Pediatric Nephrology

Pediatr Nephroi (1992) 6:476-482 9 IPNA 1992

Invited review

Nephrogenic diabetes insipidus: clinical symptoms, pathogenesis, genetics and treatment N. Knoers I and L. A. H. Monnens 2 Departments of I Human Genetics and 2Paediatrics, University of Nijmegen, E O. Box 9101, 6500 Nijmegen, The Netherlands Received December 4, 1991; received in revised form February 11, 1992; accepted February 13, 1992

Abstract. This review summarizes various aspects of the

inherited kidney disorder nephrogenic diabetes insipidus (NDI). The clinical manifestations of the disease are presented. The important role of the genetic localization of the NDI gene to the X-chromosome long arm, in region Xq28, for carrier detection and early (prenatal) diagnosis of the disorder is emphasized. Following an overview of the cellular physiology involved in the antidiuretic action of vasopressin, possible mechanisms in the pathogenesis of NDI are discussed. We hypothesize that NDI is most probably due to the absence or abnormality of the renal V2 receptor. This assumption is strengthened by recent findings in receptor studies, which indicate a general V2 receptor defect in NDI, and in experiments with somatic cell hybrid cell lines, which are consistent with a co-localization of the genes for NDI and for the V2 receptor in the Xq28 region. Finally, the efficacy of the combination amiloride-hydrochlorothiazide, compared with the indomethacin-hydrochlorothiazide regimen, in the treatment of NDI is presented and the advantages of the former combination are discussed. Key words: Nephrogenic diabetes inspidus - V2 receptor - X chromosomal localization - Amiloride

Introduction

The renal type of diabetes insipidus was appreciated as a separate clinical entity in 1945, when it was described independently by two investigators: Forssman [1] in Sweden and Waring et al. [2] in the United States. In 1947, Williams and Henry [3], who noticed that injection of large doses of the antidiuretic hormone (ADH) vasopressin

Correspondence to: N. Knoers

could not correct the defect, coined the term 'nephrogenic diabetes insipidus (NDI)' to distinguish it from the central or neurohormonal form of diabetes insipidus. The latter is caused by absence of ADH. Subsequent studies [4, 5] revealed biologically active hormone to be present in the serum and urine of affected persons and lended further support to the theory of renal vasopressin unresponsiveness. Nowadays the term 'nephrogenic diabetes insipidus' is used synonymously with 'vasopressin- or ADH-resistant diabetes insipidus' or 'diabetes insipidus renalis'.

Clinical manifestations

NDI is characterized by insensitivity of the distal renal nephron to the antidiuretic effect of vasopressin. As a consequence, the kidney loses its concentrating ability and produces large volumes of hypotonic urine (50100 mosmol/kg water), which may lead to severe dehydration and electrolyte imbalance. The defect in NDI is present from birth and manifestations of the disorder emerge within the first weeks of life. Polyuria and excessive thirst are the most typical symptoms but they may not be recognized immediately. Irritability, poor feeding and poor weight gain are often the initial symptoms. Intermittent high fever is a common complication of the dehydrated state, particularly in the neonate and infant. Therefore, symptoms are frequently considered to be caused by infection and many children with NDI are examined thoroughly for signs of bacterial or viral disease. Obstipation, nocturia and enuresis are frequent complaints later in childhood. Untreated, most patients fail to grow normally and some develop mental retardation. Growth retardation is assumed to be directly related to polyuria and polydipsia [6, 7]. Excessive fluid intake provokes anorexia and vomiting, which leads to malnutrition. Mental retardation, which can run the gamut from minor memory deficits to profound mental retardation, is not genetically determined but probably results from repeated episodes of severe dehydration, from cerebral oedema due to overzealous rehydration and from malnutrition [8-10].

477 Table 1. Causes of acquired or secondary nephrogenic diabetes insipidus

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Analgesic nephropathy Sickle cell anaemia Hypokalaemia Hypercalcaemia Obstructive uropathy posterior urethral valves Juvenile nephronophthisis Renal dysplasia Chronic pyelonephritis Chronic uraemic nephropathy Amyloidosis Sarcoidosis

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Besides organic brain alterations, the psychological development of these children is influenced by a permanent craving for water and the urge for frequent voiding, which compete with playing and learning. Therefore, many NDI patients are characterized by hyperactivity, distractibility, short attention span and restlessness. Long-lasting states of polyuria may favour the development of megacystis, megaureter and hydronephrosis, which can mimic lower urinary tract obstruction [7, 11]. Abnormal laboratory findings in NDI are in most cases the result of chronic dehydration. Serum sodium is in excess of the normal range and may be higher than 170 mmol/1. There is also an increase in serum chloride, and retention of urea and creatinine. All values can be normalized by adequate rehydration. In addition, reduced glomerular filtration rate and renal blood flow return to normal when an adequate hydration state has been achieved. Remarkably, plasma vasopressin levels are normal or only slightly increased in affected children [4, 12, 13].

Diagnosis The observation of polyuria in a dehydrated infant and the finding of a high serum sodium concentration will usually provide all the evidence for presuming a renal concentrating defect. To confirm the presence of polyuria and to distinguish the nephrogenic form of diabetes insipidus from the central from, a vasopressin test is performed by intranasal application of 1-desamino-8-D-arginine vasopressin (DDAVP), which is a synthetic analogue of the natural hormone and is characterized by a high and prolonged antidiuretic effect. In NDI patients there is no increase in urine osmolality after DDAVP, which remains below 200 mosmol/kg water (normal >805 mosmol/kg water and no reduction in urine volume or in free water clearance [14, 15]. The primary congenital form of NDI has to be differentiated from the secondary or acquired form, which is much more common than the congenital form but is rarely as severe. Some causes are listed in Table 1.

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Fig. 1. Map of the X chromosome indicating the localization of the nephrogenic diabetes insipidus (ND1) gene and various other genes. DMD, Duchenne muscular dystrophy; ND, Norrie's disease, XLRP, Xlinked retinitis pigmentosa; PGK, phosphoglycerate kinase; GALA, ot-galactosidase; HPRT, hypoxanthine phosphoribosyltransferase; ALl) adrenoleucodystrophy; G-6-PD, glucose-6-phosphate dehydrogenase; FVIII, factor VIII

Genetics Most family studies have indicated that ND[ is transmitted as an X-linked recessive disease [1, 3, 16-18]. This was supported by the observation that male-to-male transmission did not occur and that the disorder is transmitted by females and fully expressed in their male offspring. Doubts were raised whether X-linked inheritance is the only type of transmission in NDI when several investigators described the complete clinical picture of the disease in females [19, 20]. They postulated an autosomal dominant inheritance with almost complete penetrance in the male and reduced penetrance in the female. Recently, we were able to confirm X-linked inheritance in 11 NDI families by demonstrating close linkage between the NDI gene and several X-chromosomal DNA markers [21-24], which allowed precise localization of the disease gene to the subtelomeric region of the human X-chromosome long arm, at band Xq28 (Fig. 1). With the identification of closely linked DNA markers it is now possible to perform carrier detection and early (prenatal) diagnosis with a reliability of about 96%. An example of carrier detection with use of X-linked DNA markers is given in Fig. 2. Early detection is a prerequisite for early treatment of the disease, which can prevent brain damage and mental retardation. Recently, Langley et al. [25] described two sisters with severe, vasopressin-resistant, diabetes insipidus, born to healthy consanguineous Pakistani parents. DNA analysis, with one of the DNA markers known to be very tightly linked to the NDI locus on the X-chromosome, showed that each girl inherited different Xq28 regions of the maternal X-chromosomes, ruling out a diagnosis of classical X-linked NDI. On the basis of parental consanguinity,

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along with the observations that both parents concentrated urine well and the results of DNA analysis, it was suggested that NDI in these girls must be the result of inheritance of an autosomal recessive mutation. Thus, there may be two genes coding for congenital NDI, one on the long arm of the X-chromosome and the other on one of autosomes. As will be seen in the following paragraph, we found evidence for phenotypical heterogeneity in our cases of NDI as well.

Pathogenesis Cellular physiology In order to understand the potential pathophysiological mechanism(s) involved in NDI, a few words are necessary to describe the present state of knowledge on the cellular physiology of vasopressin's antidiuretic action in the distal nephron. The antidiuretic effect of vasopressin and its analogue DDAVP is mediated by specific receptors located at the outer surface of the basolateral membrane of responsive epithelial cells in the distal nephron. These vasopressin receptors are coupled to the enzyme adenylate cyclase and have been classified as V2 receptors to distinguish them from the so-called V1 receptors which are connected to a phosphoinositide-specific phospholipase and intracellular calcium mobilization [26]. The V1 receptors mediate the pressor response to vasopressin and other actions such as glycogenolysis and platelet aggregation. The cellular events secondary to vasopressin binding are only partly known [27]. The vasopressin-receptor complex activates adenylate cyclase via the intermediacy of a membrane-bound guanine nucleotide-binding protein (G protein). Adenylate cyclase catalyzes the formation of cyclic adenosine monophosphate (cAMP) from adenosine triphosphate, cAMP in turn activates a protein kinase (cAMP-dependent protein kinase), which initiates a sequence of events ultimately resulting in increased permeability of the apical (luminal) membrane. In this way the diffusion of free water from the luminal site into the medullary interstitium is achieved, which leads to the final concentration of the urine. By current view, the final event may be the insertion of water-permeable patches [intramcmbranous particle (IMP) clusters] into the luminal membrane [28]. In the mammalian collecting duct, these IMP clusters, which are believed to represent water chan-

nels, are located in pits coated by clathrin, a unique membrane protein, in the apical surface of principal cells. Exocytotic insertion of the water channels into the apical membrane is thought to be responsible for increasing the permeability to water. As long as vasopressin is present, these water channels are continuously recycled to and from the apical membrane via coated pits (Fig. 3). Upon vasopressin withdrawal, the endocytotic pathway takes precedence, so that the coated pits containing water channels are rapidly removed from the apical membrane and reside on vesicles in the cytoplasm. The mechanism underlying this recycling proces is an area under active investigation. Attempts are being made to identify and clone proteins of the water channel. The 55-kDa and 53-kDa protein components of the antidiuretic-stimulated water channel have been isolated [29]. The intermediate steps between the generation of cAMP and the final permeability changes in the apical membrane are not well defined. It is believed that the cytoskeleton [30], the calcium-calmodulin complex [31, 32], and possibly the atrial natriuretic factor [33, 34], play important roles.

Pathophysiology The defect in NDI could be located at any of the aforementioned steps from vasopressin binding to the final effect of the hormone on the luminal membrane. Reduced or no

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activity of the G-protein is not very likely. The G-protein involved in adenylate cyclase activation is assumed to be similar, if not identical, in most cells [35]. Therefore, a defect in this G-protein should lead to resistance to multiple hormones that act by stimulating adenylate cyclase, as has been shown in patients with pseudohypoparathyroidism type I [36, 37]. NDI, however, is characterized by insensitivity to vasopressin only. A defect in the enzyme adenylate cyclase per se can also be excluded by the fact that multiple hormone resistance is not observed in NDI. In the animal model of NDI, a mutant mice strain 'DI+/+ severe', which is a phenocopy of human NDI [38], an abnormally active cAMP phosphodiesterase, the enzyme which catalyzes the breakdown of cAMP, has been found [39, 40]. There are at least five major families of cAMP phosphodiesterase. The isoenzymes differ in affinity and specificity for substrate, in modulation by intracellular factors and in structure, and they are coded for by distinct genes [41]. The anomalous rapid cAMP metabolism in collecting ducts of the DI +/+ severe mice strain is due to abnormally high activities of two phosphodiesterase isoenzyme types [40]. An abnormally high activity of a specific isoenzyme of cAMP phosphodiesterase in NDI would be compatible with the fact that the disease is characterized by insensitivity to a single specific hormone. As to the defects distal to cAMP formation, an abnormality of cAMP-dependent protein kinase might be a candidate for causing NDI. The enzyme cAMP-dependent protein kinase exists as two types (type I and II), which are distinguished by their different regulatory subunits (RI and RII, respectively), whereas the catalytic subunit of both subtypes appears essentially identical [42]. It has been demonstrated that several unique and antigenetically distinct gene products exist within each R-subunit class. Some appear to be expressed in most tissues, while others are tissue specific [43, 44]. An attractive speculation might be that an abnormality in a R-subunit, which is specific for the tubular cells sensitive to vasopressin, is the cause of NDI. Recent findings of receptor studies and experiments with somatic cell hybrid cell lines, however, have indicated that NDI is not caused by an abnormally active cAMP

Fig. 4. CyclicAMP (cAMP)productionin various cell lines in responseto differentconcentrationsof arginine vasopressin(AVP),the V2 receptor-specific agonist [Mpal, Val4, Sar7] AVP(dVSAVP),AVPplus a VgVl-specificantagonist (V2-ANT),oxytocin(07) and [Mpa~Sar7] OT (dSOT). 1023, Hamsterlong fibroblastcell line (no human DNA); 908B17, humanhamster hybridcell line carryingthe human Xq28qter region; LLCPK1,porcinekidneyepithelial cell line (V2receptorexpressing,positivecontrol); M18, V~receptor-deficientmutant of LLCPK1(negative control); IBMX, 1-isobntyl-3-methylxanthine.Taken from [52], withpermission

phosphodiesterase or by a defect distal to cAMP formation, but is most probably due to absence or abnormality of the renal V2 receptor. In view of the importance of these studies for insight into the pathogenesis of the disease, they will be discussed in some detail. Receptor studies in patients. The synthetic analogue of vasopressin DDAVP has potent antidiuretic V2 activity. In addition, it exerts a considerable vasodilatory action [45] and evokes a transient release of yon Willebrand factor antigen (vWF:Ag), factor VIII activity (FVIII:C), and tissue-type plasminogen activator (t-PA) from endothelial storage sites [46, 47]. The vasodilatory coagulation and fibrinolytic responses to DDAVP are assumed to depend on extrarenal V2 receptor activation. Because of the impossibility of studying the renal V2 receptors in patients directly, the extrarenal effects of DDAVP in NDI patients have been evaluated [48-50]. While in control subjects DDAVP induced significant increases in vWF:Ag, FVIII: C, t-PA activity and t-PA antigen, no changes in these coagulation and fibrinolytic parameters were seen in NDI patients. In addition, vasodilatory responses to DDAVP appeared to be absent in patients. These findings are consistent with the concept of a general V2 receptor defect in NDI. We have recently reported on an NDI patient who showed normal extrarenal responses to DDAVP [51]. In this patient the receptor defect is assumed to be confined to the kidney. Similar patients have been reported earlier [52-54]. The finding of normal extrarenal responses in some patients, but absence of these responses in others, points to phenotypical heterogeneity in NDI, which might reflect genetic heterogeneity. Interestingly, in the family of our NDI patient, linkage between the NDI gene and Xq28 markers was excluded. There is convincing evidence that the V1 receptor is intact in NDI. Firstly, NDI patients show normal vasoconstrictive responses after administration of vasopressin [55]. Secondly, vasopressin binding to V1 receptors on thrombocytes isolated from NDI patients appeared to be normal; i.e. the binding characteristics (maximum binding capacity

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and binding affinity) in NDI patients were identical to those in control individuals [13, 56]. Using a functional assay, based on the increase of intracellular cAMP after addition of vasopressin to the medium, V2 receptor-binding activity was measured in hybrid cell lines carrying different fragments of the human X-chromosome [57]. V2 binding activity and elevation of cAMP levels was observed in all cell lines carrying the distal part of the human X-chromosome long arm (NDI-DNA carrying cells), in contrast to the rodent control cell lines (Fig. 4). Arginine vasopressin stimulation of cAMP production was concentration-dependent and could be almost completely inhibited by co-incubation with a Vz/Vl-specific antagonist. That vasopressin-binding activity was dependent on the V2-type receptor was demonstrated by using the V2 receptor-specific agonist dVSAVP, which was as potent as AVP in inducing cAMP production by NDI-DNA-carrying cells. No response was shown to other hormones such as calcitonin, oxytocin and isoproterenol. These results are E x p e r i m e n t s w i t h s o m a t i c c e l l h y b r i d c e l l lines.

Fig. 5. Illustration of the effectsof differentforms of treatment in a patient sufferingfromX-linkedNDI. CmO, free water clearance; Costa,osmolarclearance

consistent with a co-localization of the NDI gene and the V2 receptor in the Xq28 region, and strongly support the view that the V2 receptor gene is the defective gene underlying NDI.

Treatment

The treatment of NDI has posed a particularly vexing problem. Thiazide diuretics and prostaglandin synthesis inhibitots, and particularly a combination of the two, were shown to be of important benefit in the management of the disease [15, 58, 59]. Prolonged use of thiazides, however, is frequently complicated by hypokalaemia secondary to renal loss of potassium, and long-term treatment with prostaglandin synthesis inhibitors may have untoward renal and systemic side effects. Recently evidence has been obtained that the combination of the potassium-sparing diuretic amiloride with the thiazide diuretic hydrochlorothiazide is equally efficient in decreasing urine volume and increasing urine osmolality as

481 the p r o s t a g l a n d i n synthesis i n h i b i t o r - h y d r o c h l o r o t h i a z i d e r e g i m e n [60, 61]. This is e x e m p l i f i e d for one o f our N D I patients in Fig. 5. The use o f the c o m b i n a t i o n a m i l o r i d e h y d r o c h l o r o t h i a z i d e has several advantages. Firstly, a m i l o r i d e c o u n t e r b a l a n c e s the p o t a s s i u m losses s e c o n d a r y to p r o l o n g e d use o f thiazides and thus prevents h y p o k a l a e m i a [ 6 0 - 6 2 ] . S e c o n d l y , the antidiuretic actions o f a m i l o r i d e and h y d r o c h l o r o t h i a z i d e a p p e a r to b e additive [60, 63]. M o s t likely, different sites o f action o f both drugs within the n e p h r o n underlie their additive effects [ 6 4 - 6 6 ] . As d e m o n s t r a t e d in m i c r o p e r f u s i o n studies [64, 65, 67] and m i c r o c a t h e t e r i z a t i o n e x p e r i m e n t s [66], thiazides inhibit the electroneutral s o d i u m - d e p e n d e n t c h l o r i d e transport in the early distal tubule, w h e r e a s a m i l o r i d e b l o c k s the l u m i n a l m e m b r a n e s o d i u m channel in the cortical and m e d u l l a r y collecting duct. Thus, c o m b i n e d administration o f a m i l o r i d e and h y d r o c h l o r o t h i a z i d e results in a m o r e m a r k e d s o d i u m excretion than either diuretic given as a single agent. T h e efficacy o f thiazides in N D I is a s s u m e d to be related to the r e d u c t i o n o f extracellular s o d i u m content and, therefore, e n h a n c e m e n t o f r e a b s o r p t i o n in the proxim a l tubule [68, 69]. F u r t h e r a u g m e n t a t i o n o f s o d i u m excretion b y a m i l o r i d e could thus b e r e s p o n s i b l e for the additive antidiuretic effects o f both drugs [61]. Finally, in several studies it was shown that the a m i l o r i d e - h y d r o c h l o r o t h i a z i d e r e g i m e n has o n l y m i n o r l o n g - t e r m side effects [60, 61, 70].

Prospects The detailed i n f o r m a t i o n on the s u b c h r o m o s o m a l localization o f the N D I gene o b t a i n e d b y genetic l i n k a g e analysis m a k e s it feasible to a p p r o a c h the isolation o f the N D I gene itself b y m e a n s o f ' r e v e r s e g e n e t i c ' slxategies [ 7 1 - 7 3 ] . This a p p r o a c h is facilitated b y e v i d e n c e that a defect in the V2 r e c e p t o r m o s t p r o b a b l y is the p r i m a r y cause o f NDI. Transfection p r o t o c o l s can be d e v i s e d to isolate g e n o m i c sequences that e n c o m p a s s the N D I gene. E x p e r i m e n t s along this line are in progress.

Acknowledgements. We are grateful to Dr. B. A. van Oost (Department of Human Genetics, University of Nijmegen, The Netherlands) for his helpful comments on the manuscript. This study was supported by the Dutch Kidney Foundation.

References 1. Forssman H (1945) On hereditary diabetes insipidus with special regard to a sex linked form. Acta Med Scand 159:3 - 196 2. Waring AJ, Kajdi L, Tappan V (1945) A congenital defect of water metabolism. Am J Dis Child 69:323 -324 3. Williams RH, Henry C (1947) Nephrogenic diabetes insipidus: transmitted by females and appearing during infancy in males. Ann Intern Med 27:84-95 4. Holliday MA, Burstin C, Harrah J (1963) Evidence that the antidiuretic substance in the plasma of children with nephrogenic diabetes is antidiuretic hormone. Pediatrics 32: 384-388 5. Luder J, Burnett D (i954) A congenital renal tubular defect. Arch Dis Child 29: 44- 47

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