Renal aplasia is the predominant cause of congenital solitary kidneys

Transcription

1 Kidney International, Vol. 61 (22), pp Renal aplasia is the predominant cause of congenital solitary kidneys ASAHIRO HIRAOKA, HIROKAZU TSUKAHARA, YUUSEI OHSHIA, KENKOU KASUGA, YOSHINORI ISHIHARA, and ITSUFUI AYUI Department of Pediatrics, Fukui edical University School of edicine, Kasuga Ladies Clinic, and Aiiku Hospital, Fukui, Japan Renal aplasia is the predominant cause of congenital solitary lies of the kidney may be predisposed to renal failure kidneys. in early childhood. Patients with a congenital solitary Background. Congenital solitary kidneys, which are suscepkidney, which occurs more frequently than bilateral renal tible to renal failure, have been considered mostly due to unilatdevelopmental anomalies [2], may develop renal failure eral renal agenesis and partly due to renal aplasia. Risk of familial recurrence and of other associated anomalies is known in later life [3, 4]. Congenital solitary kidneys are identi- to be much higher in renal agenesis than in renal aplasia. fied largely due to renal agenesis and only partly because However, differential diagnosis between the two renal anoma- of renal aplasia (aplastic dysplasia or adysplasia) [2, 5]. lies is difficult, and renal agenesis has been found much less Differentiation between renal agenesis and renal aplasia frequently in ultrasound screening studies of fetuses than in autopsy studies. is known to be very difficult macroscopically even in au- ethods. In order to investigate the nature and incidence topsied kidneys, so that the exact differentiation may of the congenital solitary kidney, the present study performed need microscopic examination for the presence of rudiultrasound screening of the kidneys in 4 newborn babies. mentary kidney parenchyma in the aplastic kidney [6]. A diagnosis of renal agenesis was made when ultrasound identified no renal parenchyma and renoscintigraphy showed no Normal development of the kidney requires a nor- renal function, and renal aplasia when there was a renal parenchyma without any function. growth of the ureteric bud from the mesonephric duct, mal initiation of the pronephros-mesonephros sequence, Results. Primary screening detected 52 babies suspected of and advancement and proper interaction with the metahaving small kidneys and one baby with a multicystic dysplastic nephric blastema [7]. The sequence of the development kidney, but no baby with renal agenesis. Forty-seven of the 53 babies underwent a second ultrasound scanning at one month has been found to require expression of many kinds of of age. Three small kidneys in three babies further decreased genes in proper time and position within the urinary in size, had no function and were diagnosed as renal aplasia tract. Derangement in the gene expression induced by (which has an incidence rate of one in 13). Follow-up ultra- genetic mutation itself or environmental factors results sound studies showed further regression in all three, which became very hard to distinguish by one year of age. in congenital anomalies of the kidney [2]. Renal agenesis Conclusions. The present study showed that ultrasound in may be ascribed to failure of the initiation of the prothe neonatal period could identify the aplastic kidney, which nephros-mesonephros sequence or of formation of the had a reniform shape, not rudimentary, during the newborn ureteric bud, resulting in the absence of the kidney and period, and regressed rapidly thereafter. These findings indiureter. This is frequently complicated by anomalies of cate that most renal agenesis diagnosed clinically thus far might more correctly be renal aplasia. the ipsilateral genital organs, especially in females, [8] and occasionally by anomalies of other organs outside the urogenital system [6, 7]. Renal aplasia, involving rudimentary kidney parenchyma and ureter, may result from Congenital anomalies of the kidney and urinary tract are one of the main causes of renal insufficiency in childdifferentiation or defects in the ability of the branching early regression of the ureteric bud, altered metanephric hood [1]. Patients with bilateral developmental anomaureteric duct and the undifferentiated metanephric blastema to communicate [9]. The exact diagnosis of renal Key words: single kidney, inherited renal anomaly, childhood renal insufficiency, kidney development, pronephros-mesonephros sequence, agenesis or aplasia, therefore, may help in understanding uteric bud. the associated anomalies and inferring the etiology responsible for the renal anomaly. Received for publication July 1, 21 and in revised form November 15, 21 Renal agenesis has been supposed to be a predominant Accepted for publication December 17, 21 cause of the congenital solitary kidneys. In autopsy studies [6] and an ultrasound screening study of school 22 by the International Society of Nephrology chil- 184

2 Hiraoka et al: Renal aplasia in solitary kidney 1841 Table 1. Results of the ultrasound scanning and DSA renoscintigraphy Initial scanning N Second scanning DSA renoscintigraphy Total subjects 4 Normal size 3947 Abnormal size 53 Total 47 Total 9 1) Two small 11 Normal a 8 Two small 1 Two small kidneys with diminished uptake 1 2) Disparate in size 42 Normal a 2 Hydronephrosis 4 Duplication of pelvis 6 ulticystic 1 Non-functioning 1 Unilaterally small 7 Non-functioning 3 One small kidney with diminished uptake 4 a The second scanning established the presence of a normal longitudinal length, lack of disparity in the renal longitudinal section, and the absence of other abnormal renal findings dren [1], the renal agenesis is observed with an inci- on the ultrasound when the largest longitudinal section dence of approximately one in a general population of of the smaller kidney was 75% or less of the correspond- 13. However, fetal ultrasound studies for renal anoma- ing dimension of the opposite kidney [15]. The largest longitudinal lies detected renal agenesis with much lower frequency section was selected, since it seemed to be a betlies [11, 12]. Unilateral multicystic dysplastic kidney (CDK), ter simple indicator of the renal volume than the renal with an incidence of one in a general population of 43 longitudinal length [15, 17]. When the ultrasound re-exam- [13], is found to have already regressed in some before ination confirmed the presence of a solitary kidney, two birth, making it likely that the regressed CDK may small kidneys or unilaterally small kidneys, the parents of possibly be misdiagnosed as renal agenesis [14]. The the infants were recommended to have the infants unincidence of renal aplasia has not been explored thus far. dergo a diagnostic technetium-99m dimercaptosuccinate In order to clarify the exact nature and incidence of (DSA) renal scintigraphy. When the DSA renoscincongenital solitary kidneys, we performed ultrasound tigraphy revealed a non-functioning or hypoplastic kidscreening of the kidney in newborns with careful atten- ney (small functioning kidney), voiding cystourethrogtion to renal size. raphy and follow-up ultrasonography also was performed. The degree of ureteral reflux was graded using international criteria [18]. ETHODS For infants found with congenital renal maldevelop- Subjects ment, clinical records of their mothers during the preg- The subjects consisted of 4 (212 male and 1898 nancy were retrospectively examined for exposure to female) randomly selected, apparently healthy babies known teratogens [5, 19] and for any abnormal findings born at Kasuga Ladies Clinic and Fukui Aiiku Hospital. on the fetal ultrasound studies. Anamnestic family study The birthweight of the newborns ranged from 1714 g to for renal anomalies was made for all of the subjects 534 g (median 3154 g), and the age from to 28 days displaying congenital renal maldevelopment. (median 3 days). Informed consent for the study was obtained from their parents. The Fukui edical University Board of Ethics also approved this clinical study on RESULTS the congenital anomalies of the urinary tract. The study The initial ultrasound scanning of 4 subjects identi- extended from August 1991 to arch 21. Scanning of fied 53 babies suspected of having kidneys abnormal in the kidney was performed as a part of ultrasound screensize size: the two kidneys were small in 11 and disparate in ing of the urinary tract [15]. The kidneys were scanned in 42 (Table 1). The latter included one (Patient 1 from the back of the baby in the prone position. The in Table 2) with multicystic dysplastic kidney (CDK) longitudinal length of the kidney was measured more and two with a small kidney having several small cysts carefully when it seemed smaller than the lower limit of up to 8 mm in diameter (Patient 3, Fig. 1) and up to 3 body-weight-adjusted length of normal controls [16], or mm (Patient 2). No baby with renal agenesis was found. when the two kidneys showed disparity in size of the Of these, 47 infants were assessed again with detailed longitudinal section. Parents of babies with a solitary ultrasonography at one month of age, and eight were kidney, small kidney(s) or kidneys disparate in size were confirmed to have small kidneys on the second ultra- advised to bring their infants to the Fukui edical Uniultrasonography sound (one bilateral and seven unilateral). The second versity Hospital one month later for re-examination with strikingly demonstrated no growth or ultrasound. Unilaterally small kidneys were diagnosed reduction in size, and slight hyperechogenicity in three

3 1842 Hiraoka et al: Renal aplasia in solitary kidney Table 2. Ultrasound measurements of the kidneys in nine patients who were diagnosed as having multicystic dysplastic kidney (Patient 1), renal aplasia (Patients 2 to 4) and renal hypoplasia (Patients 5 to 9) length mm Patient no. Sex At birth 1 month Section cm2 1 month F F /6 35/5 (7%) 39/53 (74%) 41/5 (82%) 35/35 39/5 (78%) 4/43 (93%) 41/49 (84%) 42/47 (89%) /64 32/52 (62%) 39/53 (75%) 35/56 (63%) 39/4 4/54 (74%) 43/5 (86%) 43/53 (81%) 42/47 (89%) / /9.9 (41%) 5.5/11. (5%) 4.5/11.8 (38%) 6.4/ /11. (68%) 7.5/1.4 (72%) 7.3/1.3 (71%) 7.1/1. (7%) DSA renoscintigram % of total uptake a Diagnosis Rt-CDK Rt-aplasia Lt-aplasia Lt-aplasia Bil-hypoplasia Lt-hypoplasia Rt-hypoplasia Lt-hypoplasia Rt-hypoplasia The greatest longitudinal length (mm) and the largest longitudinal section (cm2) of the two kidneys are presented. The size of the smaller kidney was presented above a slash and the larger kidney below with a percentage of the smaller kidney size relative to the larger kidney size in parentheses. Note that aplastic kidneys had almost similar longitudinal length in comparison to hypoplastic kidneys at birth, but were smaller at one month. The difference in size is more marked when compared to the section than the length. Abbreviations are: Rt, right; Lt, left; Bil, bilateral; CDK, multicystic dysplastic kidney. a % uptake in the smaller kidney relative to total uptake Fig. 1. Renal ultrasonograms of Patient 3 at the age of four days (left), four months (middle) and one year (right). The left aplastic kidney is shown at the upper level and the right normal kidney on the bottom. The aplastic kidney was small and reniform in the newborn period with several subcapsular cysts. While the cysts did not change markedly in size during the follow-up for one year, the aplastic kidney definitely decreased in size and the parenchyma appeared slightly hyperechoic at one month (not shown) and thereafter. The right normal kidney showed hypertrophy. of the nine small kidneys in the eight children (Table 2, Patients 2 to 4). In the newborn period these three small kidneys still had a reniform shape and their parenchyma appeared almost normal, except for small cysts in Patient 3, and there was no significant difference in size from the other small kidneys in Patients 5 to 9. DSA renoscintigraphy was performed in nine children (8 children with small kidneys and one with CDK; Tables 1 and 2), delineating a non-functioning kidney in four (Patients 1 to 4), a bilateral hypoplastic kidney in one (Patient 5), and a unilateral hypoplastic kidney in four (Patients 6 to 9) infants with a range of 25 to 38% of the total radioisotope uptake. All five children (Patients 5 9) with hypoplastic kidneys were boys. Patients 2 to 4 were diagnosed as having renal aplasia based on the findings of ultrasound and DSA renoscintigraphy.

4 Hiraoka et al: Renal aplasia in solitary kidney 1843 sure to known teratogens [5, 19] that could cause renal anomalies, and normal fetal ultrasound images were shown during the second and third trimesters, except for Patient 1 with CDK. Patient 1 had normal ultrasound findings at the 21st week of gestation, but was found to have developed large cysts at the 31st week. Anamnestic family studies for these nine children found no members with renal anomalies. While voiding cystourethrography revealed the association of vesicoureteral reflux in all of the hypoplastic kidneys, no reflux was found in the aplastic kidneys and CDK. No congenital anomalies other than those of the urinary tract were found in any of these children. Follow-up ultrasound studies notably demonstrated that aplastic kidneys in Patients 2 to 4 progressively regressed during the first year of life, as shown in Figure 2 and representatively in Figure 1, in contrast to the growing of the hypoplastic kidneys. The CDK in Patient 1 showed no significant change in size or the number of cysts on follow-up ultrasound studies over a three-year span. None of the Patients 1 to 9 had an episode of urinary tract infection during a median follow-up period of 4.1 years (range.3 to 7.5 years). Retrospective examination of clinical records of the nine mothers during their pregnancies revealed no expo- Fig. 2. Follow-up ultrasound studies of the eight congenitally small kidneys during the first year after birth. Numbers in the figure represent patient numbers; Patients 2 to 4, renal aplasia, and Patients 5 to 9, renal hypoplasia. Longitudinal length of the small kidneys is shown in relation to the body weight. Dotted lines indicate upper and lower limits of normal controls [16]. Note that longitudinal length of most of the small kidneys lay around the lower normal limit in the newborn period with no definite difference between the three aplastic kidneys and the five hypoplastic kidneys, but that the aplastic kidneys showed spontaneous regression, while the hypoplastic kidneys grew along the lower normal limit. DISCUSSION The present study successfully identified maldeveloped kidneys among apparently healthy neonates by carefully evaluating kidney size with ultrasound. It should be noted that hypoplastic or aplastic kidneys were only slightly small and very difficult to detect at birth. The present study showed the importance of suspecting possible maldeveloped kidneys and using serial ultrasound scans, thereby allowing for clear detection of some babies with truly maldeveloped kidneys among many babies suspected. The present study also confirmed that measuring only the longitudinal length of the kidney was not sensitive enough to detect small kidneys and that, instead, comparing the size of both kidneys in the longitudinal section provided a more accurate diagnosis. Ultrasound screening of random newborns in the present study correctly detected congenital solitary kidneys with an incidence of one in 13 newborns and CDK with an incidence of one in 4 newborns. These num- bers are the same as in previous studies [5, 13]. However, no renal agenesis was found in the present study, in con- trast to previous observations [5, 1, 13]. Renal aplasia was found with an incidence of one in 13, which was the same as the incidence of unilateral renal agenesis observed in an autopsy study [2] and an ultrasound screen- ing study of school children [1]. The present study observed that aplastic kidneys regressed rapidly after birth. Spontaneous involution of dysplastic kidneys was first observed in children with CDK [21] and then in a few fetal cases with CDK [14]. Regressed CDK was then supposed to be incorrectly diagnosed as renal agenesis, at least in some instances [14]. None of the present cases with renal aplasia showed any large cystic lesion on fetal ultrasound studies during the second and third trimes- ters, making the possibility of CDK quite unlikely in these three children. All of the observations described previously indicate that most of the renal agenesis diag- nosed clinically thus far should have been identified as renal aplasia (aplastic dysplasia) that had involuted after birth. Patients with unilateral renal aplasia are usually asymptomatic in early life and diagnosed only in later life, when aplastic kidneys already may be rudimentary and difficult to diagnose correctly on imaging studies or in autopsy studies without microscopic examinations. Derangement in renal aplasia seems to begin as early

5 1844 Hiraoka et al: Renal aplasia in solitary kidney as the ninth week of gestation, by which time interaction REFERENCES between the ureteric bud and metanephric blastema 1. Fivush B, Jabs K, Neu A, et al: Chronic renal insufficiency in commences and formation of nephrons starts [7, 22]. It children and adolescents: The 1996 annual report of NAPRTCS. Pediatr Nephrol 12: , 1998 should be noted that aplastic kidneys had a reniform 2. Woolf A, Winnyard P: Advances in the cell biology and genetics of human kidney malformations. J Am Soc Nephrol 9:1114 shape and were slightly small, but not rudimentary, at birth. This finding suggests that aplastic kidneys are still 1125, Kiprov D, Calvin R, cluskey R: Focal and segmental glomerugrowing almost normally in size until birth even with losclerosis and proteinuria associated with unilateral renal agenesis. Lab Invest 46: , 1982 abnormal architecture, so that despite fetal ultrasound 4. Thorner P, Arbus G, Celeremajer D, Baumal R: Focal segmental being performed routinely everywhere, it has not been glomerulosclerosis and progressive renal failure associated with a possible to detect aplastic kidneys. CDK is found not unilateral kidney. Pediatrics 73:86 81, Doroshow L, Abeshouse B: Congenital unilateral solitary kidney: to be an end stage organ, but highly active in terms of Report of 37 cases and a review of the literature. Urol Surv 11:219 cell turnover and gene expression [22]. Aplastic kidneys, 226, 1961 another extreme form of dysplastic kidneys, may express 6. Fortune C: The pathological and clinical significance of congenital one-sided kidney defect with the presentation of three new cases similar genes coding for such as survival and growth of agenesia and one of aplasia. Ann Intern ed 1: , 1927 factors during fetal life, and switch to express genes de- 7. Taxy J: Renal dysplasia: A review. Pathol Annu 2: , Potter E: Bilateral absence of ureters and kidneys. Obst Gynecol clining for apoptosis, resulting in involution, in response 25:3 12, 1965 to environmental changes at birth. 9. atsell DG: Renal dysplasia: New approaches to an old problem. Am J Kidney Dis 32: , 1998 Unilateral renal anomalies are considered to be more 1. Sheih CP, Liu B, Hung CS, et al: Renal abnormalities in schoolchildren. Pediatrics 84:186 19, 1989 likely the result of an acquired insult [9]. However, there should be a genetic relationship, at least in some instances, 11. Helin I, Persson PH: Prenatal diagnosis of urinary tract abnormal- ities by ultrasound. Pediatrics 78: , 1986 between bilateral and unilateral renal agenesis/aplasia 12. Rosendahl H: Ultrasound screening for fetal urinary tract malformations: A prospective study in general population. Eur J Obstet [23], since there were members with bilateral and unilat- Gynecol Reprod Biol 36:27 33, 199 eral renal agenesis/aplasia in each of several families 13. Gordon AC, Thomas DF, Arthur RJ, Irving HC: ulticystic [23, 24]. Renal agenesis, renal aplasia and CDK may dysplastic kidney: Is nephrectomy still appropriate? J Urol 14: , 1988 be genetically related, at least in some, and can be viewed 14. esrobian H-GJ, Rushton H, Bulas D: Unilateral renal agenesis as a continuum [7], since these anomalies are found in may result from in utero regression of multicystic renal dysplasia. J Urol 15: , 1993 members of the same families [25]. On the other hand, 15. Hiraoka, Hori C, Tsukahara H, et al: Congenitally small kidthe familial recurrence risk of renal agenesis is observed neys with reflux as a common cause of nephropathy in boys. Kidney to be much higher than that of renal dysplasia [26]. Potter Int 52: , Han B, Babcock D: Sonographic measurements and appearance found that unilateral renal agenesis, unlike renal aplasia, of normal kidneys in children. Am J Roentgenol 145: , 1985 was often complicated by anomalies of internal genital 17. Thakur V, Watkins T, ccarthy K, et al: Is kidney length a good predictor of kidney volume? Am J ed Sci 313:85 89, 1997 organs, especially in females, and occasionally by anoma- 18. International Reflux Study Committee: edical versus surgical lies in other organs than those of the genitourinary tract treatment of primary vesicoureteral reflux. Prospective interna- tional reflux study in children. J Urol 125: , 1981 [8]. The present study showed that ultrasound screening 19. Brown N: Chemical teratogens: Hazards, tools and clues, in Embryos, Genes and Birth Defects, edited by Thorogood P, New of the urinary tract of neonates could detect renal aplasia York, John Wiley & Sons, 1997, pp and that most of unilateral renal agenesis reported thus 2. Cascio S, Paran S, Puri P: Associated urological anomalies in far might be more correctly classified as unilateral renal children with unilateral renal agenesis. J Urol 162: , Wacksman J, Phipps L: Report of the multicystic kidney registry: aplasia. Further studies of a larger sized cohort should Preliminary findings. J Urol 15: , 1993 facilitate an accurate definition of the incidence of renal 22. Woolf AS, Winyard PJ: Gene expression and cell turnover in agenesis and the frequency of complicated anomalies human renal dysplasia. Histol Histopathol 15: , Carter C, Evans K, Pescia G: A familial study of renal agenesis. in both renal agenesis and aplasia, and help to reveal J ed Genet 16: , 1979 responsible etiologies. 24. Roodhooft A, Birnholz J, Holmes L: Familial nature of congeni- tal absence and severe dysgenesis of both kidneys. N Engl J ed 31: , 1984 Reprint requests to asahiro Hiraoka,.D., Department of Pediat- 25. urugasu B, Cole B, Hawkins E, et al: Familial renal adysplasia. rics, Fukui edical University School of edicine, atsuoka, Fukui Am J Kidney Dis 4:49 494, , Japan. 26. Bankier A, DeCampo, Newell R: A pedigree study of perina- hiraoka@fmsrsa.fukui-med.ac.jp tally lethal renal disease. J ed Genet 22:14 111, 1985