Search

Derangements in mineral metabolism are one of the main entities in chronic kidney disease-mineral and bone disorder (CKD-MBD). This is the second of a two-part review of the physiology and pathophysiology of calcium homeostasis in feline CKD-MBD. While dysregulation in calcium homeostasis is known to contribute to the development of vascular calcification in CKD, evidence characterising the relationship between serum calcium concentration and nephrocalcinosis and nephrolithiasis is limited. Recently, fibroblast growth factor 23 (FGF23) and α-Klotho have gained increased research interest and been shown to be important biomarkers for the prediction of CKD progression in human patients. However, conflicting evidence exists on their role in calcium homeostasis and vascular and soft tissue calcification. This review details the pathophysiology of calcium disorders associated with CKD-MBD and its implications on vascular and soft tissue mineralisation in human and feline patients. Further prospective studies investigating the clinical consequences of calcium disturbances in cats with CKD are warranted and this may provide additional insight into the pathophysiology of feline CKD-MBD., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Background: The occurrence of hypomagnesemia in patients with primary hyperparathyroidism (PHPT) has been noted previously; however, the association of hypomagnesemia and severity of primary hyperparathyroidism remains unknown. The present study aimed to evaluate the association of hypomagnesemia with biochemical and clinical manifestations in patients with PHPT., Methods: This was a retrospective study conducted at a tertiary hospital. We obtained data from 307 patients with PHPT from January 2010 through August 2020. Data on demographics, history, laboratory findings, bone densitometry findings, and clinical presentation and complications were collected and were compared in normal magnesium group vs hypomagnesemia group., Results: Among the 307 patients with PHPT included in our study, 77 patients (33/102 [32.4%] males and 44/205 [21.5%] females) had hypomagnesemia. Mean hemoglobin levels in the hypomagnesemia group were significantly lower than those in the normal magnesium group in both males and females. In contrast, patients with hypomagnesemia had a higher mean serum calcium and parathyroid hormone than individuals with normal magnesium. The typical symptoms of PHPT, such as nephrolithiasis, bone pain/fractures, polyuria, or polydipsia, were more common in the hypomagnesemia group. In addition, patients with hypomagnesemia had a higher prevalence of osteoporosis, anemia, and hypercalcemic crisis. Even after adjusting for potential confounders, including age, sex, body mass index, estimated glomerular filtration rate, and parathyroid hormone levels, these associations remained essentially unchanged., Conclusion: Biochemical and clinical evidence indicates that patients with PHPT with hypomagnesemia have more severe hyperparathyroidism than those without hypomagnesemia. In addition, PHPT patients with hypomagnesemia had a higher prevalence of osteoporosis, anemia, and hypercalcemic crisis., (© 2021. The Author(s).)

When extrapolating data from animal toxicological studies a default factor (dUF) of 100 is applied to derive a heath based guidance value. The UF takes into account the interspecies differences (ID) and the intraspecies variability (IV). When re-evaluating the safety of phosphates used as food additives nephrocalcinosis was identified as the critical endpoint. The underlying mechanism for nephrocalcinosis was attributed to the precipitation of calcium phosphate in the kidney, depending on its solubility, irrespective of the species and the population. Based on the mechanism, the volume of primary urine, for which the glomerular filtration rate (GFR) was used as a proxy, was considered to be the only parameter relevant for ID and IV. Median value of GFR in rats was 4.0 ml/min/kg bw. In humans it was 1.6 ml/min/kg bw in healthy adults and 0.9 in elderly. These values were calculated from the distribution of the GFR data from 8 studies in rats (n = 191), 16 studies in adults (n = 1540) and 5 studies in elderly (n = 2608). Multiplying the distribution of the ratio rat/healthy humans (ID) with the distribution of the ratio healthy humans/elderly human (IV) resulted in a phosphate specific factor of 4.5 (3.3-6.7) (median; 25th - 75th percentile)., (Copyright © 2020. Published by Elsevier Inc.)

Background: Reduced kidney volume (KV) following prematurity is a proxy for reduced nephron number and is associated with the development of hypertension and end-stage renal disease in adults. We investigated whether extreme prematurity affects KV, function, and blood pressure in school-aged children and if nephrocalcinosis (NC) developed during the neonatal period had additional effects., Methods: We investigated 60 children at a mean age of 7.7 years: 20 born extremely preterm (EPT < 28 weeks gestational age with NC (NC+)), 20 born EPT without NC (NC-), and 19 born as full-term infants (control). We measured KV by ultrasound, collected blood and urine samples to evaluate renal function, and measured office and 24-h ambulatory blood pressure (ABPM)., Results: Children born EPT had significantly smaller kidneys (EPT (NC+ NC-) vs control (estimated difference, 11.8 (CI - 21.51 to - 2.09 ml), p = 0.018) and lower but normal cystatin C-based glomerular filtration rate compared with control (estimated difference, - 10.11 (CI - 0.69 to - 19.5), p = 0.035). KV and function were not different between NC+ and NC- groups. Change in KV in relation to BSA (KV/BSA) from the neonatal period to school age showed significantly more EPT children with neonatal NC having a negative evolution of KV (p = 0.01). Blood pressure was normal and not different between the 3 groups. Fifty percent of EPT had a less than 10% day-to-night decline in ABPM., Conclusions: Kidney growth and volume is affected by EPT birth with NC being a potential aggravating factor. Circadian blood pressure regulation seems abnormal in EPT-born children.

The proximal tubule (PT) is responsible for the majority of calcium reabsorption by the kidney. Most PT calcium transport appears to be passive, although the molecular facilitators have not been well established. Emerging evidence supports a major role for PT calcium transport in idiopathic hypercalciuria and the development of kidney stones. This review will cover recent developments in our understanding of PT calcium transport and the role of the PT in kidney stone formation.

A 72-year-old female patient presented with an end-stage renal disease on on-line hemodiafiltration and warfarin therapy with advanced ulcerated calciphylaxis on the lower extremities, complicated by two episodes of cellulitis. She was successfully treated for 8 months with intravenous sodium thiosulfate in combination with modification of medication and dialysis treatment, careful wound care, and other supportive measures. Calciphylaxis is an uncommon life-threatening systemic disease, mostly occurring in patients with chronic kidney disease and other risk factors. Vascular calcifications and inflammation lead to thrombotic occlusions of the cutaneous and subcutaneous arterioles, which provoke livedoid painful plaques with possible progression to necrotic ulcers. Conventional treatment is supportive. In recent decades, off-label treatment with sodium thiosulfate, a potent calcium chelator, antioxidant, and vasodilator, has been increasingly reported to be highly efficient in calciphylaxis, leading to significantly lower mortality rates. Knowledge of advancement in the treatment of calciphylaxis, which was previously a highly fatal disease, is important for physicians and other professionals from various medical fields.

Nephrocalcinosis often begins on a calcium phosphate deposit, at the tip of the medullo-papillary complex (MPC) known as Randall's plaque (RP). Contextualizing proximally observed biominerals within the MPC has led us to postulate a mechanobiological switch that can trigger interstitial biomineralization at the MPC tip, remote from the intratubular biominerals. Micro X-ray computed tomography scans of human MPCs correlated with transmission and scanning electron micrographs, and X-ray energy dispersive spectrometry demonstrated novel findings about anatomically-specific biominerals. An abundance of proximal intratubular biominerals were associated with emergence of distal interstitial RP. The fundamental architecture of the MPC and mineral densities at the proximal and distal locations of the MPC differed markedly. A predominance of plate-like minerals or radially oriented plate-like crystallites within spheroidal minerals in the proximal intratubular locations, and core-shell type crystallites within spheroidal minerals in distal interstitial locations were observed. Based on the MPC anatomic location of structure-specific biominerals, a biological switch within the mineral-free zone occurring between the proximal and distal locations is postulated. The "on" and "off" switch is dependent on changes in the pressure differential resulting from changes in tubule diameters; the "Venturi effect" changes the "circumferential strain" and culminates in interstitial crystal deposits in the distal tubule wall in response to proximal tubular obstruction. These distal interstitial mineralizations can emerge into the collecting system of the kidney linking nephrocalcinosis with nephrolithiasis.

The tight junction proteins claudin-10 and -16 are crucial for the paracellular reabsorption of cations along the thick ascending limb of Henle's loop in the kidney. In patients, mutations in CLDN16 cause familial hypomagnesemia with hypercalciuria and nephrocalcinosis, while mutations in CLDN10 impair kidney function. Mice lacking claudin-16 display magnesium and calcium wasting, whereas absence of claudin-10 results in hypermagnesemia and interstitial nephrocalcinosis. In order to study the functional interdependence of claudin-10 and -16 we generated double-deficient mice. These mice had normal serum magnesium and urinary excretion of magnesium and calcium and showed polyuria and sodium retention at the expense of increased renal potassium excretion, but no nephrocalcinosis. Isolated thick ascending limb tubules of double mutants displayed a complete loss of paracellular cation selectivity and functionality. Mice lacking both claudin-10 and -16 in the thick ascending limb recruited downstream compensatory mechanisms and showed hypertrophic distal convoluted tubules with changes in gene expression and phosphorylation of ion transporters in this segment, presumably triggered by the mild decrease in serum potassium. Thus, severe individual phenotypes in claudin-10 and claudin-16 knockout mice are corrected by the additional deletion of the other claudin., (Copyright © 2017 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.)

Experimental induction of hyperoxaluria by ethylene glycol (EG) administration is disapproved as it causes metabolic acidosis while the oral administration of chemically synthesized potassium oxalate (KOx) diet does not mimic our natural system. Since existing models comprise limitations, this study is aimed to develop an improved model for the induction of dietary hyperoxaluria, and nephrocalcinosis in experimental rats by administration of naturally available oxalate rich diet. Male albino Wistar rats were divided into five groups. Group I, control; group II rats received 0.75% EG, group III rats fed with 5% KOx diet and group IV and V rats were administered with spinach extract of 250 and 500 mg soluble oxalate/day respectively, for 28 d. Urine and serum biochemistry were analyzed. After the experimental period, rats were sacrificed, liver and kidney tissue homogenates were used for antioxidant and lipid peroxidation assay. Relative change in expression of kidney injury molecule-1 (KIM-1) and crystal modulators genes in kidney tissues were evaluated. Tissue damage was assessed by histology studies of liver and kidney. Experimental group rats developed hyperoxaluria and crystalluria. Urine parameters, serum biochemistry, antioxidant profile, lipid peroxidation levels and gene expression analysis of experimental group II and III rats reflected acute kidney damage compared to group V rats. Histopathology results showed moderate hyperplasia in liver and severe interstitial inflammation in kidneys of group II and III than group V rats. Ingestion of naturally available oxalate enriched spinach extract successfully induced dietary hyperoxaluria and nephrocalcinosis in rats with minimal kidney damage.

Nephrocalcinosis (NC) is defined as deposition of calcium crystals in the renal parenchyma and tubules. This is a retrospective review of all the data of 63 children presented to Pediatric Nephrology Clinic at King Hussein Medical Center (KHMC) over a 15-year period with bilateral NC. We determine their causes, clinical presentation and evaluate their growth and renal function during their follow-up. Thirty-five (55.5%) cases were males and 28 (44.5%) were females. The median (range) age at presentation was four (2-192) months. The most common leading cause to NC was hereditary tubulopathy in 48% followed by hyperoxaluria in 35%. The cause of NC remained unknown in 3% and Vitamin D excess accounts for 5% of the cases. The most presenting symptom was a failure to thrive (68%) and the second most common symptom was abdominal pain and recurrent urinary tract infection was found in 40%, polyuria and polydipsia were found in 32% of cases, and 16% of cases were diagnosed incidentally. At a median follow-up of 38 (14-200) months, estimated glomerular filtration rate had decreased from 84.0 (42-110) mL/min per 1.73 m2 body surface area to 68.2 (10-110) mL/min/1.73 m2 body surface (P = 0.001). This study illustrated the need for a national registry of rare renal diseases to help understand the causes of these conditions in our populations and provide support to affected patients and their families.

Purpose of Review: Magnesium (Mg) imbalances are frequently overlooked. Hypermagnesemia usually occurs in preeclamptic women after Mg therapy or in end-stage renal disease patients, whereas hypomagnesemia is more common with a prevalence of up to 15% in the general population. Increasing evidence points toward a role for mild-to-moderate chronic hypomagnesemia in the pathogenesis of hypertension, type 2 diabetes mellitus, and metabolic syndrome., Recent Findings: The kidneys are the major regulator of total body Mg homeostasis. Over the last decade, the identification of the responsible genes in rare genetic disorders has enhanced our understanding of how the kidney handles Mg. The different genetic disorders and medications contributing to abnormal Mg homeostasis are reviewed., Summary: As dysfunctional Mg homeostasis contributes to the development of many common human disorders, serum Mg deserves closer monitoring. Hypomagnesemic patients may be asymptomatic or may have mild symptoms. In severe hypomagnesemia, patients may present with neurological symptoms such as seizures, spasms, or cramps. Renal symptoms include nephrocalcinosis and impaired renal function. Most conditions affect tubular Mg reabsorption by disturbing the lumen-positive potential in the thick ascending limb or the negative membrane potential in the distal convoluted tubule.

Williams-Beuren syndrome is a rare neurodevelopmental disorder, characterized by congenital heart defects, abnormal facial features, mental retardation with specific cognitive and behavioral profile, growth hormone deficiency, renal and skeletal anomalies, inguinal hernia, infantile hypercalcaemia. We report a case with Williams-Beuren syndrome associated with a single kidney and nephrocalcinosis complicated by hypercalcaemia. A male infant, aged 20 months presented growth retardation associated with a psychomotor impairment, dysmorphic features and nephrocalcinosis. He had also hypercalciuria and hypercalcemia. Echocardiography was normal. DMSA renal scintigraphy showed a single functioning kidney. The FISH generated one ELN signal in 20 metaphases read and found the presence of ELN deletion, with compatible Williams-Beuren syndrome.

Familial hypomagnesemia with hypercalciuria and nephrocalcinosis is a rare autosomal recessive renal disease caused by mutations in genes for the tight junction transmembrane proteins Claudin-16 (CLDN16) and Claudin-19 (CLDN19). We present the first case report of a Mexican family with three affected sisters carrying a p.Gly20Asp mutation in CLDN19 whose heterozygous mother showed evident hypercalciuria and normal low magnesemia without any other clinical, laboratory, and radiological symptoms of renal disease making of her an unsuitable donor. The affected sisters showed variable phenotypic expression including age of first symptoms, renal urinary tract infections, nephrolithiasis, nephrocalcinosis, and eye symptoms consisting in retinochoroiditis, strabismus, macular scars, bilateral anisocoria, and severe myopia and astigmatism. End stage renal disease due to renal failure needed kidney transplantation in the three of them. Interesting findings were a heterozygous mother with asymptomatic hypercalciuria warning on the need of carefully explore clinical, laboratory, kidney ultrasonograpy, and mutation status in first degree asymptomatic relatives to avoid inappropriate kidney donors; an evident variable phenotypic expression among patients; the identification of a mutation almost confined to Spanish cases and a 3.5 Mb block of genomic homozygosis strongly suggesting a common remote parental ancestor for the gene mutation reported.

Loss-of-function mutations of CYP24A1, the enzyme that converts the major circulating and active forms of vitamin D to inactive metabolites, recently have been implicated in idiopathic infantile hypercalcemia. Patients with biallelic mutations in CYP24A1 present with severe hypercalcemia and nephrocalcinosis in infancy or hypercalciuria, kidney stones, and nephrocalcinosis in adulthood. We describe a cohort of 7 patients (2 adults, 5 children) presenting with severe hypercalcemia who had homozygous or compound heterozygous mutations in CYP24A1. Acute episodes of hypercalcemia in infancy were the first symptom in 6 of 7 patients; in all patients, symptoms included nephrocalcinosis, hypercalciuria, low parathyroid hormone (PTH) levels, and higher than expected 1,25-dihydroxyvitamin D levels. Longitudinal data suggested that in most patients, periods of increased sunlight exposure tended to correlate with decreases in PTH levels and increases in calcemia and calciuria. Follow-up of the 2 adult patients showed reduced glomerular filtration rate and extrarenal manifestations, including calcic corneal deposits and osteoporosis. Cases of severe PTH-independent hypercalcemia associated with hypercalciuria in infants should prompt genetic analysis of CYP24A1. These patients should be monitored carefully throughout life because they may be at increased risk for developing chronic kidney disease., (Copyright © 2014 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.)

Chvostek's Sign was first described in 1876, as a clinical clue associated with patients who suffered from latent tetany, and is induced by percussion of the angle of the jaw. However, over the years many clinicians have called into question the strength of the association with latent tetany, particularly in paediatric practice. This review examines the variation in techniques used to elicit the sign in studies conducted on this phenomenon in children as well as how differences in the classification of a positive Chvostek's sign have lead to varied reports on the strength of the association. Furthermore, an appraisal of the literature regarding the proposed mechanism of Chvostek's sign is reported alongside analysing other diseases which have been associated with Chvostek's sign to uncover any unifying mechanism for the presence of this clinical sign in children.

Distal renal tubular acidosis combined with medullary sponge kidney (MSK) is not uncommon in adults, but is rare in infants. We report a 13-month-old boy with MSK who had features of distal renal tubular acidosis (nephrocalcinosis, hypercalciuria, hypocitraturia) and failed to thrive. Renal ultrasound revealed bilateral increased medullary echogenicity and nephrocalcinosis. Bilateral medullary nephrocalcinosis in the ultrasound was the first sign that alerted our pediatrician to the presence of MSK in infants. Earlier treatment may increase efficacy., (2013 S. Karger AG, Basel.)

Background: Nephrocalcinosis (NC) is an important clinical problem seen in critically ill preterm neonates treated with loop diuretics. No reliable animal models are available to study the pathogenesis of NC in preterm infants. The purpose of this study was to develop a reproducible and clinically relevant animal model of NC for these patients and to explore the impact of extracellular fluid (ECF) volume contraction induced by sodium and chloride depletion in this process., Methods: Three-week-old weanling Sprague-Dawley rats were fed diets deficient in either chloride or sodium or both. A subgroup of rats from each dietary group was injected daily with furosemide (40 mg/kg i.p.)., Results: Rats fed a control diet, with or without furosemide, or a chloride-depleted diet alone, did not develop NC. By contrast, 50% of the rats injected with furosemide and fed the chloride-depleted diet developed NC. Moreover, 94% of the rats fed the combined sodium- and chloride-depleted diet developed NC, independently of furosemide use. NC was associated with the development of severe ECF volume contraction; hypochloremic, hypokalemic, metabolic alkalosis; increased phosphaturia; and growth retardation., Conclusion: Severe ECF volume contraction induced by chronic sodium and chloride depletion appears to play an important role in the pathogenesis of NC.

The aim of this study was to analyze the etiology of nephrocalcinosis (NC) and whether it has any effect on growth and renal function in children. Forty-three children who were diagnosed with bilateral NC were studied retrospectively. Two neonates treated with furosemide and five premature infants were excluded from the study. The most common condition leading to NC was hereditary tubulopathies (50%). Data of 27 children who had a follow-up period of at least two years were examined in more detail. Of the 27 patients, the median age at first examination was 12 (range: 2-132) months and median follow-up time was 57 (range: 24-209) months. Thirteen of 27 (48.1%) patients had height standard deviation scores (hSDS) <-2 at presentation, and 6 (22.2%) patients who had normal glomerular function were still below -2 SDS at the last examination. Hypercalciuria was present in 25 (92.6%) patients at the first evaluation and in 6 (22.2%) patients at the last examination. The degree of NC worsened in 6 (22.2%), remained stable in 15 (55.5%) and decreased in 6 (22.2%) patients during the followup period. Chronic renal insufficiency (CRI) developed in 5 patients without there being any increase in the degree of NC. In conclusion, growth and renal function in these patients generally depend on the nature of the underlying disease but not the degree of NC.

Background: Hypomagnesemia is frequently encountered in hospitalized patients. The aim of this study was to determine the underlying causes of hypomagnesemia as well as the clinical and biochemical characteristics, and concomitant electrolyte and acid-base abnormalities in patients with decreased serum magnesium (Mg(2+)) levels in an internal medicine clinic., Methods: We prospectively studied adult patients who, either on admission to our clinic or during their hospitalization, were found to have hypomagnesemia (serum Mg(2+) concentration <1.3 mEq/L)., Results: One hundred and seven patients out of 2284 patients had hypomagnesemia. The incidence of hypomagnesemia was 4.7%. Malnutrition, drugs (mainly diuretics and aminoglycosides), respiratory alkalosis, diabetes mellitus, acute tubular necrosis, alcohol consumption and gastrointestinal losses were the main causes of the hypomagnesemia. In the majority of patients (80%), more than one condition may have contributed to the development of hypomagnesemia. Seventy-one patients (66.3%) exhibited at least one additional electrolyte disorder. Hypophosphatemia was the most frequent electrolyte abnormality (31.1%), followed by hypokalemia (26.1%), hyponatremia (21.5%), and hypocalcemia (22%). Seventy-eight patients (72.9%) exhibited pure or mixed acid-base disorders, mainly respiratory alkalosis (20.6%), metabolic acidosis (15.8%), and mixed metabolic alkalosis and respiratory alkalosis (18.7%)., Conclusions: Hypomagnesemia in patients hospitalized in an internal medicine clinic was of multifactorial origin. A wide array of concurrent acid-base and electrolyte disorders was evident in this population.

In the kidney, tight junction proteins contribute to segment specific selectivity and permeability of paracellular ion transport. In the thick ascending limb (TAL) of Henle's loop, chloride is reabsorbed transcellularly, whereas sodium reabsorption takes transcellular and paracellular routes. TAL salt transport maintains the concentrating ability of the kidney and generates a transepithelial voltage that drives the reabsorption of calcium and magnesium. Thus, functionality of TAL ion transport depends strongly on the properties of the paracellular pathway. To elucidate the role of the tight junction protein claudin-10 in TAL function, we generated mice with a deletion of Cldn10 in this segment. We show that claudin-10 determines paracellular sodium permeability, and that its loss leads to hypermagnesemia and nephrocalcinosis. In isolated perfused TAL tubules of claudin-10-deficient mice, paracellular permeability of sodium is decreased, and the relative permeability of calcium and magnesium is increased. Moreover, furosemide-inhibitable transepithelial voltage is increased, leading to a shift from paracellular sodium transport to paracellular hyperabsorption of calcium and magnesium. These data identify claudin-10 as a key factor in control of cation selectivity and transport in the TAL, and deficiency in this pathway as a cause of nephrocalcinosis.

Background and Objectives: Familial hypomagnesemia with hypercalciuria and nephrocalcinosis is a rare autosomal recessive renal tubular disease. It is caused by mutations in CLDN16 and CLDN19, encoding claudin-16 and -19, respectively. Familial hypomagnesemia with hypercalciuria and nephrocalcinosis is usually complicated by progressive CKD. The objectives of this study were to describe the clinical and genetic features of familial hypomagnesemia with hypercalciuria and nephrocalcinosis and analyze phenotype-genotype associations in patients with CLDN16 or CLDN19 mutations., Design, Setting, Participants, & Measurements: Data from 32 genetically confirmed patients (9 patients with CLDN16 and 23 patients with CLDN19 mutations) from 26 unrelated families were retrospectively reviewed., Results: Diagnosis was based on clinical criteria at a median age of 9.5 years and confirmed by genetic testing at a median age of 15.5 years. In total, 13 CLDN16 or CLDN19 mutations were identified, including 8 novel mutations. A founder effect was detected for the recurrent CLDN16 p.Ala139Val mutation in North African families and the CLDN19 p.Gly20Asp mutation in Spanish and French families. CKD was more frequently observed in patients with CLDN19 mutations: survival without CKD or ESRD was 56% at 20 years of age in CLDN19 versus 100% in CLDN16 mutations (log rank P<0.01). Ocular abnormalities were observed in 91% of patients with CLDN19 mutations and none of the patients with CLDN16 mutations (P<0.01). Treatments seem to have no effect on hypercalciuria and CKD progression., Conclusions: Patients with CLDN19 mutations may display more severe renal impairment than patients with CLDN16 mutations. Ocular abnormalities were observed only in patients with CLDN19 mutations.

Purpose of Investigation: The objective of this study was to evaluate the electrolytic status of Na+, K+, Ca+, and Mg2+ in serum and red blood cells in idiopathic preterm and term deliveries., Methods: The study included 105 pregnant women diagnosed with idiopathic premature delivery (study group) and 36 pregnant women with physiologically term delivery (controls). Samples of mother's blood were collected and analyzed for the level of electrolytes in the serum/plasma and red blood cells., Results: Measured values of magnesium in red blood cells in the study group were far lower than physiological values, intracellular calcium levels were higher in the study group compared to levels measured in the controls. Sodium concentrations in cells were significantly lower in subjects with premature delivery., Conclusion: The magnesium intracellular level is the best representative value of magnesium in the body.

Background/aims: Hypomagnesemia may induce hypercholesterolemia, but the contrary has not been described yet. Thus, magnesium homeostasis was evaluated in rats fed a cholesterol-enriched diet for 8 days. This study has a relevant clinical application if hypomagnesemia, due to hypercholesterolemia, is confirmed in patients with long-term hypercholesterolemia., Methods: Both hypercholesterolemic (HC) and normocholesterolemic rats (NC) were divided into sets of experiments to measure hemodynamic parameters, physiological data, maximum capacity to dilute urine (C(H)((2))(O)), variations (Δ) in [Ca(2+)](i) and the expression of transporter proteins., Results: HC developed hypomagnesemia and showed high magnesuria in the absence of hemodynamic abnormalities. However, the urinary sodium excretion and C(H)((2))(O) in HC was similar to NC. On the other hand, the responses to angiotensin II by measuring Δ [Ca(2+)](i) were higher in the thick ascending limb of Henle's loop (TAL) of HC than NC. Moreover, high expression of the cotransporter NKCC2 was found in renal outer medulla fractions of HC. Taken together, the hypothesis of impairment in TAL was excluded. Actually, the expression of the epithelial Mg(2+) channel in renal cortical membrane fractions was reduced in HC., Conclusion: Impairment in distal convoluted tubule induced by hypercholesterolemia explains high magnesuria and hypomagnesemia observed in HC., (Copyright © 2011 S. Karger AG, Basel.)

Renal injury in early life may lead to hypertension and renal disease in adulthood. In this prospective study, we estimated renal glomerular and tubular function and kidney length (KL) during the first 2 years of life of preterm infants with nephrocalcinosis (NC) associated with prematurity. The study cohort comprised 107 preterm children, 63 with NC and 44 control subjects without NC who were matched for gender, gestational age and birth weight. Kidney function was estimated based on measurements of serum creatinine (Scr), estimated glomerular filtration rate (eGFR), fractional excretion (FE) of sodium (Na), potassium (K), phosphate (P), magnesium (Mg) and uric acid (UA) and on the ratios of urinary Ca, oxalate (UOx) and citrate (UCit) to urinary creatinine (UCa/Ucr, UOx/Ucr and UCit/Ucr, respectively) calculated from morning urine collections. KL was measured by ultrasonography. Measurements were made at 40 weeks postmenstrual age and at 3, 6, 12 and 24 months of age. At 3 and 6 months, the NC group had higher UCa/Ucr, FEK and FEUA than the control group; at 12 months, only the UCa/Ucr and FEUA was still higher. The UCa/UCit ratio was higher in the NC group. Scr and eGFR did not differ between the groups at any time point. The NC group had a shorter KL up to 12 months of life (left kidney) or 24 months (right kidney). Based on these results, we conclude that NC in the preterm infants enrolled in our study was associated with impaired renal tubular function and a shorter KL in the first year of life.

Renal magnesium (Mg(2+)) and sodium (Na(+)) loss are well-known side effects of cyclosporine (CsA) treatment in humans, but the underlying mechanisms still remain unclear. Recently, it was shown that epidermal growth factor (EGF) stimulates Mg(2+) reabsorption in the distal convoluted tubule (DCT) via TRPM6 (Thébault S, Alexander RT, Tiel Groenestege WM, Hoenderop JG, Bindels RJ. J Am Soc Nephrol 20: 78-85, 2009). In the DCT, the final adjustment of renal sodium excretion is regulated by the thiazide-sensitive Na(+)-Cl(-) cotransporter (NCC), which is activated by the renin-angiotensin-aldosterone system (RAAS). The aim of this study was to gain more insight into the molecular mechanisms of CsA-induced hypomagnesemia and hyponatremia. Therefore, the renal expression of TRPM6, TRPM7, EGF, EGF receptor, claudin-16, claudin-19, and the NCC, and the effect of the RAAS on NCC expression, were analyzed in vivo in a rat model of CsA nephrotoxicity. Also, the effect of EGF administration on these parameters was studied. CsA significantly decreased the renal expression of TRPM6, TRPM7, NCC, and EGF, but not that of claudin-16 and claudin-19. Serum aldosterone was significantly lower in CsA-treated rats. In control rats treated with EGF, an increased renal expression of TRPM6 together with a decreased fractional excretion of Mg(2+) (FE Mg(2+)) was demonstrated. EGF did not show this beneficial effect on TRPM6 and FE Mg(2+) in CsA-treated rats. These data suggest that CsA treatment affects Mg(2+) homeostasis via the downregulation of TRPM6 in the DCT. Furthermore, CsA downregulates the NCC in the DCT, associated with an inactivation of the RAAS, resulting in renal sodium loss.

Sotos syndrome is characterized by overgrowth, a typical facial appearance, and learning difficulties. It is caused by heterozygous mutations, including deletions, of NSD1 located at chromosome 5q35. Here we report two unrelated cases of Sotos syndrome associated with nephrocalcinosis. One patient also had idiopathic infantile hypercalcemia. Genetic investigations revealed heterozygous deletions at 5q35 in both patients, encompassing NSD1 and SLC34A1 (NaPi2a). Mutations in SLC34A1 have previously been associated with hypercalciuria/nephrolithiasis. Our cases suggest a contiguous gene deletion syndrome including NSD1 and SLC34A1 and provide a potential genetic basis for idiopathic infantile hypercalcemia.

Rationale: Hyperaldosteronism, important in hypertension, is associated with electrolyte alterations, including hypomagnesemia, through unknown mechanisms., Objective: To test whether aldosterone influences renal Mg(2+) transporters, (transient receptor potential melastatin (TRPM) 6, TRPM7, paracellin-1) leading to hypomagnesemia, hypertension and target organ damage and whether in a background of magnesium deficiency, this is exaggerated., Methods and Results: Aldosterone effects in mice selectively bred for high-normal (MgH) or low (MgL) intracellular Mg(2+) were studied. Male MgH and MgL mice received aldosterone (350 μg/kg per day, 3 weeks). SBP was elevated in MgL. Aldosterone increased blood pressure and albuminuria and increased urinary Mg(2+) concentration in MgH and MgL, with greater effects in MgL. Activity of renal TRPM6 and TRPM7 was lower in vehicle-treated MgL than MgH. Aldosterone increased activity of TRPM6 in MgH and inhibited activity in MgL. TRPM7 and paracellin-1 were unaffected by aldosterone. Aldosterone-induced albuminuria in MgL was associated with increased renal fibrosis, increased oxidative stress, activation of mitogen-activated protein kinases and nuclear factor-NF-κB and podocyte injury. Mg(2+) supplementation (0.75% Mg(2+)) in aldosterone-treated MgL normalized plasma Mg(2+), increased TRPM6 activity and ameliorated hypertension and renal injury. Hence, in a model of inherited hypomagnesemia, TRPM6 and TRPM7, but not paracellin-1, are downregulated. Aldosterone further decreased TRPM6 activity in hypomagnesemic mice, a phenomenon associated with hypertension and kidney damage. Such effects were prevented by Mg(2+) supplementation., Conclusion: Amplified target organ damage in aldosterone-induced hypertension in hypomagnesemic conditions is associated with dysfunctional Mg(2+)-sensitive renal TRPM6 channels. Novel mechanisms for renal effects of aldosterone and insights into putative beneficial actions of Mg(2+), particularly in hyperaldosteronism, are identified.

Familial hypomagnesemia with hypercalciuria and nephrocalcinosis (FHHNC) is an autosomal recessive renal tubular disorder that typically presents with disturbances in magnesium and calcium homeostasis, recurrent urinary tract infections, and polyuria and/or polydipsia. Patients with FHHNC have high risk of the development of chronic kidney disease and end-stage renal disease in early adolescence. Multiple distinct mutations in the CLDN16 gene, which encodes a tight junction protein, have been found responsible for this disorder. In addition, mutations in another member of the claudin family, CLDN19, were identified in a subset of patients with FHHNC with visual impairment. The claudins belong to the family of tight junction proteins that define the intercellular space between adjacent endo- and epithelial cells. Claudins are especially important for the regulation of paracellular ion permeability. We describe a Brazilian family with 2 affected siblings presenting with the typical FHHNC phenotype with ocular anomalies. The clinical diagnosis of FHHNC was confirmed using mutational analysis of the CLDN19 gene, which showed 2 compound heterozygous mutations. In the context of the case vignette, we summarize the clinical presentation, diagnostic criteria, and therapeutic options for patients with FHHNC. We also review recent advances in understanding the electrophysiologic function of claudin-16 and -19 in the thick ascending limb of the loop of Henle and implications for ion homeostasis in the human body., (Copyright © 2011 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.)

Background and Objectives: The objective of this study was to describe the renal and extrarenal findings in patients with recessively inherited familial hypomagnesemia with hypercalciuria and nephrocalcinosis (FHHNC) associated with CLDN19 mutations., Design, Setting, Participants, & Measurements: Medical records of three patients from two French unrelated families with CLDN19 mutations were retrospectively examined., Results: Direct sequencing of CLDN19 identified a known variant (p.Gly20Asp) in all patients and a new missense mutation (p.Val44Met) in one (compound heterozygous). The patients' renal phenotype closely mimicked CLDN16-related nephropathy: low serum Mg2+ (<0.65 mmol/L) despite oral supplementation, hypercalciuria partly thiazide-sensitive, and progressive renal decline with ESRD reached at age 16 and 22 years in two individuals. Primary characteristics (failure to thrive, recurrent urinary tract infections, or abdominal pain), age at onset (0.8 to 16 years), and rate of renal decline were highly heterogeneous. Ocular involvement was identified in all patients, although two patients did not have visual loss. Additionally, exercise intolerance with pain, weakness, and electromyographical alterations mimicking a Ca2+/K+ channelopathy (pattern V) were observed in two of three individuals. These features persisted despite the normalization of serum K+ and Mg2+ after renal transplantation., Conclusions: Ocular manifestations, even subtle, and exercise intolerance mimicking mild to moderate periodic paralysis are two symptoms that need to be searched for in patients with FHHNC and may indicate CLDN19 mutations.

Psychological eating disorders--anorexia nervosa (AN), bulimia nervosa (BN), binge eating disorder--are an increasing public health problem with severe clinical manifestations: hypothermia, hypotension, electrolyte imbalance, endocrine disorders and kidney failure; they are of interest to nephrologists, but pathophysiological mechanisms in determining the renal involvement are still unclear. We describe pathophysiology, histological features and clinical manifestations of the most frequent psychological eating disorders: AN and BN. Regarding AN, we analyze the recent literature, and identify 3 principal pathways towards renal involvement: chronic dehydration-hypokalemia, nephrocalcinosis and chronic rhabdomyolysis. Regarding BN, we describe the correlation between obesity and many proinflammatory cytokines, chemokines, growth factors and adipokines, having potential metabolic and hemodynamic effects on the kidney and an important role in the pathogenesis of obesity-related renal injury, independently of hypertension and diabetes., (© 2011 S. Karger AG, Basel)

Introduction: Renal involvement is uncommon in sarcoidosis, occurring in less than 5% of the patients. Diagnostic delay should be minimal to improve the outcome., Methods: From 1996 to 2009, 78 patients were seen for sarcoidosis in the Department of Internal Medicine of Rouen University hospital., Results: Five patients (6.4%) had renal involvement. Diagnosis of renal involvement and sarcoidosis were concomitant in two patients while in the three remaining patients, renal manifestations occurred during the course of sarcoidosis. The five patients with renal manifestations exhibited: isolated sarcoid granulomatous interstitial nephritis (n=2), sarcoid granulomatous interstitial nephritis and nephrocalcinosis (n=2), renal failure due to hypercalcemia (n=1)., Conclusion: This series underlines that renal function tests should be performed systematically both during initial evaluation and the follow-up of patients with sarcoidosis., (Copyright © 2010 Société nationale française de médecine interne (SNFMI). Published by Elsevier SAS. All rights reserved.)

Intratubular nephrocalcinosis is defined as the histological observation of calcium oxalate and/or calcium phosphate deposits retained within the lumen of the renal tubules. As the tubular epithelium is the primary interaction partner of crystals formed in the tubular fluid, the role of the epithelial cells in nephrocalcinosis has been investigated intensively. This review summarizes our current understanding on how the tubular epithelium mechanistically appears to be involved both in the initiation and in the course of nephrocalcinosis, with emphasis on in vivo observations.

Claudin-16 (CLDN16) is critical for renal paracellular epithelial transport of Ca(2+) and Mg(2+) in the thick ascending loop of Henle. To gain novel insights into the role of CLDN16 in renal Ca(2+) and Mg(2+) homeostasis and the pathological mechanisms underlying a human disease associated with CLDN16 dysfunction [familial hypomagnesemia with hypercalciuria and nephrocalcinosis (FHHNC), OMIM 248250], we generated a mouse model of CLDN16 deficiency. Similar to patients, CLDN16-deficient mice displayed hypercalciuria and hypomagnesemia. Contrary to FHHNC patients, nephrocalcinosis was absent in our model, indicating the existence of compensatory pathways in ion handling in this model. In line with the renal loss of Ca(2+), compensatory mechanisms like parathyroid hormone and 1,25(OH)(2)D(3) were significantly elevated. Also, gene expression profiling revealed transcriptional upregulation of several Ca(2+) and Mg(2+) transport systems including Trpv5, Trpm6, and calbindin-D9k. Induced gene expression was also seen for the transcripts of two putative Mg(2+) transport proteins, Cnnm2 and Atp13a4. Moreover, urinary pH was significantly lower when compared with wild-type mice. Taken together, our findings demonstrate that loss of CLDN16 activity leads to specific alterations in Ca(2+) and Mg(2+) homeostasis and that CLDN16-deficient mice represent a useful model to further elucidate pathways involved in renal Ca(2+) and Mg(2+) handling.

Aim: To review the data of children with NC and to analyse aetiology, clinical manifestations, growth and renal function at presentation; to relate growth and renal function to changes in NC in patients with a follow-up of at least 12 months., Methods: Data of 41 children from four institutions were gathered retrospectively., Results: Presenting symptoms were failure to thrive in the first year of life (41%), urinary tract infections, bladder voiding dysfunction or abdominal pain (17%) and psychomotor delay (10%). In 24% of cases NC was detected incidentally. Glomerular function at diagnosis was normal in 83% of children. During a median follow-up of 4 yrs and 5 months in 28 patients, growth standard deviation score improved from a median of -2.2 to -1.0 and glomerular function remained stable in 89% of patients, in spite of worsening of the degree of NC in 62% of cases. The most frequent causes of NC were hereditary tubulopathies and vitamin D intoxication., Conclusion: Our results show that the treatment of the underlying conditions is associated with catch-up growth and stabilization of glomerular function in many children, but not with the reduction in the degree of NC in the majority of cases. We believe that early recognition of conditions leading to NC is clinically useful and suggest a diagnostic flowchart, which may be helpful in the approach to NC.

The thick ascending limb (TAL) of Henle mediates transcellular reabsorption of NaCl while generating a lumen-positive voltage that drives passive paracellular reabsorption of divalent cations. Disturbance of paracellular reabsorption leads to Ca(2+) and Mg(2+) wasting in patients with the rare inherited disorder of familial hypercalciuric hypomagnesemia with nephrocalcinosis (FHHNC). Recent work has shown that the claudin family of tight junction proteins form paracellular pores and determine the ion selectivity of paracellular permeability. Importantly, FHHNC has been found to be caused by mutations in two of these genes, claudin-16 and claudin-19, and mice with knockdown of claudin-16 reproduce many of the features of FHHNC. Here, we review the physiology of TAL ion transport, present the current view of the role and mechanism of claudins in determining paracellular permeability, and discuss the possible pathogenic mechanisms responsible for FHHNC.

Background and Objectives: Lowe syndrome is defined by congenital cataracts, mental retardation, and proximal tubulopathy and is due to mutations in OCRL. Recently, mutations in OCRL were found to underlie some patients with Dent disease, characterized by low molecular weight proteinuria, hypercalciuria, and nephrocalcinosis. This phenotypic heterogeneity is poorly understood., Design, Setting, Participants, & Measurements: The renal phenotype of 16 patients with Lowe syndrome (10.9 +/- 7.0 yr) under care of the authors was characterized to define overlap of symptoms with Dent disease and infer clues about OCRL function. Medical charts of patients were reviewed for data regarding glomerular filtration rate and markers of proximal tubular function., Results: All patients had low molecular weight proteinuria and albuminuria. Lysosomal enzymuria was elevated in all 11 patients assessed. Fifteen patients had hypercalciuria, and 14 aminoaciduria. Seven patients required bicarbonate and three required phosphate replacement; all others maintained normal serum values without supplementation. None of the patients had detectable glycosuria, and none had clinically overt rickets. GFR was mildly to moderately impaired and highly variable, with a trend of deterioration with age., Conclusions: Patients with Lowe syndrome do not have renal Fanconi syndrome but a selective proximal tubulopathy, variable in extent and dominated by low molecular weight proteinuria and hypercalciuria, the classical features of Dent disease. These findings suggest that OCRL and ClC-5, the chloride channel mutated in Dent disease, are involved in similar reabsorption pathways in the proximal tubule.

Idiopathic hypercalciuria is a defect occurring in 5-10% of the general population and most commonly detected in patients with calcium kidney stones or osteoporosis. Although high-penetrance autosomal dominant inheritance cannot be ruled out, hypercalciuria is probably a polygenic phenomenon. Findings obtained in monogenic disorders characterized by renal calcium stones, and/or hypercalciuria, and/or nephrocalcinosis, have suggested a number of genes as candidate genes in the pathogenesis of idiopathic hypercalciuria, i.e. soluble adenylate cyclase, calcium sensing receptor, vitamin D receptor and 1-alpha hydroxylase, sodium-phosphate co-transporter-2, claudin-16, chloride channel 5, etc. All the genetic findings obtained so far do not support the idea of different types of idiopathic hypercalciuria, i.e. absorptive, renal, and resorptive. On the contrary, they support clinical observations, which suggest idiopathic hypercalciuria as a single disorder characterized by altered calcium transport in the intestine, kidney and bone, due to various different combinations of multiple genetic and dietary players.

The production of concentrated urine inevitably leads to the precipitation of poorly soluble waste salts in the renal tubular fluid. These crystallization processes are physiologic and without consequences as long as all crystals are excreted with the urine. The retention of crystals in the renal tubules, however, may lead to tubular nephrocalcinosis. Here, we present a brief survey of the possible mechanisms involved in this process, which seems to depend predominantly on the presence of regenerating/(re)differentiating cells in the renal tubules. Crystal binding to the surface of these cells can be mediated by a number of luminal membrane molecules, including acidic fragment of nucleolin-related protein, annexin-II, osteopontin, and hyaluronan.

This retrospective survey examines the etiology of nephrocalcinosis (NC) in 40 patients (26 boys), over an 8-year period. The median age at onset of symptoms and presentation was 36 months and 72 months, respectively. Clinical features included marked failure to thrive (82.5%), polyuria (60%) and bony deformities (52.5%). The etiology of NC included distal renal tubular acidosis (RTA) in 50% patients and idiopathic hypercalciuria and hyperoxaluria in 7.5% each. Other causes were Bartter syndrome, primary hypomagnesemia with hypercalciuria, severe hypothyroidism and vitamin D excess. No cause for NC was found in 12.5% patients. Specific therapy, where possible, ameliorated the biochemical aberrations, although the extent of NC remained unchanged. At a median (range) follow up of 35 (14-240) months, glomerular filtration rate (GFR) had declined from 82.0 (42-114) ml/min per 1.73 m2 body surface area to 70.8 (21.3-126.5) ml/min per 1.73 m2 body surface area (P = 0.001). Our findings confirm that, even with limited diagnostic facilities, protocol-based evaluation permits determination of the etiology of NC in most patients.

Distal renal tubular acidosis (RTA) with nerve deafness is caused by mutations in the ATP6V1B1 gene causing defective function of the H+ -ATPase proton pump. We report five acidotic children (four males) from four unrelated families: blood pH 7.21-7.33, serum bicarbonate 10.8-14.7 mEq/l, minimum urinary pH 6.5-7.1 and fractional excretion of bicarbonate in the presence of normal bicarbonatemia 1.1-5.7%. Growth retardation and nephrocalcinosis, but not hypercalciuria, were common presenting manifestations. Hearing was normally preserved in one of the patients whose sister was severely deaf. One child was homozygous for a known mutation in exon 1: C>T (R31X). Three children were homozygous for a splicing mutation, intron 6 + 1G>A. The other patient was a compound heterozygote, having this mutation and a previously unreported mutation in exon 10: G>A (E330K). Our report shows that hearing loss is not always present in the syndrome of distal renal tubular acidosis with nerve deafness and the absence of hypercalciuria at diagnosis and describes a new mutation responsible for the disease in the ATP6V1B1 gene.

Nephrocalcinosis is the result of a myriad of hereditary or acquired diseases in the calcium, phosphate or oxalate metabolism that lead to deposition of calcium containing precipitates within the kidney. Nephrocalcinosis and nephrolithiasis are pathophysiologically tightly related and often co-exist. In the case of recurrent nephrolithiasis, nephrocalcinosis has to be excluded. Stone analysis can yield important clues to the underlying disease process. The best way to diagnose nephrocalcinosis and an accompanying nephrolithiasis is by native computer tomography scans. Untreated, nephrocalcinosis will lead to a progressive decline in renal function and eventually to end stage renal disease. Thus, for each case, the underlying disease process has to be determined and a causative therapy initiated.

Hypercalcemia is a highly prevalent complication of sarcoidosis. A medical history of a patient with sarcoidosis is shown as case report. Depending on the population studied about 2-63% of sarcoidosis patients show hypercalcemia. The major difference in the prevalence of hypercalcemia may be in part due to the undulating course of subacute sarcoidosis, so hypercalcemia may be missed when serum calcium is not frequently measured. Hypercalciuria appears to be twice as prevalent then hypercalcemia and should be looked for in every sarcoidosis patient. Hypercalcemia in sarcoidosis is due to the uncontrolled synthesis of 1,25-dihydroxyvitamin D3 by macrophages. 1,25-dihydroxyvitamin D3 leads to an increased absorption of calcium in the intestine and to an increased resorption of calcium in the bone. Immunoregulatory properties have been ascribed to 1,25-dihydroxyvitamin D3. It is an important inhibitor of interleukin-2 and of interferon-gamma-synthesis, two cytokines that are important in granuloma formation in sarcoidosis. It is thought that 1,25-dihydroxyvitamin D3 counterregulates uncontrolled granuloma formation. Treatment of hypercalcemia depends on the serum level of hypercalcemia and its persistence. Generally sarcoidotic patients should be advised to avoid sun exposition to reduce vitamin D3 synthesis in the skin, to omit fish oils that are rich of vitamin D and to produce more than two liters urine a day by adapting fluid intake. Although severe hypercalcemia seems to be rare, glucocorticosteroid treatment should be started if corrected total calcium level rises beyond 3 mmol/l. If hypercalcemia is symptomatic, treatment should be started even at lower levels. Glucocorticosteroids act by inhibition of the overly 1alpha-hydroxylase activity of macrophages. Alternatively, treatment with chloroquine or ketoconazole can be established. If isolated hypercalciuria without hypercalcemia is present with evidence for recurrent nephrolithiasis, patients can be treated with a thiazide diuretic.

Objective: The aim of our study was to examine long-term effects of nephrocalcinosis in prematurely born children., Patients and Methods: Preterm neonates (gestational age <32 weeks) with (n = 42) and without (n = 32) nephrocalcinosis were prospectively studied at a mean age of 7.5 (+/-1.0) years., Results: Blood pressure did not differ in ex-preterm infants with and without nephrocalcinosis but was significantly higher than expected for healthy children. In comparison to healthy children, more ex-preterm infants with neonatal nephrocalcinosis had (mild) chronic renal insufficiency (glomerular filtration rate: <85 mL/min per 1.73 m2; 6 of 40); this is in contrast to ex-preterm infants without neonatal nephrocalcinosis (2 of 32). Tubular phosphate reabsorption and plasma bicarbonate were significantly lower in children with nephrocalcinosis compared with children without nephrocalcinosis. In addition, more ex-preterm infants with and without nephrocalcinosis than expected had low values for plasma bicarbonate and early-morning urine osmolality compared with healthy children. Kidney length of ex-preterm infants with and without nephrocalcinosis was significantly smaller than expected in healthy children of the same height. Nephrocalcinosis persisted long-term in 4 of 42 children but was not related to blood pressure, kidney length, or renal function., Conclusions: Nephrocalcinosis in preterm neonates can have long-term sequelae for glomerular and tubular function. Furthermore, prematurity per se is associated with high blood pressure, relatively small kidneys, and (distal) tubular dysfunction. Long-term follow-up of blood pressure and renal glomerular and tubular function of preterm neonates, especially with neonatal nephrocalcinosis, seems warranted.

Aims: To assess the spontaneous resolution of neonatal nephrocalcinosis and its long term effects on renal function., Methods: Fourteen very low birthweight preterm babies with nephrocalcinosis were followed up at 5-7 years of age; 14 controls were matched for sex, gestation, and birth weight. Height, weight, blood pressure, and renal symptomatology were recorded, and a renal ultrasound scan was performed. Early morning urine osmolality and creatinine ratios of albumin, phosphate, calcium, oxalate and beta microglobulin were determined. Urea and electrolytes in the study group were determined, and glomerular filtration rate (GFR) and TmP/GFR (tubular reabsorption of phosphate per GFR) were calculated. Statistical analysis was performed on a group basis using the Mann-Whitney confidence interval., Results: Mean age was 6.9 years (range 5.81-7.68). An early morning urine osmolality >700 mOsm/kg was achieved in all cases. In two cases and four controls, the calcium/creatinine ratio was >0.7 mmol/mmol. In all cases, the GFR was normal (median 132.6 ml/min/1.73 m(2) (range 104.1-173.1)). Median TmP/GFR was 1.22 mmol/l (0.73-1.61), with two having levels below the normal range. These did not have persisting nephrocalcinosis. Nephrocalcinosis was found in three of the 12 cases scanned and one control. There were no significant differences in urine biochemistry., Conclusions: Resolution of nephrocalcinosis occurred in 75% of cases. No evidence was found to suggest that nephrocalcinosis is associated with renal dysfunction in the long term. There was evidence of hypercalciuria in the cases and controls, suggesting that prematurity may be a risk factor.

Familial Hypomagnesemia, Hypercalciuria with Nephrocalcinosis is a rare autosomal recessive inherited disease associated with renal failure. Two girls born of consanguineous parentage aged 16 and 17 presented to us with renal failure, nephrocalcinosis and bone deformities. On evaluation they were found to have hypomagnesemia, hypercalciuria, increased fractional excretion of magnesium, hypocitraturia, renal failure and elevated PTH. Their parental screening was normal. There were no extra-renal features in them. One sibling had nephrolithiasis and the stone analysis revealed calcium phosphate stones. Both were treated with sodium bicarbonate, thiazides, calcitriol and calcium carbonate. They did not require dialysis during hospital stay. Both of them were treated conservatively. They are on regular outpatient follow up. The primary defect in this syndrome is impaired paracellular reabsorption of magnesium and calcium in the medullary thick ascending limb. Mutations in the PCLN-1gene which encodes for the tight junction protein paracellin -1 is identified as the underlying genetic defect. Ocular abnormalities and deafness are the commonly reported associations. End stage renal failure usually occurs in second to third decade. Renal transplantation is the definite treatment.

Claudin-16 (Cldn16) is selectively expressed at tight junctions (TJs) of renal epithelial cells of the thick ascending limb of Henle's loop, where it plays a central role in the reabsorption of divalent cations. Over 20 different mutations in the CLDN16 gene have been identified in patients with familial hypomagnesemia with hypercalciuria and nephrocalcinosis (FHHNC), a disease of excessive renal Mg2+ and Ca2+ excretion. Here we show that disease-causing mutations can lead to the intracellular retention of Cldn16 or affect its capacity to facilitate paracellular Mg2+ transport. Nine of the 21 Cldn16 mutants we characterized were retained in the endoplasmic reticulum, where they underwent proteasomal degradation. Three mutants accumulated in the Golgi complex. Two mutants were efficiently delivered to lysosomes, one via clathrin-mediated endocytosis following transport to the cell surface and the other without appearing on the plasma membrane. The remaining 7 mutants localized to TJs, and 4 were found to be defective in paracellular Mg2+ transport. We demonstrate that pharmacological chaperones rescued surface expression of several retained Cldn16 mutants. We conclude that FHHNC can result from mutations in Cldn16 that affect intracellular trafficking or paracellular Mg2+ permeability. Knowledge of the molecular defects associated with disease-causing Cldn16 mutations may open new venues for therapeutic intervention.