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.
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.
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.
Glycogen storage disease
Hereditary fructose intolerance
Pyruvate carboxylase deficiency
Mitochondrial phosphoenolpyruvate carboxykinase deficiency
Cytochrome C oxidase deficiency
Aceyl-CoA dehydrogenase deficiency
Vitamin D deficiency (can be inherited)
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.
PROXIMAL RENAL TUBULAR ACIDOSIS
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).
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.
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.
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.
CLASSICAL DISTAL RENAL TUBULAR ACIDOSIS
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.
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.
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.
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 WITH HYPERKALEMIA
Renal tubular acidosis (RTA) associated with hyperkalemia has been designated type 4 RTA.
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 hyper-chloremic metabolic acidosis. Hyperkalemia results in lower ammonia production by the proximal tubule, which exacerbates the metabolic acidosis by limiting urinary buffer excretion.