouse kidney into a normal control mouse results in normal phosphate transport. Transplantation of a normal mouse kidney into a Hyp mouse results in renal phosphate wasting. Thus, there is a humoral factor that impairs proximal tubule phosphate transport and is responsible for the abnormal vitamin D metabolism.

The gene, which is mutated in patients with X-linked hypophosphatemia and in Hyp mice, is PHEX (phosphate regulating endopeptidase on the X chromosome).15,16 Patients and mice with XLH have elevated levels of fibroblast growth factor 23 (FGF-23). FGF-23 inhibits proximal tubule phosphate transport and results in a decrease in serum 1,25-dihydroxy vitamin D levels. Patients with autosomal-dominant hypophosphatemia have a mutation in FGF-23 that impairs its degradation of FGF-23, resulting in high serum levels of the active hormone. Patients with tumor-induced osteomalacia have high levels of FGF-23 due to enhanced tumor production. In both autosomal-dominant hypophosphatemia and tumor-induced hypophosphatemia, there is hypophosphatemia and abnormal vitamin D metabolism.

Diagnosis

The diagnosis of X-linked hypophosphatemia (XLH) is established by concordance of the family history, clinical and roentgenographic findings of rickets, consistent laboratory data, and exclusion of other causes of hypophosphatemia. Diagnosis is further confirmed by identification of the PHEX mutation. Patients with XLH present with rickets and short stature at 12 to 18 months of age. Males tend to be more severely affected than females. Patients with XLH have hypophosphatemia and elevated alkaline phosphatase levels. 1,25-Dihydroxy vitamin D levels are normal, which is inappropriate for a patient with hypophosphatemia because hypophosphatemia stimulates 1,25-dihydroxy vitamin D production. Patients with XLH have reduced 25-hydroxyvitamin D-1-α -hydroxylase and higher levels of 1,25-hydroxyvitamin D-24 hydroxylase, the enzyme that converts the active hormone to an inactive metabolite. As patients grow older, they have multiple dental abscesses and bone pain.

Treatment

The rickets is resistant to physiologic replacement with vitamin D. Treatment of X-linked hypophosphatemia (XLH) includes administration of calcitriol (25-70 ng/kg/d) and elemental phosphorus (0.25-3 g daily, beginning at a dose of 30 mg/kg/d and increasing to 70 mg/kg/d) administered in four to six divided daily doses, depending on age, size, compliance, and response to therapy. Vitamin D and phosphate therapy can produce nephrocalcinosis, with resultant renal tubular acidosis (RTA) and progressive renal injury.

Bartter syndrome is an autosomal-recessive disorder of chloride absorption in the thick ascending limb of the loop of Henle.

Pathophysiology

The thick ascending limb is the nephron segment that reabsorbs about 30% of the filtered NaCl. The thick ascending limb has an apical electroneutral Na/K/2Cl cotransporter, the transporter inhibited by furosemide, on the apical membrane. The potassium recycles across the apical membrane, resulting in a lumen-positive potential difference and a driving force for the paracellular absorption of magnesium and calcium. The transported sodium exits across the basolateral membrane via the Na+-K+-ATPase and chloride exits via a chloride channel that requires a cofactor called barttin.17 Bartter syndrome I is due to mutations in the SLC12A1 gene coding for in the Na/K/2Cl cotransporter; Bartter syndrome II is due to mutations in the ROMK1 gene coding for the apical potassium channel. Two other forms of Bartter syndrome are caused by defects associated with the basal chloride channel in the thick ascending limb. Bartter syndrome III is due to mutations in the gene (CLCNKB) encoding the channel itself. Bartter syndrome IV is due to mutations in the gene (CLCNKA) encoding barttin, that controls the chloride channel. Mutation in barttin is associated with sensory neural deafness. Mutations in any of the transporters that cause Bartter syndrome or inhibition of the Na/K/2Cl cotransporter with furosemide results in a decrease in the lumen-positive potential difference to zero. This contributes to the hypokalemia and can increase urinary magnesium and calcium excretion.

Diagnosis

Bartter syndrome usually presents in the first year of life with failure to thrive.18 There is often a history of polyhydramnios and prematurity. Infants and children have polydipsia and polyuria due to a renal concentrating defect. Older children can have a history of constipation, salt craving, and often complain of muscle cramps. These symptoms are the result of hypokalemia and chronic volume depletion due to renal salt wasting.

Patients with Bartter syndrome have a hypokalemic metabolic alkalosis and may also have hyponatremia and hypomagnesemia. The hypokalemic alkalosis is due to volume depletion, with high serum aldosterone levels stimulating collecting tubule potassium and proton secretion in the face of distal sodium delivery. Their blood pressure is usually normal, but they may have orthostatic changes in their blood pressure and pulse. Plasma renin, aldosterone levels, and urinary prostaglandin excretion are elevated as a result of volume depletion.

Extrarenal volume depletion is a possible reason for low blood pressure, high aldosterone excretion, and potassium loss, but in this case, the kidneys retain sodium and chloride, and urinary chloride concentrations should be low. High urine chloride levels with low blood pressure, high aldosterone secretion, and high urinary potassium levels are found only with long-term diuretic use and Bartter or Gitelman syndrome. Patients with Bartter syndrome usually have very high urinary calcium levels (the urinary calcium/creatinine ratio is usually > 0.40), which leads to nephrocalcinosis. However, some patients with chloride channel defects have normal rates of calcium excretion.

Treatment

Bartter syndrome therapy is centered on replacement of electrolytes lost in the urine. Neonates and infants require NaCl and KCl to increase the intravascular volume and correct the hypokalemia. Older children increase their salt intake themselves, and sodium supplements are usually not necessary. Magnesium supplementation should be provided in those patients with hypomagnesemia. The increase in renal prostaglandin production exacerbates urinary sodium losses. Indomethacin therapy can be very beneficial, but gastritis and gastrointestinal bleeding is a potential complication that must be monitored.

Gitelman syndrome is an autosomal-recessive renal salt wasting disorder, which results in volume contraction and a hypokalemic alkalosis that is often confused with Bartter syndrome.19 All patients studied with Gitelman syndrome have an inactivating mutation in the gene for the thiazide-sensitive NaCl cotransporter in the distal convoluted tubule. Unlike Bartter syndrome, patients with Gitelman are usually born at term, there is no history of polyhydramnios, and patients usually present in the first decade of life. Patients with Gitelman syndrome do not have failure to thrive and usually present in late childhood. Although hypomagnesemia can be seen in Bartter syndrome, it is almost invariably present in Gitelman syndrome. The most profound difference is in the urinary calcium excretion, which is low in Gitelman syndrome (calcium/creatinine ratio is > 0.1) but is usually elevated in Bartter syndrome. Most patients with Gitelman syndrome have a history of tetany and muscle cramps secondary to the hypomagnesemia. The treatment of Gitelman syndrome is to provide magnesium and potassium supplements to replace that lost in the urine. Patients with Gitelman syndrome have chronic volume depletion and increase their salt intake to replete their urinary losses.

Familial hypomagnesemia with hypercalciuria and nephrocalcinosis (FHHNC) is a rare autosomal-recessive disorder. The lumen-positive potential difference due to luminal potassium secretion in the thick ascending limb provides a driving force for paracellular magnesium and calcium absorption. This occurs because of a protein in the tight junction called paracellin-1 or claudin-16, which confers the unique paracellular permeability properties. Mutations in claudin-16 result in a decrease in paracellular magnesium and calcium absorption and hypomagnesemia with hypercalciuria and nephrocalcinosis and progressive renal disease.20

Liddle syndrome is an autosomal-dominant disorder characterized by hypertension, hypokalemia, and metabolic alkalosis. These are characteristic features of hyperaldosteronism, where the high serum mineralocorticoid levels cause augmented collecting tubule sodium transport via the epithelial sodium channel designated ENaC. The increase in sodium transport results in volume expansion and hypertension. The augmented luminal sodium transport via the sodium channel results in a more lumen-negative potential difference, which increases potassium and proton secretion, resulting in hypokalemia and metabolic alkalosis. However, patients with Liddle syndrome have low plasma aldosterone levels.

Liddle found that patients with this disorder had normalization of their blood pressure and the electrolyte disorder by treatment with a low sodium diet and the sodium channel blocker, triamterene. There was no response to spironolactone, an aldosterone receptor antagonist. Liddle postulated that the hypertension and electrolyte disorders were due to an intrinsic renal tubular defect in sodium absorption. The molecular basis for Liddle syndrome has been clarified with the cloning of ENaC, the epithelial sodium channel. All patients with Liddle syndrome have had a defect in ENaC. The number of sodium channels on the apical membrane is dependent on the rate at which they are inserted and removed. In Liddle syndrome, the mutations are in a portion of the channel necessary for sodium channel removal.21 Thus, there is an increase in the density of sodium channels on the apical membrane. The sodium channel is like a gate that can be open or closed. In Liddle syndrome, there is also evidence that the sodium channel has a greater probability of being open. Both factors result in augmented sodium transport and volume expansion, validating Liddle hypothesis. The augmented collecting tubule sodium transport leads to the volume expansion and low plasma renin and aldosterone levels and the hypertension in these patients. The lumen-negative potential difference resulting from increase ENaC activity, and density results in high rates of potassium and proton secretion, causing the hypokalemic alkalosis seen in Liddle syndrome.

Patients with apparent mineralocorticoid excess have hypertension and hypokalemic metabolic alkalosis, but have low plasma renin and aldosterone levels. The serum cortisol concentration is greater than that of aldosterone. Both cortisol and aldosterone bind to the mineralocorticoid receptor in the collecting tubule. Cortisol would have the same effect as aldosterone if it were not for 11β-hydroxysteroid dehydrogenase, which converts cortisol to cortisone, an inactive metabolite. Patients with 11β-hydroxysteroid dehydrogenase deficiency, an autosomal-recessive disorder, have apparent hyperaldosteronism due to the mineralocorticoid effect of cortisol. The diagnosis is confirmed by finding low levels of cortisone/cortisol metabolites in the urine. 11β-Hydroxysteroid dehydrogenase can also be inhibited by glycyrrhizic acid, which is in black licorice and chewing tobacco.

Glucocorticoid-remediable aldosteronism is a rare autosomal-dominant disorder where the patient appears to have primary hyperaldosteronism. These patients have hypertension and usually have hypokalemia and metabolic alkalosis. The serum aldosterone levels are high, and the renin levels are suppressed. Aldosterone synthase, which is regulated by angiotensin II and potassium, and 11β-hydroxylase, which is regulated by adrenocorticotrophic hormone (ACTH), are normally found in tandem on chromosome 8. Gene duplication and a cross-over event results in a hybrid gene where the regulatory portion of 11β-hydroxylase is fused to aldosterone synthase. ACTH regulates aldosterone production in this disorder, causing high plasma aldosterone levels. Patients with glucocorticoid-remediable hypertension have improvement in their blood pressure and the associated electrolyte disturbances with the administration of glucocorticoids, which decreases ACTH secretion.