A.F. van Lieburg

Clinical phenotype of nephrogenic diabetes insipidus in females heterozygous for a vasopressin type 2 receptor mutation

Nephrogenic diabetes insipidus (NDI) usually shows an X-linked recessive mode of inheritance caused by mutations in the vasopressin type 2 receptor gene (AVPR2). In the present study, three NDI families are described in which females show clinical features resembling the phenotype in males. Maximal urine osmolality in three female patients did not exceed 200 mosmol/kg and the absence of extra-renal responses to 1-desamino-8-d-arginine vasopressin was demonstrated in two of them. All affected females and two asymptomatic female family members were shown to be heterozygous for an AVPR2 mutation. Skewed X-inactivation is the most likely explanation for the clinical manifestation of NDI in female carriers of an AVPR2 mutation. It is concluded that, in female NDI patients, the possibility of heterozygosity for an AVPR2 gene mutation has to be considered in addition to homozygosity for mutations in the aquaporin 2 gene.

Renal transplant thrombosis in children

Data concerning 100 consecutive renal transplantations in children were analyzed to determine factors enhancing the risk of renal transplant thrombosis. The incidence of renal transplant thrombosis was high, at 12%. It is concluded that in addition to young age and low body weight of recipient and young age of the donor, also a high preoperative urine production contributes to the occurrence of thrombosis. Children with hypoplastic or dysplastic kidneys are at greater risk for thrombosis. Considering the influence of high urine production of the native kidneys, it may be possible to prevent thrombosis by albumin and ample fluid administration.

Discovery of aquaporins: a breakthrough in research on renal water transport

Several membranes of the kidney are highly water permeable, thereby enabling this organ to retain large quantities of water. Recently, the molecular identification of water channels responsible for this high water permeability has finally been accomplished. At present, four distinct renal water channels have been identified, all members of the family of major intrinsic proteins. Aquaporin 1 (AQP1), aquaporin 2 (AQP2) and the mercury-insensitive water channel (MIWC) are water-selective channel proteins, whereas the fourth, referred to as aquaporin 3 (AQP3), permits transport of urea and glycerol as well. Furthermore, a putative renal water channel (WCH3) has been found. AQP1 is expressed in apical and basolateral membranes of proximal tubules and descending limbs of Henle, AQP2 predominantly in apical membranes of principal and inner medullary collecting duct cells and AQP3 in basolateral membranes of kidney collecting duct cells. MIWC is expressed in the inner medulla of the kidney and has been suggested to be localised in the vasa recta. The human genes encoding AQP1 and AQP2 have been cloned, permitting deduction of their amino acid sequence, prediction of their two-dimensional structure by hydropathy analysis, speculations on their way of functioning and DNA analysis in patients with diseases possibly caused by mutant aquaporins. Mutations in the AQP1 gene were recently detected in clinically normal individuals, a finding which contradicts the presumed vital importance of this protein. Mutations in the AQP2 gene were shown to cause autosomal recessive nephrogenic diabetes insipidus. The renal unresponsiveness to arginine vasopressin, which characterises this disease, is in accordance with the assumption that AQP2 is the effector protein of the renal vasopressin pathway. The influence of amino acid substitutions on the functioning of AQP1 and 2 was demonstrated by in vitro expression studies in oocytes of the toadXenopus laevis. Future research on renal water transport will focus on the search for other aquaporins, structure-function relationship of aquaporins, the development of aquaporin inhibitors and their possible use as diuretics, and further elucidation of the renal vasopressin pathway.

Physiology and pathophysiology of aquaporins

The biophysical properties of water-filled pores in biological membranes have been studied for decades, and this has cumulated in an accurate description of water channel properties [1]. In spite of all this knowledge, the molecular identification of water channels resulted from a serendipitous discovery. Denker et al. [2] copurified a 28-kD protein together with a 32-kD Rhesus antigen from human red blood cells, and this discovery led to the cloning of the first molecular water channel, CHIP28 [3]. CHIP28 appeared to be a member of the major intrinsic protein (MIP) family of intrinsic membrane proteins, named after the first cloned protein of this family, the major intrinsic protein of lens fibre cells [4]. The molecular fingerprint of MIP family members consists of two repeats, presumably the result of an ancient gene duplication event [5]. Each repeat is characterized by a very conserved region in which an NPA box (asparagine–proline–alanine) is unchanged from bacteria to mammals (Fig.1). Owing to this property, new family members were discovered by homology cloning using reverse transcription–polymerase chain reaction (RT–PCR) and primers corresponding to these conserved sequences [6–12]. It is now clear that genes coding for MIP proteins are ubiquitous in nature. For the functional characterization of water channels, theXenopus oocyte expression system has played a dominant role, merely because the osmotic swelling test of oocytes expressing water channels is of appealing simplicity. For MIP family members that were proven to be water selective, a new more appropriate name was chosen and since then water channels discovered in mammalian tissues have been rebaptized as aquaporins 0 to 5, in the rank order of their discovery [13]. In this review, we will focus on publications that appeared in 1994 and 1995 and we restrict ourselves to mam-malian aquaporins. A number of excellent reviews on water channels have recently been published, reflecting the excitement which surrounds the discovery of aquaporins and their role in water homeostasis of the body [14–17].

Persistent arterial hypotension after bilateral nephrectomy in a 4-month-old infant

Abstract A patient with congenital nephrotic syndrome underwent bilateral nephrectomy at the age of 4 months. She showed persistent hypotension from the fourth postoperative day until death at the age of nearly 5 months. No cause for the hypotension could be found. It is postulated that, especially in young infants, a deficiency of renin after bilateral nephrectomy may cause persistent hypotension. An explanation for the putative increased risk of this complication in young infants may be their need for a highly active renin-angiotensin system. Until more is known about the incidence of this complication and its predisposing factors, reluctancy towards the performance of bilateral nephrectomy in children under the age of 6 months is warranted.