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      An Unusual Patient with Hypercalciuria, Recurrent Nephrolithiasis, Hypomagnesemia and G227R Mutation of Paracellin-1

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          Abstract

          A 19-year-old female patient with hypercalciuria and recurrent nephrolithiasis/urinary tract infection unresponsive to thiazide type diuretics is presented. The patient first experienced nephrolithiasis at the age of 4 years. Afterwards, recurrent passages of stones and urinary tract infection occurred. On diagnostic evaluation at the age of 19 years, she also had hypocitraturia and hypomagnesemia. Her serum calcium concentrations were near the lower limit of normal (8.5–8.8 mg/dl; normal range: 8.5–10.5), her serum magnesium concentrations were 1.15–1.24 mg/dl (normal range: 1.4–2.5) and urinary calcium excretion was 900 mg/24 h. PTH concentrations were increased (110–156 pg/ml; normal range: 10–65). We tried to treat the patient with hydrochlorothiazide at a dose of 50 mg/day. During treatment with thiazide diuretics, PTH concentration remained high and the patient had recurrent urinary tract infections and passages of stones. Serum magnesium concentration did not normalize even under the parenteral magnesium infusion. Her mother had a history of nephrolithiasis 20 years ago. Severe hypomagnesemia in association with hypercalciuria/urinary stones is reported as a rare autosomal recessive disorder caused by impaired reabsorption of magnesium and calcium in the thick assending limp of Henle’s loop. Recent studies showed that mutations in the CLDN16 gene encoding paracellin-1 cause the disorder. In exon 4, a homozygous nucleotide exchange (G679C) was identified for the patient. This results in a point mutation at position Glycine227, which is replaced by an Arginine residue (G227R). The mother was heterozygous for this mutation. G227 is located in the fourth transmembrane domain and is highly conserved in the claudin gene family. This case indicates the pathogenetic role of paracellin-1 mutation in familial hypomagnesemia with hypercalciuria and nephrocalcinosis and further underlines the risk of stone formation in heterozygous mutation carriers.

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          Most cited references 13

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          Randomized study of Lapatinib alone or in combination with trastuzumab in women with ErbB2-positive, trastuzumab-refractory metastatic breast cancer.

          Preclinical studies in ErbB2-positive cell lines demonstrated a synergistic interaction between lapatinib and trastuzumab, suggesting that dual blockade is more effective than a single agent alone. EGF104900 compared the activity of lapatinib alone or in combination with trastuzumab in patients with ErbB2-positive, trastuzumab-refractory metastatic breast cancer (MBC). Patients with ErbB2-positive MBC who experienced progression on prior trastuzumab-containing regimens were randomly assigned to receive either lapatinib alone or in combination with trastuzumab. The primary end point was progression-free survival (PFS). Secondary efficacy end points included overall response rate (ORR), clinical benefit rate (CBR; complete response, partial response, and stable disease for >/= 24 weeks), and overall survival (OS). In the intent-to-treat population (N = 296) who received a median of three prior trastuzumab-containing regimens, the combination of lapatinib with trastuzumab was superior to lapatinib alone for PFS (hazard ratio [HR] = 0.73; 95% CI, 0.57 to 0.93; P = .008) and CBR (24.7% in the combination arm v 12.4% in the monotherapy arm; P = .01). A trend for improved OS in the combination arm was observed (HR = 0.75; 95% CI, 0.53 to 1.07; P = .106). There was no difference in ORR (10.3% in the combination arm v 6.9% in the monotherapy arm; P = .46). The most frequent adverse events were diarrhea, rash, nausea, and fatigue; diarrhea was higher in the combination arm (P = .03). The incidence of symptomatic and asymptomatic cardiac events was low (combination therapy = 2% and 3.4%; monotherapy = 0.7% and 1.4%, respectively). Despite disease progression on prior trastuzumab-based therapy, lapatinib in combination with trastuzumab significantly improved PFS and CBR versus lapatinib alone, thus offering a chemotherapy-free option with an acceptable safety profile to patients with ErbB2-positive MBC.
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              Recurrent renal stone disease-advances in pathogenesis and clinical management.

              Kidney stones are common in industrialised nations: up to 15% of white men and 6% of all women will develop one stone, with recurrence in about half these people. Risk factors for formation of stones include urinary promoters (calcium, urate, cystine, and sodium) and urinary inhibitors (magnesium, citrate, and nephrocalcin). Acute renal colic can be precipitated by dehydration and reduced urine output, increased protein intake, heavy physical exercise, and various medicines. Such colic manifests as severe loin pain and can be accompanied by frequent urination, dysuria, oliguria, and haematuria. Documentation of stone characteristics is extremely important: type, size, location, and underlying metabolic abnormalities. Such details can be obtained with a combination of biochemical investigations, microscopic examination of urine under polarised light, and an intravenous pyelogram. Ultrasonography and plain abdominal radiographs are also useful, especially for patients unable to tolerate an intravenous pyelogram. Acute therapy includes complete pain relief, rehydration, and encouragement of diuresis. Long-term management encompasses education of patients with regard to diet and fluid intake, control of calciuria, citrate replacement, and treatment of any underlying urinary-tract infection or metabolic abnormality. Stones smaller than 5 mm normally pass spontaneously, whereas larger stones, as big as 2 cm, are best treated with extracorporeal shock-wave lithotripsy. All physicians should have a clear understanding of the pathogenesis and clinical management (acute treatment and prevention of recurrence) of renal stone disease.
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                Author and article information

                Journal
                HRE
                Horm Res Paediatr
                10.1159/issn.1663-2818
                Hormone Research in Paediatrics
                S. Karger AG
                1663-2818
                1663-2826
                2006
                September 2006
                20 September 2006
                : 66
                : 4
                : 175-181
                Affiliations
                aDepartment of Endocrinology and Metabolism, Istanbul Faculty of Medicine, Istanbul University, Istanbul, Turkey; bPediatric Nephrology, University Children’s Hospital, Inselspital, Berne, Switzerland
                Article
                94253 Horm Res 2006;66:175–181
                10.1159/000094253
                16804318
                © 2006 S. Karger AG, Basel

                Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher. Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug. Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.

                Page count
                Figures: 2, Tables: 1, References: 27, Pages: 7
                Categories
                Novel Insights from Clinical Practice

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