UNILATERAL RENAL AGENESIS and the CONGENITAL SOLITARY FUNCTIONING KIDNEY WOOLF and HILLMAN

Mini rev Article UNILATERAL RENAL AGENESIS AND THE CONGENITAL SOLITARY FUNCTIONING KIDNEY WOOLF and HILLMAN

Unilateral renal agenesis and the congenital solitary functioning kidney: developmental, genetic and clinical perspectives Adrian S. Woolf and Katherine A. Hillman* Nephro-Urology Unit, UCL Institute of Child Health, and *Centre for Nephrology, Royal Free and University College Medical School, London, UK Accepted for publication 3 July 2006

KEYWORDS based on >9000 (postnatal) autopsies. ASSOCIATED ANOMALIES, AND GENETIC However, in clinical practice the clinician is AND TERATOGENIC CAUSATION agenesis, dysplasia, gene, hypertension, generally faced with making a radiological proteinuria, renal failure, syndrome diagnosis of ‘URA’ in a child or adult, or Anomalies outside the renal tract can be perhaps in a fetus in which just one kidney associated with URA, including absence has been visualized on ultrasonography (US) of a uterine horn [16] or vas deferens INTRODUCTION during mid-gestation. Using US, URA can be [17] ipsilateral to the absent kidney, ‘missed’ in the fetus or neonate because the respectively, emphasizing close We review the condition termed ‘unilateral adrenal, which then occupies the renal bed, relationships between paramesonephric renal agenesis’ (URA), i.e. individuals born can be mistaken for a kidney [6]. Using US, and mesonephric duct development and with non-ectopic, solitary functioning kidneys Roodhooft et al. [7] reported that URA nephrogenesis itself. Dursun et al. [18] (SFKs), with contralateral kidneys which fail to occurred in ≈1 : 500 of the general detected non-urological anomalies in 44% of form. We discuss the causes, diagnosis and population, which is more frequent than 87 consecutive cases of congenital SFK, with long-term ‘renal prognosis’ of URA. We do not the autopsy value cited above [5]. There cardiac and gastrointestinal malformations consider in detail other anomalies resulting in are caveats about using an ‘empty renal being especially common. Sometimes RA SFK, such as unilateral multicystic dysplastic bed’ assessed by US to diagnose URA. occurs as part of a multi-organ syndrome kidney (MCDK) and fused renal tracts [1,2]. Renal ectopia (e.g. pelvic and cross-fused) (Table 1), and several of these have defined SFK also follows unilateral nephrectomy for kidneys should be considered and sought genetic bases [19–31]. Not unexpectedly, disease and living renal transplant donation; by US [8] and, if necessary, by functional the normal versions of genes mutated the long-term outcomes for these scenarios scanning with IVU and/or isotope renography in such individuals are expressed during have been reviewed [3]. (e.g. with 99mTc-DMSA, concentrated in differentiation of normal kidneys and ureters functioning tubules). Furthermore, all [4]. Gene mutations in branchio-oto-renal these radiological techniques might fail [19], Townes Brockes [30] and the renal to detect a very small (<2 cm across) cysts and diabetes [29] syndromes encode DEVELOPMENTAL BIOLOGY contralateral kidney affected by renal transcription factor and related proteins ‘aplasia’ (a tiny, dysplastic organ, containing that modulate expression of other genes; in ‘RA’ implies that the embryonic kidney undifferentiated and metaplastic tissues) or Fraser [22] and X-linked Kallmann [23,24] has failed to begin to form. The human atrophy secondary to renal artery stenosis or syndromes, the relevant proteins are on metanephros is the direct precursor of neonatal renal venous thrombosis [9–11]. surfaces of renal epithelia, and probably the mature kidney; it becomes a distinct entity Such ‘remnants’, confirmed at laparotomy, mediate cell–cell and cell–matrix interactions; in the fifth gestational week when the have rarely been implicated in causing in Rokitansky-Kuster-Hauser syndrome, there ureteric bud epithelium branches from the hypertension [10,12]; MRI might prove a is a report of mutation of a locally acting mesonephric duct [4]. Thereafter, renal sensitive technique with which to find such growth factor [26]. mesenchyme condenses to envelop the rudiments [10]. advancing bud, and forms primitive nephron Even in the absence of non-renal tract vesicles; the bud forms the ureter and With the advent of routine fetal US screening, features, RA can be familial, sometimes branches to generate collecting ducts. Thus, it became apparent that dysplastic kidneys, apparently inherited as a dominant trait with RA must be the result of either failure of the either of modest size, or even greatly enlarged incomplete penetrance [7,32,33]. The risk to ureteric bud to arise, or failure of the bud to MCDK, can spontaneously involute prenatally close relatives might be greater when the engage with renal mesenchyme. or in the first years after birth [10,13,14]. This index case has bilateral RA, and Roodhooft process might be driven by apoptosis, a et al. [7] recommend ‘ultrasonographic metabolically active form of ‘cell-suicide’, i.e. screening for parents and siblings of infants excess apoptosis [15]. Possibly, URA is rarer born with agenesis or dysgenesis of both INCIDENCE AND DIAGNOSIS than previously considered because some kidneys or with agenesis of one kidney individuals so classified might actually have and dysgenesis of the other, since renal Kiprov et al. [5], in a histopathology study, regressed, malformed kidneys rather than malformations may have medical implications reported an incidence of URA of ≈1 : 1000, true agenesis. even for asymptomatic patients’.

WOOLF and HILLMAN

Finally, regarding teratogenic causation, TABLE 1 Multi-organ syndromes associated with RA poorly controlled maternal diabetes mellitus and use of specific drugs during pregnancy Syndrome (e.g. those which inhibit the renin- Branchio-oto–renal syndrome: EYA1 (Eyes Absent 1) dominant mutation; hearing loss, pre-auricular angiotensin system) have been associated pits, branchial clefts [19]. with RA in progeny [34,35]. Other agents, DiGeorge syndrome: deletion of 22q11: congenital heart disease, hypocalcaemia, immunodeficiency, such as high doses of vitamin A derivates, can and neurocognitive disorders [20]. cause RA in experimental animals [36]. Fanconi anaemia: caused by recessive mutation of several genes; pancytopenia [21]. Fraser syndrome: FRAS1 autosomal recessive mutations; cryptophthalmos, cutaneous syndactyly, malformations of the larynx and ambiguous genitalia [22]. THE CONTRALATERAL RENAL TRACT Kallmann syndrome: Anosmin-1 X-linked recessive mutation: hypogonadotrophic hypogonadism and anosmia [23,24]. Having diagnosed URA, the next step is to Klinefelter syndrome: 47,XXY: small, firm testis, gynaecomastia, azoospermia and hypergonadotrophic exclude disease of the contralateral renal hypogonadism [25]. tract. First, is the SFK ‘normal’? Congenital Rokitansky-Kuster–Hauser syndrome: WNT4 (wingless-type MMTV integration site family member 4) SFKs are often larger than normal [37,38], and dominant mutation; absent/rudimentary upper vagina and uterus [26]. overgrowth initiated prenatally; in one study, MURCS association: genetic basis undefined; Müllerian duct aplasia-hypoplasia (MU), renal the lengths of human fetal SFKs were malformations (R) and cervicothoracic somite dysplasia (CS) [27]. increased in 44% of cases assessed by US, Poland syndrome: genetic basis undefined; unilateral hypoplasia of pectoralis major muscle and a phenomenon detectable as early as mid- ipsilateral syndactyly [28]. gestation [37]. The remarkable process has Renal cysts and diabetes syndrome: HNF1β (hepatocyte nuclear factor β) dominant mutations; diabetes been called ‘hypertrophy’, implying simply mellitus, hyperuricaemia and uterine malformations [29]. an increase in cell size, although other Townes–Brocks syndrome: SALL1 (sal-like 1/homologue of Drosophila spalt) dominant mutation: mechanisms are probably operative. In sheep, imperforate anus, triphalangeal/bifid thumb, rocker bottom feet, sensorineural hearing loss, after experimental unilateral nephrectomy hypospadias [30]. during the period of normal nephrogenesis, Williams–Beuren syndrome; deletion of 7q11.23; developmental delay, cardiovascular anomalies, mental final glomerular numbers in the SFK are retardation and facial dysmorphology [31]. strikingly greater than in control kidney, bringing the final complement of nephrons in the single kidney to ≈70% of that in two normal kidneys [39]. One histological report which compared a ‘healthy (human) renography, and most had cystography; from rat experiments (reviewed in [3]), that congenitally solitary kidney’ with a normal almost half had an anomaly of the such compensatory growth and functional control, suggested the former contained more contralateral renal tract, including VUR (often responses might be detrimental in the long nephrons [40]; however, larger scale studies high-grade) and ‘obstruction’, especially at term, with the onset of hypertension, quantifying glomerular numbers by the ‘gold- the PUJ. Kaneyama et al. [46] found a similar glomerulosclerosis, proteinuria and even standard’ technique of stereology [41] are spectrum and incidence of anomalies, and progressive renal failure. Is there any evidence needed to confirm this impression. Only even suggested that ‘All children with that humans, who initially have overtly 20–40% of individuals with URA have a (congenital) solitary kidney should undergo a normal SFKs and lower renal tracts, might significant increase in renal length above the screening voiding cysto-urethrography . . .’. acquire a similar spectrum of dysfunction? upper normal age-adjusted limits [37,38]; one While these studies show the range of The answer is ‘yes’, although frustratingly we explanation for this is that kidney length is contralateral anomalies that can occur, index cannot yet predict the risk for a specific highly variable even in individuals with two cases in such series might not have been individual with URA. normal kidneys [37,42,43]. typical of all individuals with URA (e.g. half of the cases analysed by Cascio et al. [45] In a survey of children with URA, Wasilewska A congenital SFK of ‘normal length’ which is presented with UTI), and hence suggestions et al. [38] found that serum cystatin C, a echogenically bright, or one which is shorter for extra investigations in addition to US substance cleared by glomerular filtration, than the normal range, might well be are difficult to generalize into clinical tended to be increased in those over 12 years considered abnormal, and might itself either imperatives. old, a rise positively correlated with kidney have a degree of dysplasia/hypoplasia, or have overgrowth. Mei-Zahav et al. [47] used been damaged postnatally. The most severe ambulatory blood pressure monitoring and contralateral tract anomaly (apart from RA LONG-TERM PROGNOSIS concluded that daytime and night-time itself), is severe renal dysplasia. Indeed, URA systolic blood pressures were significantly and MCDK can coexist [44]; many such The tendency for ‘normal’ kidneys opposite higher (4–5 mmHg) in children with URA fetuses will be terminated or, if born, will soon URA to increase in length can be viewed as than in controls; increased blood pressure die from renal failure and lung hypoplasia a positive, adaptive response. Indeed, in correlated with increased renal length. associated with oligohydramios. Cascio et al. children with uncomplicated URA, SFKs By contrast, children with unilateral [45] reviewed 46 consecutive children with maintain GFRs similar to that of two normal nephrectomy for renal disease had pressures URA diagnosed in one hospital: all had US and kidneys [38]. However, it has been contended, similar to healthy controls. Perhaps these

UNILATERAL RENAL AGENESIS AND THE CONGENITAL SOLITARY FUNCTIONING KIDNEY

studies give indications of ‘trouble ahead’ for an individual with two functioning kidneys. and dietary advice to normalize an increased children with URA, who are born with Kiprov et al. [5] reviewed 29 cases of body mass index. presumed nephron deficits. Keller et al. [41] histologically confirmed focal quantified glomerular numbers in kidneys of glomerulosclerosis and found that five had Suggestions for long-term follow-up and adults (with two kidneys), aged 35–59 years, URA; in the same study, in 9200 autopsies, treatments are given with the caveat that we who died in road traffic accidents, and found seven had URA and, of these, two had died currently lack good evidence with which to that individuals with histories of ‘essential from chronic renal failure and had accurately predict the risk of life-long hypertension’ had on average only half the glomerulosclerosis. complications for any individual with URA. number of glomeruli/kidney than had age- matched normotensive controls. Although not a study of URA, perhaps there is a CONFLICT OF INTEREST message here for the long-term prognosis of CONCLUSIONS individuals with congenital SFKs. None declared. URA occurs in ≈1 : 500–1000 individuals; Heinonen [16] studied pregnant women with from the practical clinical perspective, we URA and associated uterine anomalies; suggest that the diagnosis of ‘URA’ should REFERENCES outcomes were compared with a control prompt the clinician to consider several group of age-matched pregnancies in women points: 1 Woolf AS. Unilateral multicystic with similar uterine malformations who had dysplastic kidney. Kidney Int 2006; 69: two normal kidneys. The relative risk of • Give consideration to alternative diagnoses 190–3 gestational hypertension, pre-eclampsia or of ectopic kidney or a regressed dysplastic 2 Fekak H, Mezzour MH, Rabii R, gestational proteinuria was 2.3, significantly kidney; in the latter, remnants have been Joual A, Bennani S, El Mrini M. higher. Argueso et al. 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46 Kaneyama K, Yamataka A, Satake S 48 Argueso LR, Ritchey ML, Boyle ET Correspondence: Prof Adrian S. Woolf, et al. Associated urologic anomalies in Jr, Milliner DS, Bergstralh EJ, Kramer Nephro-Urology Unit, UCL Institute of Child children with solitary kidney. J Pediatr SA. Prognosis of patients with unilateral Health, 30 Guilford Street, London WC1N 1EH, Surg 2004; 39: 85–7 renal agenesis. Pediatr Nephrol 1992; 6: UK. 47 Mei-Zahav M, Korzets Z, Cohen I et al. 412–6 e-mail: [email protected] Ambulatory blood pressure monitoring in 49 Gonzalez E, Gutierrez E, Morales E et al. children with a solitary kidney – a Factors inﬂuencing the progression of Abbreviations: MCDK, multicystic dysplastic comparison between unilateral renal renal damage in patients with unilateral kidney; RA, renal agenesis; SFK, solitary agenesis and uninephrectomy. Blood renal agenesis and remnant kidney. functioning kidney; URA, unilateral renal Press Monit 2001; 6: 263–7 Kidney Int 2005; 68: 263–70 agenesis; US, ultrasonography.