Rare but Relevant Kidney Disorders

Abstract

Occurrence of hypomagnesemia (serum Mg2+ levels <0.7 mmol/L) in the general population has been estimated to be approximately 2%. The kidney is central for the maintenance of the Mg+ balance. A large body of knowledge has been generated from the study of inherited defects of renal Mg2+ handling. The majority of filtered Mg+ is reabsorbed along the proximal tubule and thick ascending limb of Henle's loop via a passive paracellular pathway. Claudin 16, formerly paracellin 1, and claudin 19 are renal tight junction proteins that are important for paracellular reabsorption of calcium and magnesium in thick ascending limb. Mutations of the corresponding genes, CLDN 16 and 19, result in a rare autosomal recessive tubular disorder that is characterized by familial hypomagnesemia, hypercalciuria, and nephrocalcinosis (FHHNC). This disease is frequently associated with progressive renal failure as a result of both intrarenal calcium deposition and additional roles of claudins in the maintenance of tight junction integrity. Children with a complete loss of function of CLDN16 have a more rapid progression of renal failure than those with residual function (1). The thiazide-sensitive sodium chloride co-transporter in the distal convoluted tubule (DCT) is mutated in Gitelman syndrome. Hypokalemic metabolic alkalosis and hypocalciuria are associated with hypomagnesemia. At the apical membrane of DCT cells is also present the Mg2+-permeable transient receptor potential cation channel, subfamily M (TRPM6). Mg2+ uptake from the tubular fluid via TRPM6 is primarily driven by the negative potential across the luminal membrane. Hypomagnesemia with secondary hypocalcemia is caused by mutations in TRPM6. Mutations in FXYD2, encoding the γ-subunit of the basolateral Na+-K+-ATPase, is responsible for dominant isolated renal Mg2+ wasting, as a result of misrouting of this subunit. This defect has been described so far in a single family (but read this summary to the end). Finally, the recently discovered magnesiotropic hormone EGF causes isolated recessive renal hypomagnesemia (see references in Glaudemans et al.). Glaudemans et al. identified a new mechanism for autosomal dominant hypomagnesemia. A large Brazilian family was studied. Twenty-one affected members had serum Mg2+ levels <0.4 mmol/L, which was responsible for muscle symptoms and tetany from infancy. The locus was identified on chromosome 12. The mutation was found in KCNA1, a gene encoding the voltage-gated K+ channel, Kv1.1. This channel co-localized with TRPM6 along the luminal membrane of DCT. Upon overexpression in a human kidney cell line, patch-clamp analysis revealed that the mutation resulted in a nonfunctional channel, with a dominant negative effect on wild-type Kv1.1 channel function. The negative potential across the apical membrane is normally maintained by an apical K+ efflux via Kv1.1 energized by the action of Na+-K+-ATPase. When Kv1.1 function is lost, Mg2+ reabsorption in DCT is impaired. Recently, an unexpected mechanism of renal magnesium wasting and hypomagnesemia was discovered by Adalat et al. (2). They first identified a teenager who had hepatocyte nuclear factor 1B (HNF 1B) mutation and presented with tetany and hypomagnesemia (0.620 mmol/L). Then they retrospectively reviewed 91 pediatric cases of renal malformation screened for HNF 1B mutation. Twenty-one had heterozygous mutations. Eight (44%) of 18 mutation carriers had hypomagnesemia (<0.65 mmol/L) compared with one (2%) of 48 of those without mutations. HNF 1B is a transcription factor that is expressed in developing kidneys, whereas, postnatally, proximal and distal tubules express the gene. Hnf 1b in mouse upregulates transcription of various genes whose human homologues are involved in inherited cystic kidney diseases. Adalat et al. (2) detected a highly conserved HNF 1B recognition site in FXYD2. They demonstrated HNF 1B–mediated transactivation of FXYD2. Thus, HNF 1B regulates transcription of FXYD2, which participates in the tubular handling of Mg2+. These results extend the phenotype of HNF 1B mutations to include hypomagnesemia. Serum Mg2+ levels should be measured in patients with HNF 1B mutations (2).