Permanently reduced plasma ionized magnesium among renal transplant recipients on cyclosporine

Hypomagnesemia is common after kidney transplantation. Until recently, only the determination of total plasma magnesium was possible, whereas the assessment of ionized magnesium has since become practicable. One hundred and nine renal transplant patients on cyclosporine with allografts functioning stably for more than 6 months and plasma creatinine levels of less than 200 μmol/l entered the study. Total and ionized circulating magnesium were assessed among these 109 patients, as well as among 15 renal transplant patients not on cyclosporine and 21 healthy volunteers. Cyclosporine patients showed significantly lower total and ionized circulating magnesium values than the two control groups. Plasma total and ionized magnesium levels were also significantly lower among cyclosporine patients treated concurrently with insulin or oral hypoglycemic agents than among those who were not. No correlation was noted between time after transplantation and plasma magnesium with respect to patients on cyclosporine. In conclusion, the study demonstrates that a large subset of renal transplant patients treated with cyclosporine have permanent deficiencies of ionized and total magnesium. The tendency towards hypomagnesemia is also more pronounced among patients with diabetes mellitus. Received: 28 May 1998 Received after revision: 27 November 1998 Accepted: 18 December 1998     

Paracellin-1 gene mutation with multiple congenital abnormalities

Familial hypomagnesemia with hypercalciuria and nephrocalcinosis is an autosomal recessive renal tubular disorder characterized by renal magnesium wasting, hypercalciuria, advanced nephrocalcinosis and progressive renal failure. Mutations in the paracellin-1 (CLDN16) gene have been defined as the underlying genetic defect. The tubular disorders and progression in renal failure are usually resistant to magnesium substitution and hydrochlorothiazide therapy, but hypomagnesemia may improve with advanced renal insufficiency. We present a patient with a homozygous truncating CLDN16 gene mutation (W237X) who had early onset of renal insufficiency despite early diagnosis at 2 months. He also had additional abnormalities including horseshoe kidney, neonatal teeth, atypical face, cardiac abnormalities including coarctation of the aorta associated with atrial and ventricular septal defects, umbilical hernia and hypertrichosis. To the best of our knowledge, this is the youngest case diagnosed as familial hypomagnesemia with hypercalciuria and nephrocalcinosis and the first case having such additional congenital abnormalities independent of the disease itself.     

Hypomagnesemia and renal magnesium wasting in patients treated with cisplatin

Cisplatin (cis-diamminedichloroplatinum II), a chemotherapeutic agent used against epithelial neoplasms, is known to cause hypomagnesemia and renal magnesium wasting. In order to further characterize the effect of multiple doses of this drug upon serum magnesium levels and renal magnesium handling, we prospectively studied 28 patients who received a total of 82 doses of cisplatin. All patients developed hypomagnesemia that was dose-related (r = .66, P less than .001, n = 101); the lowest serum magnesium level reached in individual patients ranged from 0.3 to 1.7 mg/dL. Renal magnesium wasting was documented in 19 patients, with urinary fractional excretion of magnesium ranging from 2.9% to 22.3% despite serum magnesium levels of greater than or equal to 1.5 mg/dL. Evidence of renal tubular injury (renal tubular epithelial cells or tubular cell casts) was detected in 47 of 47 urine sediment examinations performed two to four days after cisplatin administration. There was no clear evidence that cisplatin caused defects in renal handling of electrolytes other than magnesium; in fact, 16 of the 28 patients demonstrated avid renal reabsorption of one or more other electrolytes despite significant magnesium wasting. We conclude that cisplatin alters renal tubular handling of magnesium, resulting in significant prolonged dose-related hypomagnesemia.     

Recent advances in molecular genetics of hereditary magnesium-losing disorders

Recent advances in molecular genetics in hereditary hypomagnesemia substantiated the role of a variety of genes and their encoded proteins in human magnesium transport mechanisms. This knowledge on underlying genetic defects helps to distinguish different clinical subtypes and gives first insight into molecular components involved in magnesium transport. By mutation analysis and functional protein studies, novel pathophysiologic aspects were elucidated. For some of these disorders, transgenic animal models were generated to study genotype-phenotype relations and disease pathology. This review will discuss genetic and clinical aspects of familial disorders associated with magnesium wasting and focuses on the recent progress that has been made in molecular genetics. Besides isolated renal forms of hereditary hypomagnesemia, the following disorders will also be presented: familial hypomagnesemia with hypercalciuria and nephrocalcinosis, hypomagnesemia with secondary hypocalcemia, Ca2+/Mg2+-sensing receptor-associated disorders, and disorders associated with renal salt-wasting and hypokalemic metabolic alkalosis, comprising the Gitelman syndrome and the Bartter-like syndromes.     

Report of a family with two different hereditary diseases leading to early nephrocalcinosis

The etiologies of early onset nephrocalcinosis in consanguineous families include five major inherited recessive disorders: primary hyperoxaluria (PH), familial hypomagnesemia with hypercalciuria and nephrocalcinosis (FHHNC), distal renal tubular acidosis (dRTA), hereditary hypophosphatemic rickets with hypercalciuria (HHRH) and antenatal Bartter syndrome. In this paper, we describe two girls from consanguineous parents with early onset nephrocalcinosis. Based on both clinical and biochemical assessment in combination with molecular genetics, we have shown that the etiology of nephrocalcinosis is different in each girl: one had FHHNC and her sister had dRTA.     

Inherited forms of renal hypomagnesemia: an update

The kidney plays an important role in ion homeostasis in the human body. Several hereditary disorders characterized by perturbations in renal magnesium reabsorption leading to hypomagnesemia have been described over the past 50 years, with the most important of these being Gitelman syndrome, familial hypomagnesemia with hypercalciuria and nephrocalcinosis, familial hypomagnesemia with secondary hypocalcemia, autosomal dominant hypomagnesemia with hypocalciuria, and autosomal recessive hypomagnesemia. Only recently, following positional cloning strategies in affected families, have mutations in renal ion channels and transporters been identified in these diseases. In this short review, I give an update on these hypomagnesemic disorders. Elucidation of the genetic etiology and, for most of these disorders, also the underlying pathophysiology of the disease, has greatly increased our understanding of the normal physiology of renal magnesium handling. This is yet another example of the importance of studying rare disorders in order to unravel physiological and pathophysiological processes in the human body.     

Maintenance hemodialysis and circulating ionized magnesium

BACKGROUND: Circulating magnesium exists in the bound and in the free ionized form, that is biologically active. In kidney disease the relationship between ionized and total circulating magnesium is often altered. Little information is available on the influence of hemodialysis on the relationship between ionized and total circulating magnesium in end-stage kidney disease. METHODS: Plasma total and ionized magnesium and the plasma ionized magnesium fraction were assessed before and after hemodialysis (dialysate magnesium content 0.75 mmol/l) in 46 patients with end-stage kidney disease and in a control group of 25 healthy subjects. RESULTS: In patients plasma total (from 1.19 [1.05-1.33] to 1.10 [1.02-1.16] mmol/l; median and interquartile range) and ionized (from 0.71 [0.66-0.78] to 0.65 [0.63-0.69] mmol/l) magnesium significantly decreased during dialysis (control subjects: 0.82 [0.80-0.92], respectively, 0.57 [0.54-0.59] mmol/l). The plasma ionized magnesium fraction was significantly lower in patients both before (0.61 [0.58-0.64)] and after (0.60 [0.56-0.62]) hemodialysis than in controls (0.68 [0.65-0.70]). CONCLUSIONS: The study demonstrates a tendency towards a reduced circulating ionized magnesium fraction in end-stage kidney disease that is not corrected by hemodialysis.     

Familial hypomagnesemia-hypercalciuria in 2 siblings

Familial hypomagnesemia-hypercalciuria with nephrocalcinosis and renal insufficiency in childhood is a rarely described disease. Two siblings of consanguineous Tunesian parents (first cousins), a 2-year-old boy and a 4-year-old girl presented with renal insufficiency and severe bilateral nephrocalcinosis. Both were found to have decreased serum and intracellular magnesium concentrations, increased urinary excretion of magnesium and calcium, mild glomerular and severe tubular proteinuria and low citrate excretion in urine. Pathological biochemical findings and the severity of nephrocalcinosis of the boy compared to findings of the sister were strongly marked, Histology of the boy's kidney showed severe medullary nephrocalcinosis, tubular atrophy, focal lymphoplasmacellulary infiltration, focal cortical fibrosis, immature glomerula, segmental and global glomerulosclerosis. Subsequent mutation analysis revealed a homozygous frameshift mutation in the gene paracellin-1 in both affected individuals. Therapy consisted of sodium bicarbonate, cholecalciferol, calcitriol, hydrochlorothiazide, citrate salts and oral magnesium administration. Hypercalciuria decreased in both children by therapy with thiazide diuretics, but hypomagnesemia was unresponsive to magnesium administration. After a 32-month follow-up the boy commenced hemodialysis at the age of 5 years, whereas his sister showed no decline in renal function.     

Follow-up of five patients with FHHNC due to mutations in the Paracellin-1 gene

Familial hypomagnesemia, hypercalciuria and nephrocalcinosis (FHHNC) is a rare autosomal recessive inherited disorder that has recently been attributed to a defect in the paracellin-1 ( PCLN-1)gene, encoding for a protein responsible for the tubular reabsorption of magnesium and calcium. Limited information is available on clinical course, therapy and prognosis. We provide information on five patients with FHHNC and their follow-up at our institution. Polyuria, nephrocalcinosis and hyperuricemia were the main clinical findings of a diagnosis at a median age of 4.4 years. The clinical course of PCLN-1 mutations as presented in this study is highly variable, ranging from compensated renal failure to end-stage renal failure - as happened in two of our patients. The progression to renal failure cannot be deduced from the initial presentation. Medical treatment does not appear to influence the progression of the disease. Despite calcium and magnesium substitution, normal values could not be achieved in these patients. Early treatment with vitamin D and calcium was essential to maintain growth. Adequate treatment allows for a normal height and pubertal development.     

Renal hypomagnesemia,hypercalciuria and nephrocalcinosis in a middle-aged man

We report a 41-year-old man with hypomagnesemia, hypercalciuria, nephrocalcinosis, myopia and horizontal nystagmus. The hypomagnesemia was due to primary renal magnesium loss. He was diagnosed as having the syndrome of renal hypomagnesemia, hypercalciuria and nephrocalcinosis. This is a rare condition generally diagnosed by the first to third decades of life. Renal failure is common and end-stage renal disease can occur in children or young adults. The patient was treated with oral magnesium, chlorthalidone, potassium citrate and allopurinol and was followed up for 3 years. Treatment resulted in an improvement in hypercalciuria but serum magnesium level could not be normalized. The patient's renal function remains stable, with a mild degree of renal insufficiency.     

Inherited disorders of renal magnesium handling

The genetic basis and cellular defects of a number of primary magnesium wasting diseases have been elucidated over the past decade. This review correlates the clinical pathophysiology with the primary defect and secondary changes in cellular electrolyte transport. The described disorders include (1) hypomagnesemia with secondary hypocalcemia, an earlyonset, autosomal-recessive disease segregating with chromosome 9q12-22.2; (2) autosomal-dominant hypomagnesemia caused by isolated renal magnesium wasting, mapped to chromosome 11q23; (3) hypomagnesemia with hypercalciuria and nephrocalcinosis, a recessive condition caused by a mutation of the claudin 16 gene (3q27) coding for a tight junctional protein that regulates paracellular Mg(2+) transport in the loop of Henle; (4) autosomal-dominant hypoparathyroidism, a variably hypomagnesemic disorder caused by inactivating mutations of the extracellular Ca(2+)/Mg(2+)-sensing receptor, CASR: gene, at 3q13.3-21 (a significant association between common polymorphisms of the CASR: and extracellular Mg(2+) concentration has been demonstrated in a healthy adult population); and (5) Gitelman syndrome, a recessive form of hypomagnesemia caused by mutations in the distal tubular NaCl cotransporter gene, SLC12A3, at 16q13. The basis for renal magnesium wasting in this disease is not known. These inherited conditions affect different nephron segments and different cell types and lead to variable but increasingly distinguishable phenotypic presentations. No doubt, there are in the general population other disorders that have not yet been identified or characterized. The continued use of molecular techniques to probe the constitutive and congenital disturbances of magnesium metabolism will increase the understanding of cellular magnesium transport and provide new insights into the way these diseases are diagnosed and managed.     

Correction of ionized plasma magnesium during cardiopulmonary bypass reduces the risk of postoperative cardiac arrhythmia

We conducted this randomized controlled trial to determine whether the intraoperative measurement and correction of ionized plasma magnesium can reduce the risk of cardiac arrhythmia after cardiopulmonary bypass. Eighty-five patients presenting for coronary artery bypass grafting were randomly assigned either to the magnesium-corrected group, which received magnesium sulfate on the basis of measured levels of ionized plasma magnesium (n = 43), or to the control group, in which magnesium levels were identified but not corrected (n = 42). Ionized magnesium was determined with an ion-selective electrode with minimal delay, and further samples were taken for laboratory analysis of total plasma magnesium. All patients had Holter electrocardiogram monitoring for 72 h after surgery. Total hypomagnesemia (45 patients; 53% of all patients) was more common than ionized hypomagnesemia (11 patients; 13%) before cardiopulmonary bypass. Both total and ionized magnesium levels declined further during the course of cardiopulmonary bypass in the control group. The incidence of ventricular tachycardia in the first 24 h was less frequent in the magnesium-corrected group (3 patients; 7%) than the control group (12 patients, 30%; P < 0.01). Patients in the magnesium-corrected group were more likely to display continuous sinus rhythm (Lown Grade 0) in the first 24 h (14 patients; 34%) than patients in the control group (2 patients, 5%; P < 0.001). Our results suggest that the intraoperative correction of ionized magnesium is associated with a reduction in postoperative ventricular arrhythmia in cardiac surgical patients. IMPLICATIONS: In this study the correction of ionized plasma magnesium during cardiopulmonary bypass was guided by measurements from an ion-selective electrode. This intervention resulted in a reduction in the incidence of postoperative ventricular tachycardia and an increased frequency of continuous sinus rhythm. Ion-selective electrodes constitute a convenient near-patient test, providing a basis for the targeted replacement of ionized plasma magnesium.     

Familial hypomagnesemia with hypercalciuria and nephrocalcinosis: report of three Turkish siblings

Familial hypomagnesemia with hypercalciuria and nephrocalcinosis (FHHNC), an autosomal recessive renal tubular disorder is characterized by the impaired tubular reabsorption of magnesium and calcium in the thick ascending limb of the loop of Henle. This disease is caused by mutations in the claudin-16 gene (CLDN16), which encodes the tight junction protein, claudin-16. Claudin-16 belongs to the claudin family and regulates the paracellular transport of magnesium and calcium. Here, we report on three Turkish siblings with typical clinical features of FHHNC in association with the homozygous mutation Leu151Phe.     

Whole blood ionized magnesium: age-related differences in normal values and clinical implications of ionized hypomagnesemia in patients undergoing surgery for congenital cardiac disease

OBJECTIVES: We sought to (1) determine reference values for whole blood ionized magnesium concentrations in newborns, children, and young adults and (2) evaluate the frequency and clinical implications of ionized hypomagnesemia in patients undergoing surgery for congenital heart disease. METHOD: We prospectively measured ionized magnesium concentrations in 299 subjects (113 control subjects and 186 patients undergoing surgery for congenital heart disease). Subjects were categorized by age. In the surgical group blood samples were obtained before bypass, during bypass (cooling and rewarming), after bypass, and during admission to the intensive care unit. Ionized hypomagnesemia was defined as ionized magnesium level 2 standard deviations below the mean of control subjects in the same age group. Patients were analyzed, controlling for cardiopulmonary bypass time. RESULTS: In the control group ionized magnesium concentrations differed by age. Neonates and adults showed lower ionized magnesium concentrations compared with those of other age groups. Infants exhibited the highest ionized magnesium concentration. In the surgical group patients older than 1 month showed a higher proportion of ionized hypomagnesemia compared with that found in neonates at baseline (P <.001), after bypass (P =. 03), and at admission to the intensive care unit (P =.02). Controlling for cardiopulmonary bypass time, patients older than 1 month who were hypomagnesemic during bypass showed longer intubation time (P =.001) and longer intensive care stay (P =.01) and tended to have a higher pediatric severity of illness score on intensive care admission (P =.14) compared with patients without ionized hypomagnesemia. CONCLUSIONS: There are age-related differences in normal ionized magnesium concentrations. Ionized hypomagnesemia is a common and clinically relevant occurrence among patients older than 1 month of age undergoing surgery for congenital heart disease.     

Aminoglycosides and renal magnesium homeostasis in humans.

BACKGROUND: The use of aminoglycosides has been linked with hypomagnesaemia in scattered reports. The objective of the study was to measure prospectively the effect of treatment with the aminoglycoside amikacin on renal magnesium homeostasis. METHODS: Twenty-four cystic fibrosis patients (aged 9-19 years) admitted because of exacerbation of pulmonary symptoms caused by Pseudomonas aeruginosa were treated with the aminoglycoside amikacin and the cephalosporin ceftazidime for 14 days. Renal values and plasma and urinary electrolytes were measured before and at the end of the systemic anti-pseudomonal therapy. RESULTS: In the patients with cystic fibrosis, treatment with amikacin and ceftazidime did not modify plasma creatinine or urea and plasma or urinary sodium, potassium and calcium. Treatment with amikacin and ceftazidime significantly decreased both plasma total magnesium (from 0.77 (0. 74-0.81) to 0.73 (0.71-75) mmol/l; median and interquartile range) and ionized magnesium (from 0.53 (0.50-0.55) to 0.50 (0.47-0.52) mmol/l) concentration and increased fractional urinary magnesium excretion (from 0.0568 (0.0494-0.0716) to 0.0721 (0.0630-0.111)) and total urinary magnesium excretion (from 30.7 (26.5-38.0) to 38.5 (31. 5-49.0) micromol/l glomerular filtration rate). CONCLUSIONS: The present study demonstrates that systemic therapy with amikacin plus ceftazidime causes mild hypomagnesaemia secondary to renal magnesium wasting even in the absence of a significant rise in circulating creatinine and urea.     

A familial hypomagnesemia--hypercalciuria (Manz syndrome)

We report a case of a rare inherited tubular disorder of linked transport of magnesium and calcium at the level of ascending limb of loop of Henle, characterized by hypomagnesemia, hypercalciuria and nephrocalcinosis, known as "Manz syndrome," who presented with polyuria, nystagmus and recurrent episodes of tetany with radiological evidence of rickets and nephrocalcinosis.     

Renal magnesium wasting in two families with autosomal dominant inheritance

Hypomagnesemia due to isolated renal magnesium loss was demonstrated in two unrelated families with autosomal dominant mode of inheritance. Magnesium infusions performed in two patients showed not only a reduced renal magnesium threshold but also a lowered renal tubular maximum for magnesium. All members of both families who presented with hypomagnesemia had also a lowered excretion of calcium in the urine, presumably as a consequence of increased reabsorption in Henle's loop.     

Serum ionized magnesium levels in type 2 diabetic patients with microalbuminuria or clinical proteinuria

BACKGROUND/AIMS: The association between microalbuminuria and magnesium depletion is a controversial issue, and serum ionized magnesium levels have not been previously studied in patients with different grades of diabetic nephropathy. Therefore, the aim of this study was to evaluate circulating ionized magnesium concentrations in patients with non-insulin-dependent diabetes mellitus (NIDDM) and incipient or overt diabetic nephropathy. METHODS: We measured fasting plasma glucose, creatinine, creatinine clearance estimate, total cholesterol and triglycerides, and serum ionized magnesium (ion-selective electrodes, ISE) in 30 NIDDM patients with urinary albumin excretion rate (UAER) <20 microg/min (normoalbuminuria), 30 NIDDM patients with microalbuminuria (20 < UAER < 200 microg/min), 30 NIDDM patients with clinical proteinuria (UAER >200 microg/min), and 20 healthy subjects. RESULTS: Serum ionized magnesium levels were significantly reduced in diabetic patients when compared to control subjects (0.39 +/- 0.06 vs. 0.58 +/- 0.05 mmol/l, p < 0.001). Moreover, diabetic patients with microalbuminuria or clinical proteinuria showed a significant decrease in serum ionized magnesium with respect to normoalbuminuria group (normoalbuminuria: 0.45 +/- 0. 02 mmol/l; microalbuminuria: 0.36 +/- 0.05 mmol/l, p < 0.001; clinical proteinuria: 0.35 +/- 0.04 mmol/l, p < 0.001). Serum ionized magnesium showed a significant negative correlation with plasma HbA1c and triglycerides in both microalbuminuria and clinical proteinuria groups. Multiple linear regression analysis showed that circulating ionized magnesium levels decrease together with the increase of plasma HbA1c and triglycerides in NIDDM patients with incipient or overt nephropathy, also after adjusting for age, sex, BMI, diabetes duration, systolic and diastolic blood pressure, hypoglycemic therapy, plasma creatinine, creatinine clearance, plasma cholesterol and fasting glucose. CONCLUSIONS: Microalbuminuria and clinical proteinuria, as well as poor glycometabolic control and hypertriglyceridemia, are associated to relevant alterations in magnesium metabolism, and the measurement of serum ionized magnesium seems to represent a useful biochemical tool for the study of magnesium disturbances in patients with different grades of diabetic nephropathy.     

Two heterozygous mutations of CLDN16 in a Japanese patient with FHHNC

Familial hypomagnesemia with hypercalciuria and nephrocalcinosis (FHHNC, MIN 248250) is a rare autosomal recessive tubular disorder that eventually progresses to renal failure. However, the progression to end-stage renal failure can vary from patient to patient. A primary defect is related to impaired tubular resorption of magnesium and calcium in the thick ascending limb of Henles loop. Recently, paracellin-1 was identified as a renal tight junction protein predominantly expressed in TAL. Mutations of its gene (CLDN16) have been shown to cause FHHNC. We describe a sporadic Japanese case of FHHNC. The male patient showed hematuria, hypercalciuria, and nephrocalcinosis at 5 years of age. Hypomagnesemia was also noticed at this time. As renal function gradually deteriorated, further evaluation was performed at 14 years of age and a diagnosis of FHHNC was made. Despite several medications (magnesium supplementation, citrate, and hydrochlorothiazide), he eventually progressed to renal insufficiency at 19 years of age. Analysis of the CLDN16 gene demonstrated two heterozygous mutations (R149Q and R216C). Mutations of the same amino acids have already been described in FHHNC and thus these mutations might be the cause of the disease in our patient. Hence, we confirm the genetic impairment of the CLDN16 gene in a Japanese patient with FHHNC.     

Familial hypomagnesemia with hypercalciuria and nephrocalcinosis associated with CLDN16 mutations

Familial hypomagnesemia with hypercalciuria and nephrocalcinosis (FHHNC), an autosomal recessive renal tubular disorder, is characterized by the impaired tubular reabsorption of magnesium and calcium in the thick ascending limb of the loop of Henle and an eventual progression to end-stage renal disease. Recent studies have reported that this disease is caused by mutations in the CLDN16 gene, which encodes the tight junction protein, paracellin-1. Paracellin-1 belongs to the claudin family and regulates the paracellular transport of magnesium and calcium. Here, we report on two Korean siblings with typical clinical features of FHHNC in association with compound heterozygous mutations, G233C and 800delG, in CLDN16. Their parents were asymptomatic heterozygous carriers of the single mutations. This is the first report of FHHNC in Korea, and the mutations reported are novel.