Nephrogenic diabetes insipidus, thiazide treatment and renal cell carcinoma

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1 Nephrol Dial Transplant (2006) 21: doi: /ndt/gfk024 Advance Access publication 19 January 2006 Case Report Nephrogenic diabetes insipidus, thiazide treatment and renal cell carcinoma Mohamed Zaki 1, Torsten Scho neberg 2, Tareq Al Ajrawi 3, Abdul Nasser Al Said 4, Katrin Sangkuhl 2 and Holger Ro mpler 2 1 Pediatric Department, Farwania Hospital, Safat, Kuwait, 2 Institute of Biochemistry, Department of Molecular Biochemistry, Medical Faculty, University of Leipzig, Leipzig, Germany, 3 Pathology Unit, Laboratory Department, Farwania Hospital, Safat, Kuwait and 4 Surgical Department, Farwania Hospital, Safat, Kuwait Keywords: aquaporin-2; mutation; nephrogenic diabetes insipidus; renal cell carcinoma; thiazide diuretics Introduction Congenital nephrogenic diabetes insipidus (NDI) is a rare disorder characterized by the kidneys inability to respond to vasopressin (AVP). As a consequence, the kidney loses its concentrating ability and produces large volumes of hypotonic urine, which may lead to severe dehydration and electrolyte imbalance, mainly hypernatraemia and hyperchloraemia [1]. NDI can be accompanied by megacystis, pelvis dilatation, hydronephrosis, mental retardation and even, inner ear deafness [2,3]. Two candidate genes have been identified in humans as causes of three inherited NDI forms. The X chromosome-linked NDI is caused by inactivating mutations in the V2 vasopressin receptor (AVPR2) gene [4]. Males are seriously affected by X chromosome-linked NDI if they inherit the mutant gene, whereas females are usually not or only mildly (partial NDI) affected. The autosomal recessive and dominant NDI forms are extremely rare types of inherited NDI, affecting both genders, and are caused by mutations in the aquaporin-2 (AQP2) gene [5]. Case After a full-term pregnancy, a Bedouin-Arab girl was referred to us at the age of 50 days, because of fever, Correspondence and offprint requests to: Dr T. Scho neberg, Institute of Biochemistry, Molecular Biochemistry, Medical Faculty, University of Leipzig, Johannisallee 30, Leipzig, Germany. schoberg@medizin.unileipzig.de refusal to feed, occasional vomiting and poor weight gain. She is the first-born child of healthy cousin parents who subsequently had five healthy children (Figure 1A). Her initial analysis showed moderate dehydration and hypernatraemia (Table 1), which was corrected by parenteral fluid substitution. However, the girl was readmitted 2 weeks later with the same symptoms. She had lost weight and showed significant hypernatraemia (Table 1). Given the association of dehydration with hypernatraemia, increased serum osmolality and decreased urine osmolality, diabetes insipidus (DI) was considered and a vasopressin-response test was performed. Failure to increase urinary osmolality 1 h after intramuscular injection of 5 mg desmopressin suggested NDI. To confirm this diagnosis by molecular genetic analysis, genomic DNA from the patient and her parents was prepared and subjected to polymerase chain reaction (PCR) amplification of the coding sequence of the AQP2 gene, including parts of the flanking introns. DNA sequence analysis revealed a novel missense mutation (Ile 107 Asn). The patient was homozygous for this mutation, whereas both parents were heterozygous carriers (Figure 1B). A number of co-segregating single polymorphisms within the coding region (codon 167, TCC! TCT) and within introns revealed the identity of both parental Ile 107 Asn alleles and supported the consanguine relation of the parents. The child was treated with hydrochlorothiazide (3 mg/kg/day) and indomethacin (3 mg/kg/day). However, long-term indomethacin therapy was discontinued because of significant gastric irritation. At the age of 7 years, intracranial calcification was detected by computed tomography scan of the brain. Ultrasonography of the renal system showed progressive dilation of her ureters and urinary bladder. At the age of 16 years, she was found to have a right renal mass (Figure 2), which proved to be a renal cell carcinoma (stage T1 N0 M0) and radial nephrectomy was performed (Figure 2). The patient did not require ß The Author [2006]. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved. For Permissions, please journals.permissions@oxfordjournals.org

2 NDI and renal cell carcinoma 1083 Fig. 1. Identification of a novel missense mutation in AQP2. (A) The pedigree of the investigated family is presented. (B) Genomic DNA was prepared from blood samples and fragments spanning the entire coding exons of the AQP2 gene were amplified by PCR as described [17]. PCR fragments were directly sequenced by an automated sequencer. Sequence traces containing the mutated position in exon 1 of a wild-type control individual, the mother (III-2) and the patient (IV-1) are shown. Table 1. Clinical parameters of the index patient 50 days 64 days Weight (kg) Serum-Na þ (mmol/l) Serum-K þ (mmol/l) Serum-Cl (mmol/l) Serum-HCO 3 (mmol/l) Serum osmolality (mosmol/kg) ND 340 Urinary osmolality (mosmol/kg) ND 79 Urine specific gravity ND 1004 Vasopressin (pmol/l) ND 12.9 ND, not determined. chemo- or radiotherapy. After >1 year, no tumour recurrence was detected in a follow-up computed tomography scan and the patient is under continuous surveillance by ultrasonography every 3 months. She is currently on no drug therapy (patient and family refused any medication) and continues to pass 6 7 l urine per day. Her current weight is 41 kg and height is 150 cm (both below the 5th percentile for the corresponding age). Discussion To date, about 25 mutations of the AQP2 gene have been identified in families with autosomal recessive NDI. Most missense mutations have been found in the transmembrane domains (TMD) and in pore-forming loops B and E (Figure 3). In the described case, all the clinical and laboratory findings and consanguinity of the parents suggested an inherited NDI. The diagnosis was further strengthened by the identification of a novel homozygous missense mutation (Ile 107 Asn) in the AQP2 gene. Ile 107 is located at the C-terminal end of TMD3 (Figure 3), as suggested by the position of the corresponding Ile 111 in the AQP1 crystal structure [6]. Ile 107 has a hydrophobic site chain. The hydrophobicity of this position is highly preserved during 200 million years of AQP2 evolution and only the hydrophobic Leu residue can substitute for Ile (Figure 3). Further, the corresponding positions of Ile 107 in human AQP paralogs always contain hydrophobic amino acid residues, such as Ile (AQP1, AQP9), Leu (AQP3, AQP7, AQP10) or Val (AQP4 6, AQP8). Therefore, it is very likely that substitution of Ile 107 in AQP2 by the more hydrophilic Asn residue interferes with proper

3 1084 M. Zaki et al. Fig. 2. Detection of a renal tumour in the proposita. (A) Abdominal ultrasonography showed a well-defined mass ( cm) with a heterogeneous echo pattern at the lower pole of the right kidney. (B) An abdominal i.v.-contrast computed tomography was performed and revealed an enlarged right kidney with a well-circumscribed mass measuring cm at the lower pole of the kidney. (C) Excision of the right kidney was performed (kidney size: cm). The tumour was confined to the lower pole and compressed the surrounding renal tissues without penetrating the capsule of the kidney. Histopathological analysis confirmed a non-capsulated renal cell carcinoma. AQP2 function. Further in vitro investigation with heterologously expressed mutant AQP2 will clarify the molecular basis of Ile 107 Asn dysfunction. However, a dominant-negative effect of the mutant AQP2, as found in the autosomal dominant NDI [7], is very unlikely because of the lack of NDI symptoms in the parents. To date, there is no causal cure for inherited NDI. Affected patients are treated with abundant water intake, a low-sodium diet and thiazide diuretics often in combination with indomethacin. Long-term treatment with indomethacin is often limited by gastric adverse effects, as in the described case, whereas long-term treatment with thiazide diuretics is usually considered to be safe. However, recent analyses suggest an increased risk for renal cell carcinoma and colon carcinoma in patients long-term treated with thiazides, especially in women [8,9]. To the best of our knowledge, the development of a renal cell carcinoma in NDI patients or in NDI animal models [10,11] has not been reported before. Although the occurrence of autosomal recessive NDI together with a renal cell carcinoma may be of unrelated coincidence, one has to consider thiazide diuretics as one possible cause. Thiazide diuretics are extensively used in antihypertensive therapy. Although hypertension has been manifold documented to be a general risk factor for carcinoma, and renal cell carcinoma appears to be preferentially associated with hypertension [12], meta-analyses estimated a 2-fold increase in the risk of renal cell carcinoma, especially in woman, when thiazide diuretics were used [13]. In the presented case, the female patient received a well-established hydrochlorothiazide therapy with a cumulative dose of >300 g over the past 16 years. Risk factors for renal cell carcinoma, such as hypertension, obesity or smoking [14] can be excluded in this case. However, a hereditary contribution, because of consanguineous parents, in cancer development cannot be ruled out. Herein, we describe a rare case of an autosomal recessive NDI harboring a new AQP2 mutation, who developed a renal cell carcinoma. Although the causal link between hereditary NDI treated with thiazide and the development of renal cell carcinoma remains open, the presented case adds to an increasing number of associations between thiazide diuretics and renal cell carcinoma. NDI patients may have an even higher risk because of the early and long-term thiazide exposure. As a consequence, NDI patients treated long-term with thiazide diuretics should be periodically screened for occult renal cell carcinoma. Alternatively, new therapeutic protocols which include, for example, sildenafil [15] and cyclooxygenase-2 inhibitors [16] may reduce the need of thiazide diuretics

4 NDI and renal cell carcinoma 1085 Fig. 3. Localization of Ile 107 Asn and structural conservation during AQP2 evolution. The found mutation Ile 107 Asn is located at the very end of TMD3. Public sequence databases (NCBI and genomic trace archives) were utilized to determine the evolutionary conservation of the amino acid sequence in avian and mammalian AQP2 orthologs within the mutated region. All AQP2 sequences were aligned using the Clustal V and the PAM matrices implemented in the software package MegAlign 4.00 (DNASTAR Inc., Madison, WI, USA). Amino acid residues that are identical to the human AQP2 sequence are boxed. The numbering of Ile 107 refers to the amino acid sequence of the human AQP2. at least for NDI patients with V2 vasopressin-receptor defects. Acknowledgements. We thank Peter Gross for helpful comments and discussion. The work on NDI is supported by the Deutsche Forschungsgemeinschaft, Bundesministerium fu r Bildung und Forschung, IZKF Leipzig, Leipzig Formel 1 programme to K.S. and H.R. and the NDI foundation ( Conflict of interest statement. None declared. References 1. Bichet DG. Nephrogenic diabetes insipidus. Am J Med 1998; 105: Schulz A, Sangkuhl K, Lennert T et al. Aminoglycoside pretreatment partially restores the function of truncated V(2) vasopressin receptors found in patients with nephrogenic diabetes insipidus. J Clin Endocrinol Metab 2002; 87: Pasel K, Schulz A, Timmermann K et al. Functional characterization of the molecular defects causing nephrogenic

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