There are many developmental, hereditary, or metabolic defects of the kidneys and collecting system. The clinical consequences include metabolic abnormalities, failure to thrive, nephrolithiasis, renal glomerular or tubular dysfunction, and chronic renal failure. Table 24–4 lists some of the major entities.
Table 24–4.Inherited or developmental defects of the urinary tract. |Favorite Table|Download (.pdf) Table 24–4.Inherited or developmental defects of the urinary tract.
Cystic diseases of genetic origin
Other syndromes that include either form
Medullary cystic kidney disease
Glomerulocystic kidney disease
Renal cysts and diabetes (HNF1-β)
Dysplastic renal diseases
Cystic renal dysplasia
Multicystic dysplastic kidney
Hereditary diseases associated with nephritis
Hereditary nephritis with deafness and ocular defects (Alport syndrome)
Hereditary osteolysis with nephropathy
Hereditary diseases associated with intrarenal deposition of metabolites
Various storage diseases (eg, GM1 monosialogangliosidosis, Hurler syndrome, Niemann-Pick disease, familial metachromatic leukodystrophy, glycogenosis type I [von Gierke disease], glycogenosis type II [Pompe disease])
Hereditary amyloidosis (familial Mediterranean fever, heredofamilial urticaria with deafness and neuropathy, primary familial amyloidosis with polyneuropathy)
Hereditary renal diseases associated with tubular transport defects
Oculocerebrorenal syndrome of Lowe
Cystinosis (infantile, adolescent, adult types)
Hereditary fructose intolerance
Renal tubular acidosis
Vitamin D–resistant rickets
Nephrogenic diabetes insipidus
Hereditary diseases associated with lithiasis
Lesch-Nyhan syndrome and variants, gout
Nephropathy due to familial hyperparathyroidism
Cystinuria (types I, II, III)
DISORDERS OF THE RENAL TUBULES
Three subtypes of RTA are recognized: (1) the classic form, called type I or distal RTA; (2) the bicarbonate-wasting form, called type II or proximal RTA; and (3) type IV, or hyperkalemic RTA (rare in children), which is associated with hyporeninemic hypoaldosteronism or inherited in an autosomal manner. Types I and II and their variants are encountered most frequently in children. Type III is described historically as a combination of types I and II. Other primary tubular disorders in childhood, such as glycinuria, hyperuricosuria, or renal glycosuria, may result from a defect in a single tubular transport pathway (see Table 24–4).
1. Distal Renal Tubular Acidosis (Type I)
The most common form of distal RTA in childhood is the hereditary form. The clinical presentation is one of failure to thrive, anorexia, vomiting, and dehydration. Hyperchloremic metabolic acidosis, hypokalemia, and a urinary pH exceeding 6.5 are found. Concomitant hypercalciuria may lead to nephrocalcinosis, nephrolithiasis, and renal failure. Other situations that may be responsible for distal RTA are found in some of the entities listed in Table 24–4.
Distal RTA results from a defect in the distal nephron in the tubular transport of hydrogen ion or in the maintenance of a steep enough gradient for proper excretion of hydrogen ion. Historically the diagnosis could be established with an acid loading test, but this is rarely pursued currently. Instead, the findings of hypercalciuria or nephrocalcinosis with RTA support a distal defect, as does the relatively low requirement of alkali to normalize serum pH and bicarbonate concentration (1–3 mEq/kg/d). Some forms of genetic distal RTA are associated with hearing loss. Correction of acidosis with citrate or less commonly bicarbonate reduces complications and improves growth. Distal RTA is often permanent. However, if renal damage from calcinosis is prevented, the prognosis with treatment is good.
2. Proximal Renal Tubular Acidosis (Type II)
Proximal RTA, the most common form of RTA in childhood, is characterized by failure to reabsorb bicarbonate appropriately in the proximal tubule with associated reduced serum bicarbonate concentration and normal anion gap hyperchloremic metabolic acidosis. Once a steady state is reached, the intact distal nephron appropriately excretes hydrogen ion, leading to a low urine pH.
Proximal RTA is often an isolated defect, and in the newborn can be considered an aspect of renal immaturity which improves with increasing gestational age. Proximal RTA in infants is accompanied by failure to thrive and sometimes hypokalemia. Secondary forms result from reflux or obstructive uropathy or occur in association with other tubular disorders (see Table 24–4). Due to bicarbonate wasting, children with proximal RTA typically require 5–20 mEq/kg/d citrate to achieve normal serum pH and bicarbonate concentration.
3. Evaluation & Treatment
The diagnosis of RTA is made with the finding of normal anion gap, hyperchloremic metabolic acidosis in the absence of diarrhea, or intravascular volume depletion. A concomitant urine pH is helpful in many cases, as it is elevated in distal RTA despite the metabolic acidosis. The finding of hypophosphatemia or glycosuria should lead to further investigation of proximal tubular function (eg, Fanconi syndrome that is also associated with aminoaciduria). A renal ultrasound should be obtained to exclude urinary tract obstruction (which can be seen with either proximal or distal RTA) and nephrocalcinosis (seen in distal RTA). A urine calcium creatinine ratio may be helpful in the latter condition. In either proximal or distal RTA, citrate or bicarbonate supplementation is provided to target a serum bicarbonate level of 20–24 mEq/L, as an index of normal serum pH. Citrate solutions are more effective and often better tolerated than sodium bicarbonate. Sodium citrate contains 1 mEq/mL of Na+ and citrate. Potassium citrate contains 2 mEq/mL of citrate and 1 mEq/mL each of Na+ and K+. The medication is administered three times per day, targeting a trough serum bicarbonate at goal. Potassium supplementation may be required (and can often be accomplished simply with a change from sodium citrate to potassium citrate) because the added sodium load presented to the distal tubule may exaggerate potassium losses.
The prognosis is excellent in cases of isolated proximal RTA, especially when the problem is related to renal immaturity. Alkali therapy can usually be discontinued after several months to a few years. Growth should be normal, and the gradual increase in the serum bicarbonate level to greater than 24 mEq/L heralds the normalization of the threshold for proximal tubular bicarbonate reabsorption. If the defect is part of Fanconi syndrome or distal RTA, the prognosis depends on the underlying disorder or syndrome.
Cystinosis is the most common cause of Fanconi syndrome in children and results from mutations in the CTNS gene, which encodes the cystine transporter. There are three types of cystinosis: adult, adolescent, and infantile. The adult form is characterized by ocular cystinosis without renal involvement. In the adolescent and infantile types, cystine accumulation in lysosomes causes cell death in numerous organs, including the kidneys. Treatment with oral cysteamine aids in the metabolic conversion of cystine (unable to exit cells) to cysteine (able to exit cells) and delays intracellular accumulation and associated complications, which include Fanconi syndrome with salt-wasting and functional nephrogenic diabetes insipidus, proximal RTA, hypophosphatemic rickets, eventual progression to ESRD, hypothyroidism, ocular cystinosis with eventual blindness, and neurologic deterioration. The infantile type is most common and the most severe. Characteristically, children present in the first or early second year of life with Fanconi syndrome and failure to thrive. If left untreated, ESRD is reached by 7–10 years of age in the infantile form. Whenever the diagnosis of cystinosis is suspected, slit-lamp examination of the corneas should be performed. Cystine crystal deposition causes an almost pathognomonic ground-glass “dazzle” appearance. Increased white blood cell (WBC) cystine levels are diagnostic. The condition does not recur in transplanted kidneys, but ongoing cysteamine therapy is required to prevent complications in other organs.
et al: Nephropathic cystinosis: an international consensus document. Nephrol Dial Transplant 2014;29(Suppl 4):iv87–94 PMID:
OCULOCEREBRORENAL SYNDROME (LOWE SYNDROME)
Lowe syndrome results from various mutations in the OCRL1 gene, which codes for a Golgi apparatus phosphatase. Affected males have anomalies involving the eyes, brain, and kidneys. The physical stigmata and degree of mental retardation vary with the location of the mutation. In addition to congenital cataracts and buphthalmos, the typical facies includes prominent epicanthal folds, frontal prominence, and a tendency to scaphocephaly. Muscle hypotonia is a prominent finding. The renal abnormalities are tubular and include hypophosphatemic rickets with low serum phosphorus levels, low to normal serum calcium levels, elevated serum alkaline phosphatase levels, proximal RTA, and aminoaciduria. Renal treatment includes alkali therapy, phosphate replacement, and vitamin D support. Antenatal diagnosis is possible.
HYPOKALEMIC ALKALOSIS (BARTTER SYNDROME, GITELMAN SYNDROME, & LIDDLE SYNDROME)
There are a number of genetic tubular disorders which result in hypokalemic metabolic alkalosis. Bartter syndrome is characterized by severe hypokalemic, hypochloremic metabolic alkalosis, extremely high levels of circulating renin and aldosterone, and a paradoxical absence of hypertension. On renal biopsy (rarely pursued in the current era), a striking juxtaglomerular hyperplasia is seen. A neonatal form of Bartter syndrome is thought to result from mutations in two genes (NKCC2, ROMK) affecting nephron Na+-K+ or K+ transport. These patients typically have a history of polyhydramnios and following birth have recurrent life-threatening episodes of fever and dehydration with the aforementioned electrolyte and acid-base disturbances, hypercalciuria, and early-onset nephrocalcinosis. Classic Bartter syndrome presenting in infancy with polyuria and growth retardation (but not nephrocalcinosis) is thought to result from mutations in a chloride channel gene. Gitelman syndrome occurs in older children and features episodes of muscle weakness and tetany associated with severe hypokalemia, and hypomagnesemia. These children have hypocalciuria. Treatment with prostaglandin inhibitors and potassium-conserving diuretics (eg, amiloride) and potassium and magnesium supplements where indicated is beneficial in Bartter or Gitelman syndrome. These are lifelong conditions which require ongoing electrolyte supplementation.
Liddle syndrome is associated with constitutive activation of the epithelial sodium channel with associated salt and water retention. Thus, the initial presenting abnormality is often hypertension associated with hypokalemia and metabolic alkalosis. Serum renin and aldosterone are suppressed due to the sodium and fluid retention. Treatment in Liddle syndrome is with a low-sodium diet and blockade of the epithelial sodium channel with amiloride or triamterene. Spironolactone is ineffective in this condition as aldosterone is typically suppressed.
NEPHROGENIC DIABETES INSIPIDUS (NDI)
Hereditary nephrogenic (vasopressin-resistant) diabetes insipidus is most often caused by X-linked mutations in the AVPR2 gene that encodes the vasopressin V2 receptor. Autosomal (recessive and dominant) forms of NDI occur less commonly due to mutations of the AQP2 gene that codes for the collecting tubule water channel protein, aquaporin-2. Such children often have a profound impairment in maximal urinary concentrating capacity, which rarely exceeds 100 mOsm/kg H2O. Genetic counseling and mutation testing are available.
Acquired nephrogenic diabetes insipidus (NDI) is observed in numerous conditions including sickle cell anemia, chronic pyelonephritis, hypokalemia, hypercalcemia, Fanconi syndrome, obstructive uropathy, chronic renal insufficiency, and lithium treatment.
The symptoms of NDI include polyuria and polydipsia. In severe cases, water intake is preferred to formula, leading to failure to thrive. In some children, particularly if the solute intake is unrestricted, adjustment to an elevated serum osmolality may develop. Children with genetic NDI are particularly susceptible to episodes of dehydration, fever, vomiting, and hypernatremia when access to free water is limited.
The diagnosis can be suspected on the basis of a history of polydipsia and polyuria. The family history may be informative in hereditary cases while a review of the patient’s medical history, medications, and serum chemistries can help identify a source of acquired NDI. The diagnosis is confirmed by performing a water deprivation test, during which time serum and urine osmolality are assessed and either arginine vasopressin or desmopressin administered to assess tubular response. When hereditary NDI is suspected, it is imperative that a water deprivation test be performed in the hospital in a controlled setting. Due to the severe concentrating defect, restricting water intake overnight at home in such children can lead to severe intravascular volume depletion and hyperosmolality. In addition to hyperglycemia, the differential diagnosis of polydipsia and polyuria includes primary polydipsia, which occurs in children as young as infancy.
In infants with NDI, it is usually best to allow water as demanded and to restrict salt intake. Caregivers must be aware of the risks of dehydration and hypernatremia if fluid intake is restricted either due to lack of provision by the caregiver or inability to keep fluids down (eg, vomiting). A low-salt diet limits the amount of urine that must be produced for daily solute excretion. Due to the need for high-volume free water intake, caloric intake may be limited and affected children often benefit from routine follow-up with a renal dietitian. Treatment with hydrochlorothiazide decreases urine volume by limiting the amount of free water delivered to the distal nephron for excretion. Prostaglandin inhibitors such as indomethacin or tolmetin are efficacious by decreasing renal blood flow, thereby diminishing GFR and by preventing reclamation of the AQP2 water channel from the apical membrane of the collecting duct cell. Prostaglandin inhibitors, however, are associated with risk of gastritis/ulceration.
DG: Urinary concentration: different ways to open and close the tap. Pediatr Nephrol 2014;29(8):1297–1303 PMID:
SS: Water deprivation test in children with polyuria. J Pediatr Endocrinol Metab 2012;25(9–10):869–874 PMID:
Renal calculi in children may result from hereditary errors of metabolism, such as cystine in cystinuria, glycine in hyperglycinuria, urates in Lesch-Nyhan syndrome, and oxalates in primary hyperoxaluria. Stones may occur secondary to hypercalciuria in distal RTA, and large stones are quite often seen in children with spina bifida who have paralyzed lower limbs or any situation where immobilization promotes calcium mobilization from the bones or there is recurrent UTI with urease-producing organisms (struvite calculi). Treatment is focused on the primary condition, if possible. Most cases of nephrolithiasis have no basis in a metabolic disturbance, however, and are initially addressed with attention toward maintaining optimal hydration. Surgical removal of stones or lithotripsy should be considered only for obstruction, intractable severe pain, and chronic infection.
L: Evaluation and medical management of kidney stones in children. J Urol 2014;192(5):1329–1336 PMID:
Cystinuria is primarily an abnormality of amino acid transport across both the enteric and proximal renal tubular epithelium. There are at least three biochemical types. In the first type, the bowel transport of basic amino acids and cystine is impaired, but transport of cysteine is not impaired. In the renal tubule, basic amino acids are again rejected by the tubule, but cystine absorption appears to be normal. The reason for cystinuria remains obscure. Heterozygous individuals have no aminoaciduria. The second type is similar to the first except that heterozygous individuals excrete excess cystine and lysine in the urine, and cystine transport in the bowel is normal. In the third type, only the nephron is involved. The only clinical manifestations are related to stone formation: ureteral colic, dysuria, hematuria, proteinuria, and secondary UTI. Urinary excretion of cystine, lysine, arginine, and ornithine is increased.
The most reliable way to prevent stone formation is to maintain a constantly high free-water clearance. This involves generous fluid intake. Alkalinization of the urine is helpful. If these measures do not prevent significant renal lithiasis, the use of tiopronin (Thiola) is recommended.
DS: Update on cystinuria. Curr Opin Nephrol Hypertens 2013;22(4):427–431 PMID:
Oxalate in humans is derived from the oxidative deamination of glycine to glyoxylate, the serine-glycolate pathway, and from ascorbic acid. At least two enzymatic blocks have been described. Type I is a deficiency of liver-specific peroxisomal alanine–glyoxylate aminotransferase. Type II is glyoxylate reductase deficiency. Recently a type III primary hyperoxaluria has been described in association with increased mitochondrial 4-hydroxy-2-oxoglutarate aldolase activity; this type appears to be milder than types I or II.
Excess oxalate combines with calcium to form insoluble deposits in the kidneys, lungs, and other tissues, beginning during childhood. The joints are occasionally involved, but the main effect is on the kidneys, where progressive oxalate deposition leads to fibrosis and eventual renal failure.
A low-oxalate diet with normal calcium intake and high fluid intake is recommended. High-dose pyridoxine can be administered in type I primary hyperoxaluria as it is a cofactor for the defective pathway, but the overall prognosis is poor, with half of patients developing ESRD by 15 years of age. Renal transplantation is not very successful because of destruction of the transplant kidney with continued oxalate overproduction. However, encouraging results have been obtained with concomitant liver transplantation that corrects the metabolic defect. Types II and III primary hyperoxaluria appear to have better long-term renal outcomes.
Hyperoxaluria may also be a consequence of severe ileal disease or ileal resection due to excessive absorption of dietary oxalate.