Nephrolithiasis With Hypomagnesemia: What Is the Cause?

What Is Your Diagnosis? 

We first considered heritable causes of renal failure with calcium oxalate nephrolithiasis. Primary hyperoxaluria (PH) type 1 is associated with multiple bilateral renal calculi on ultrasonography and is more common in people of Maghrebian origin. However, neither soft-tissue nor vascular calcifications were found, and bone density measurements did not show areas of bone hyperdensity. Moreover, hypomagnesemia is not seen in patients with PH type I. Finally, there was no evidence of a mutation in the AGXT gene that would cause an isoleucine-to-threonine substitution at amino acid 244, thus definitively excluding the common Maghrebian form of PH type 1. Hypercalciuria with nephrocalcinosis and renal failure association might also suggest Dent disease, but the absence of other signs of a proximal tubular defect argued against this possibility. Neither PH type 1 nor Dent disease cause hypomagnesemia, the critical clinical observation in this case.

Hypomagnesemia, defined as serum magnesium level less than 1.7 mg/dL (<0.7 mmol/L), has many possible causes. Table 1 lists the major causes of inherited hypomagnesemia (including some not discussed because of space constraints). However, of these, only a few are associated with recurrent urinary stones leading to total renal failure. Such disorders comprise a set of rare tubular disorders with different modes of inheritance including isolated renal magnesium loss (Online Mendelian Inheritance in Man [OMIM] 154020 and OMIM 248250),1 Gitelman syndrome (OMIM 263800),2 and autosomal recessive familial hypomagnesemia with hypercalciuria and nephrocalcinosis (FHHNC; OMIM 248250 and OMIM 603959).3 The combination of hypercalciuria and hypomagnesemia seen in our patient helps eliminate isolated renal magnesium loss and Gitelman syndrome because urinary calcium excretion is usually low or normal in these conditions. However, this combination of abnormalities is observed in patients with FHHNC.

Table 1. Major Causes of Inherited Hypomagnesemia

	Diseases	Features
		Inheritance/OMIM No./Chromosome	Urinary Magnesium	Urinary Calcium	Renal Stone/Nephrocalcinosis
	FHHNC	AR/603959/3q27	High	High	Yes/yes
	Isolated dominant hypomagnesemia	AD/154020/11q23	High	Low	No/no
	Isolated recessive hypomagnesemia	AR/248250/?	High	?	No/no
	Hypomagnesemia and secondary hypocalcemia	AR/602014/9q22	Normal or high	Normal or high
	AD hypoparathyroidism	AD/601198/3q13.3-21	High	High	Yes/yes
	Gitelman syndrome	AR/263800/16q13	High	Low	No/no
	Classic Bartter syndrome	AR/602023/1p36	Normal or high	Variable	No/rare

Abbreviations: OMIM, Online Mendelian Inheritance in Man; FHHNC, familial hypomagnesemia, hypercalciuria, and nephrocalcinosis; AR, autosomal recessive; AD, autosomal dominant.

The diagnosis of FHHNC was confirmed by means of mutational analysis of the CLDN16 (claudin 16) gene, which encodes paracellin 1. Sequencing showed a mutation in CLDN16 that would cause an alanine-to-valine substitution at amino acid 139; this mutation was homozygous in the patient and heterozygous in the donor. FHHNC, first described by Michelis et al4 in 1972, is an autosomal recessive tubulopathy characterized by excessive renal magnesium and calcium wasting, bilateral nephrocalcinosis, and progressive renal failure. The condition results from CLDN16 mutations,5 making it the first identified human disease associated with a tight-junction protein defect.

Magnesium is one of the most abundant divalent cations in the intracellular fluid. It has a critical role in a wide variety of metabolic and cellular processes, including cellular energy storage, DNA/RNA processing, ion transport, membrane stabilization, and nerve conduction.6 In the kidney, approximately 80% of total serum magnesium is filtered at the glomeruli, and more than 95% of filtered magnesium is reabsorbed along the nephron (15% to 20% in the proximal tubule, 65% to 75% in the thick ascending limbs of the loops of Henle, and 5% to 10% in distal convoluted tubules).7, 8 Thus, less than 5% of filtered magnesium should be finally excreted in urine. In thick ascending limbs of the loops of Henle, magnesium is passively reabsorbed with calcium through paracellular tight junctions; the driving force of this reabsorption is a lumen-positive electrochemical gradient. Conversely, magnesium reabsorption in the distal convoluted tubule is an active transcellular process.7, 8 Paracellin 1 is expressed predominantly in medullary thick ascending limb, the nephron site where active control of magnesium and calcium takes place. Recently, Efrati et al9 showed that paracellin 1–mediated magnesium transport may be regulated at the transcriptional level by hypermagnesemia or hypomagnesemia, hypercalcemia, and 1,25-vitamin D, as well as by cyclosporine A therapy, which causes hypomagnesemia as a side effect.

Incidences of hypercalciuria and nephrolithiasis are exceptionally high in family members heterozygous for CLDN16 mutations, which indicates that CLDN16 is a candidate gene for idiopathic hypercalciuria.3, 10, 11 Clinical manifestations of FHHNC are variable; the majority of patients present early in childhood with recurrent urinary tract infections, polyuria/polydipsia, isosthenuria, or renal stones. Progression to chronic renal failure was considered to result from chronic progressive tubulointerstitial nephropathy associated with nephrocalcinosis.11, 12 According to Weber et al,3 the median age of end-stage renal failure is 14.5 years (range, 5.5 to 37.5 years). Similarly, nephrocalcinosis associated with other diseases does not always correlate with chronic renal failure, as shown in patients with distal renal tubular acidosis or antenatal Bartter syndrome.3, 13

Other findings in patients with FHHNC are unexplained. Hyperuricemia is present in the majority of patients with this syndrome,11, 12, 14 but the mechanism is not known. No paracellular secretory process for uric acid was described or even proposed. Ocular abnormalities, such as severe myopia, nystagmus, coloboma, bilateral keratoconus, corneal calcifications, tapetoretinal degeneration or chorioretinitis,3, 11, 15 and hearing impairment were reported.15 These abnormalities were not apparent in the index case or family members.

There is no specific treatment; magnesium supplements, citrate, and thiazide diuretics are not effective in preventing the progression of nephrocalcinosis.11 However, kidney transplantation corrects the tubular disorder. Twelve kidney recipients with FHHNC were reported in the literature, all with cadaveric donors. No recurrence of tubular dysfunction has been noticed.3

Living related kidney transplantation can be performed with a family member lacking the mutation. Furthermore, it is reasonable to consider heterozygous subjects as potential living related kidney donors if they are asymptomatic in adulthood, given the incomplete heterozygous mutation penetrance.3

In our patient, renal transplantation was performed in late 2006. The postoperative course was uneventful. After 2 months of follow-up, results of laboratory tests of the recipient (treated with a calcineurin inhibitor) were as follows: serum creatinine, 0.98 mg/dL (87 μmol/L); serum calcium, 10.0 mg/dL (2.50 mmol/L); serum magnesium, 1.21 mg/dL (0.5 mmol/L); and urinary calcium excretion, 0.06 mmol/kg/d.