Genetically Based Kidney Transport Disorders

Selective Proximal Transport Defects

Sodium resorption in the proximal tubule occurs through secondary active transport processes in which the entry of sodium is coupled either to the entry of substrates (e.g., glucose, amino acids, or phosphate) or to the exit of protons. Autosomal recessive conditions of impaired transepithelial transport of glucose and dibasic amino acids have been shown to be caused by mutations in sodium-dependent transporters that are expressed in both kidney and intestine, resulting in urinary losses and intestinal malabsorption of these solutes. Other disorders with kidney-selective transport defects result from mutations in transporters expressed specifically in kidney.

Impaired Proximal Phosphate Reabsorption

Hypophosphatemic rickets can be inherited in X-linked, autosomal dominant, and autosomal recessive patterns. All three modes are associated with kidney phosphate wasting, with a reduced maximal transport capacity for phosphate. In all three, serum levels of the phosphate-regulating hormone (phosphatonin) FGF23 are elevated, and serum levels of 1,25-dihydroxyvitamin D are not elevated despite the stimulus of hypophosphatemia.

X-linked (dominant) hypophosphatemic rickets (XLHR) is the most common form of hereditary rickets. Mutations in XLHR involve a phosphate-regulating gene with homologies to a neutral endopeptidase on the X chromosome (PHEX) that is expressed in bone and is indirectly involved in the degradation and processing of FGF23. Elevations in FGF23 are sufficient to explain the kidney phosphate wasting, but other factors independent of FGF23 appear to contribute as well to the bone demineralization and rickets. Recent studies demonstrate the effectiveness of a monoclonal anti-FGF23 antibody, burosumab, to correct hypophosphatemia and improve bone mineralization in children with XLHR, further validating a central role for FGF23 in this disease.

The rare ADHR is associated with mutations in the gene encoding FGF23 that protects the phosphatonin from proteolytic cleavage. FGF23 disrupts kidney phosphate reabsorption by inhibiting expression of two genes encoding sodium-dependent phosphate transporters in proximal tubule, SLC34A1 (encoding the Na-dependent phosphate transporter Npt2a) and SLC34A3 (encoding Npt2c). FGF23 inhibits the 1-hydroxylation of 25-hydroxyvitamin D, likely explaining why hypophosphatemia in these three conditions is not associated with either elevated levels of 1,25-dihydroxyvitamin D or hypercalciuria. A single kindred has been reported with autosomal dominant hypophosphatemia and rickets with mutation in SGK3 , encoding a proximal tubular protein kinase SGKL.

Autosomal recessive inheritance of hypophosphatemic rickets has been reported in association with mutations in one of three genes. In ARHR type 1, the mutated gene is DMP1 , encoding the dentin matrix protein 1 (DMP-1), a bone matrix protein that appears to play a role with PHEX in regulating bone mineralization and FGF23 production. ARHR2 is associated with mutations in ENPP1 , encoding ectonucleotide pyrophosphatase/phosphodiesterase 1. Patients with either subtype resemble those with autosomal dominant (i.e., FGF23 mutations) and X-linked (PHEX mutations) hypophosphatemic rickets. ARHR3 is associated with mutations in FAM20C , encoding a protein kinase that phosphorylates FGF23; this subtype may also manifest features of osteosclerosis.

Hereditary hypophosphatemic rickets with hypercalciuria (HHRH), an autosomal recessive disorder, is different from XLHR, ADRH, and ARHR, all of which are associated with reduced urinary calcium excretion. In contrast, hypophosphatemia in HHRH is associated with appropriate elevations of 1,25-dihydroxyvitamin D levels, and FGF23 levels are normal or reduced. This profile in HHRH is consistent with a primary defect in phosphate transport and, indeed, the disease is associated with mutations in SLC34A3 , encoding the proximal tubule phosphate transporter Npt2c. Expression of this transporter, as well as that of SLC34A1 encoding the more abundant transporter Npt2a, responds to physiologic stimuli such as parathyroid hormone (PTH) and dietary phosphate. Knockout of the mouse homologue of SLC34A1 reproduces the features of human HHRH except for rickets, mouse knockout of SLC34A3 manifests hypercalcemia and hypercalciuria, but not hypophosphatemia, nephrocalcinosis, or rickets, and a double knockout of both genes produces mice with the full phenotype of hypophosphatemia, hypercalciuria, nephrocalcinosis, and rickets. In one human kindred, apparent autosomal dominant inheritance of HHRH was associated with compound heterozygosity for SLC34A3 and SLC34A1 .

Excessive Proximal Phosphate Reabsorption

Inherited hyperphosphatemia in the familial hyperostosis-hyperphosphatemia syndrome represents a mirror image of ADHR and XLHR, with excessive kidney phosphate reabsorption, persistent hyperphosphatemia, inappropriately normal levels of 1,25-dihydroxyvitamin D, and low levels of FGF23. This can result from mutations in one of three genes identified to date. These genes encode FGF23 itself, a Golgi-associated biosynthetic enzyme, N -acetylglucosaminyl (GalNac) transferase 3 that is involved in glycosylation of FGF23 and is necessary for its secretion, and Klotho, a transmembrane protein that complexes with the FGF23 receptor and regulates its affinity for FGF23. Together, these discoveries augment our understanding of the role of bone in the complex regulation of mineral metabolism.

Impaired Proximal Bicarbonate Transport

Selective proximal renal tubular acidosis (RTA) is inherited in an autosomal recessive manner and is associated with mutations that inactivate the basolateral sodium bicarbonate cotransporter NBC1, encoded by the gene SLC4A4 . These patients typically exhibit short stature and often suffer blindness from ocular abnormalities, including band keratopathy, cataracts, and glaucoma; these ocular manifestations probably are a consequence of impaired bicarbonate transport in the eye. Mutations in the SLC4A4 gene result in impaired transporter function or aberrant trafficking of the protein to the basolateral surface. This gene belongs to the same group as the gene encoding the anion exchanger AE1 (now designated SLC4A1 ), which is mutated in distal RTA. Proximal RTA can also be inherited in an autosomal dominant fashion, though the responsible gene(s) have not yet been identified.

Inherited Fanconi Syndrome: Hereditary Fructose Intolerance, Lowe Syndrome, and Dent Disease

The Fanconi syndrome represents a generalized impairment in reabsorptive function of the proximal tubule and comprises proximal RTA with aminoaciduria, glycosuria, hypouricemia, and hypophosphatemia. Some or all of these abnormalities are present in individual patients with Fanconi syndrome. Generalized Fanconi syndrome is genetically heterogeneous. It has been reported with autosomal dominant inheritance in association with mutations in genes encoding glycine amidinotransferase, the enzyme L-PBE, and the nuclear hormone receptor HNF4A (associated with MODY), and with recessive inheritance in the cases of genes encoding the sodium-phosphate transporter NaPi-IIa and the NADH:ubiquinone oxidoreductase complex assembly factor 6. Inherited causes of partial or complete Fanconi syndrome also include hereditary fructose intolerance, Lowe syndrome, and Dent disease.

Hereditary fructose intolerance is caused by mutations that result in deficiency of the aldolase B isoenzyme, which cleaves fructose-1-phosphate. Symptoms are precipitated by intake of sweets. Massive accumulation of fructose-1-phosphate occurs, leading to sequestration of inorganic phosphate and deficiency of adenosine triphosphate (ATP). Acute consequences can include hypoglycemic shock, severe abdominal symptoms, and impaired function of the Krebs cycle that produces metabolic acidosis; this is exacerbated by impaired kidney bicarbonate reabsorption. ATP deficiency leads to impaired proximal tubular function in general, including the full expression of the Fanconi syndrome with consequent rickets and stunted growth. ATP breakdown can be so dramatic as to produce hyperuricemia, as well as hypermagnesemia from the dissolution of the magnesium-ATP complex. Avoiding dietary sources of fructose can minimize acute symptoms and chronic consequences such as liver disease.

Characteristic features of the oculocerebrorenal syndrome of Lowe include congenital cataracts, mental retardation, muscular hypotonia, and the Fanconi syndrome. In contrast, Dent disease is confined to the kidney. In both syndromes, low-molecular-weight (LMW) proteinuria is a prominent feature along with other evidence of proximal tubulopathy such as glycosuria, aminoaciduria, and phosphaturia. One important and puzzling difference is that proximal RTA with growth retardation can be severe in patients with Lowe syndrome, but it is not a part of Dent disease. Some patients with Lowe syndrome or Dent disease may have rickets, which is thought to be a consequence of hypophosphatemia and, in Lowe syndrome, of acidosis as well. Hypercalciuria is a characteristic feature of Dent disease and is associated with nephrocalcinosis in most and kidney stones in many patients with Dent disease; nephrocalcinosis and nephrolithiasis are less common in Lowe syndrome. Kidney failure is common in both of these conditions, typically occurring in young adulthood in Dent disease and even earlier in patients with Lowe syndrome.

Dent disease is caused in most cases by mutations that inactivate the chloride transporter CLC-5. This transport protein is expressed in the proximal tubule, the medullary thick ascending limb (MTAL) of the loop of Henle, and the α-intercalated cells of the collecting tubule. In the cells of the proximal tubule, CLC-5 co-localizes with the H ⁺ -ATPase in subapical endosomes. These endosomes are important in the processing of proteins that are filtered at the glomerulus and taken up by the proximal tubule through adsorptive endocytosis. The activity of the H ⁺ -ATPase acidifies the endosomal space, releasing the proteins from membrane-binding sites and making them available for proteolytic degradation. CLC-5 mediates electrogenic exchange of chloride for protons in these endosomes, facilitating endosomal acidification. Mutations that inactivate CLC-5 in patients with Dent disease interfere with the mechanism for reabsorption of LMW proteins and explain the consistent finding of LMW proteinuria. Glycosuria, aminoaciduria, and phosphaturia occur commonly but less consistently and may reflect altered membrane protein recycling, as CLC-5 interacts directly with several trafficking proteins. Hypercalciuria appears largely to reflect a dysregulation of kidney 1-hydroxylation of 25(OH)-vitamin D.

Lowe syndrome is associated with mutations in OCRL1, which encodes a phosphatidylinositol-4,5-bisphosphate-5-phosphatase. In tubular epithelial cells, this phosphatase is localized to the trans -Golgi network, which plays an important role in directing proteins to the appropriate membrane. The CLC-5 protein and the OCRL1 phosphatase interact with the actin cytoskeleton and are involved in assembly of the endosomal apparatus. Similarities in the kidney features of these two syndromes may be the result of defective membrane trafficking. A subset of patients with mutations in OCRL1 have no cataracts or cerebral dysfunction and no RTA (“Dent 2” disease). Such mutations occur predominantly in the 5′ end of the gene and are critical to expression of the gene in the kidney, but apparently not to expression of transcripts in eye or brain.

Bartter Syndrome

Solute transport in the MTAL involves the coordinated functions of a set of transport proteins depicted in Fig. 37.1 . These proteins are the loop diuretic-sensitive Na ⁺ -K ⁺ -2Cl ⁻ cotransporter (NKCC2) and the renal outer medullary potassium channel (ROMK) on the apical surface of cells of the MTAL, and the chloride channel ClC-Kb on the basolateral surface. Optimal function of the ClC-Kb chloride channel requires interaction with a subunit called barttin . Mutations in any of the genes encoding these four proteins lead to the phenotype of Bartter syndrome. In addition, activation of the epithelial CaSR inhibits activity of the ROMK potassium channel. Mutations producing constitutive activation of the CaSR cause familial hypocalcemic hypercalciuria. Some patients with hypocalcemic hypercalciuria have the phenotype of Bartter syndrome, and mutations in the CaSR may be considered a fifth molecular cause of this syndrome. However, defects in these five genes still do not account for all patients with Bartter syndrome.

The ClC-Kb basolateral chloride channel provides the route for chloride exit to the interstitium. Flow of potassium through the ROMK channel ensures that potassium concentrations in the tubular lumen do not limit the activity of the NKCC2 while maintaining a positive electrical potential in the lumen of this nephron segment. This positive charge is the driving force for paracellular reabsorption of calcium and magnesium.

Bartter syndrome manifests in infancy or childhood with polyuria and failure to thrive, often occurring after a pregnancy with polyhydramnios. It is characterized by hypokalemic metabolic alkalosis, typically with hypercalciuria, and these patients resemble patients chronically taking loop diuretics that inhibit activity of NKCC2 pharmacologically. Defective function of NKCC2, ROMK, ClC-Kb, or barttin leads to impaired salt reabsorption in the MTAL, resulting in volume contraction and activation of the renin-angiotensin-aldosterone axis, which subsequently stimulates distal tubular secretion of potassium and protons, resulting in hypokalemic metabolic alkalosis. Despite impaired reabsorption of magnesium, serum magnesium levels are usually normal or only mildly reduced in patients with Bartter syndrome. Severity, age at onset of symptoms, and particular clinical features vary with the gene abnormality. For example, nephrocalcinosis as a consequence of hypercalciuria is most common in individuals with mutations in genes encoding NKCC2 and ROMK. Barttin is expressed in the inner ear, and patients with mutations in its gene have sensorineural deafness. As Barttin is also expressed beyond the TAL in the DCT, patients with type IV Bartter syndrome often have more severe salt wasting and typically lack hypercalciuria; they often develop progressive GFR loss. Cases of severe but transient antenatal Bartter syndrome have been reported with mutations in MAGED2 on the X chromosome, which regulates expression of NKCC2 in the MTAL, and of the thiazide-sensitive sodium-chloride cotransporter NCC in DCT.

Bartter syndrome is discussed further in Chapter 10.

Inherited Hypomagnesemic Hypercalciuria

Reabsorption of calcium and magnesium in the MTAL occurs through the paracellular route, driven by the positive electrical potential in the tubular lumen. The tight junctions between the epithelial cells determine the selective movement of cations (i.e., calcium, magnesium, and sodium). Disturbance of this selective paracellular barrier would be expected to produce parallel disorders in the reabsorption of calcium and magnesium.

Familial hypomagnesemia with substantial kidney magnesium losses, hypercalciuria, and nephrocalcinosis (FHHNC) is inherited in an autosomal recessive fashion. These patients develop kidney failure and kidney stones. Investigation of families first led to identification by positional cloning of the gene encoding a tight junction protein designated claudin 16 (also called paracellin 1 ). This was the first instance of a disease shown to result from mutations that alter a tight junction protein. Another member of this family, claudin 19, is mutated in other pedigrees in whom FHHNC is associated with ocular abnormalities (e.g., macular colobomas, myopia, horizontal nystagmus) with severe visual impairment. Both claudin 16 and claudin 19 are expressed in the thick ascending limb (TAL; Fig. 37.2 ), but claudin 19 also is expressed in the retina. These two proteins interact in the tight junction to regulate cation permeability. It is unclear why a defect in tight junctions is associated with hyperuricemia, a consistent finding in this disease.