Accepted Manuscript The natural history of the multicystic dysplastic kidney – is limited follow-up warranted? A.B. Eickmeyer, N.F. Casanova, M.D. M.S. Chang He, E.A. Smith, M.D. J. Wan, M.D. D.A. Bloom, M.D. J.R. Dillman, M.D. PII:
S1477-5131(14)00169-7
DOI:
10.1016/j.jpurol.2014.06.001
Reference:
JPUROL 1725
To appear in:
Journal of Pediatric Urology
Received Date: 4 March 2014 Accepted Date: 9 June 2014
Please cite this article as: Eickmeyer AB, Casanova NF, Chang He MS, Smith EA, Wan J, Bloom DA, Dillman JR, The natural history of the multicystic dysplastic kidney – is limited follow-up warranted?, Journal of Pediatric Urology (2014), doi: 10.1016/j.jpurol.2014.06.001. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
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The natural history of the multicystic dysplastic kidney – is limited follow-up warranted?
a
The University of Michigan Departments of Urology and Radiology
1500 E Medical Center Drive
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Ann Arbor, MI 48109, USA
Chang He: [email protected] E.A. Smith: [email protected] J. Wan: [email protected]
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D.A. Bloom: [email protected] J.R. Dillman: [email protected]
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Corresponding author:
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A.B. Eickmeyer: [email protected] N.F. Casanova: [email protected]
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A.B. Eickmeyera, N.F. Casanova M.D.a, M.S. Chang Hea, E.A. Smith M.D.a, J. Wan M.D.a, D.A. Bloom M.D.a, J.R. Dillman M.D.a
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Summary
Objective: Imaging of patients with multicystic dysplastic kidney (MCDK) has increased over the past three decades. This increased use of imaging has provided additional insights into the
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natural history of MCDK. The present study looked at this data for predictors of involution and associated anomalies.
Methods and materials: Institutional review board approval was obtained for this retrospective
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study. The University of Michigan Departments of Urology and Radiology records were
searched to identify unilateral MCDK patients during 1980–2012. Available clinical, radiological
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and surgical records were reviewed, and pertinent data were recorded. The log-rank test and a Cox proportional regression analysis were performed to identify predictors of MCDK involution. Probability of involution over time was assessed using Kaplan-Meier methodology.
Results: 301 unilateral MCDKs were identified; 195 (64.8%) were detected antenatally. Of the MCDKs found, 136 (45.2%) were in girls; 160 (53.2%) were right-sided. Mean size at baseline
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was 5.0 ± 0.2 cm (Mean ± SE). Associated abnormalities included: contralateral ureteropelvic junction obstruction (n = 10; 3.3%); contralateral ureterovesical junction obstruction/primary megaureter (n = 6; 2.0%); ipsilateral VUR (n = 21; 7.0%); contralateral VUR (n = 63; 20.1%); and renal fusion anomaly (n = 4; 1.3%). The cumulative probability of involution was: 9.8% at
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one year, 38.5% at five years, and 53.5% at ten years of age. Baseline MCDK size was the only significant predictor of involution at bivariate (p < 0.0001) and multivariate (p < 0.0001; HR
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0.58 [95% CI: 0.49, 0.69]) analyses. No MCDK developed malignancy during the follow-up period.
Conclusion: As many MCDKs eventually involute and the risk of associated malignancy appears to be very low, there is no absolute indication for nephrectomy. Based on the data and other recent studies, it is believed that pediatric MCDK patients with no other urologic abnormalities can safely tolerate more limited urological and radiological follow-up.
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Keywords: Multicystic dysplastic kidney (MCDK); Involution; Wilms’ tumor
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Introduction Multicystic dysplastic kidney (MCDK) is a congenital condition present in approximately
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1 in 1000 to 4000 live births.1 The anomaly was first described by Cruveilhier in 18362 and then reintroduced by Schwartz in 1936.3,4 The condition classically results in a dysmorphic kidney with multiple non-communicating cysts, whose appearance is similar to that of a cluster of
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grapes with little to no identifiable functional renal parenchyma. Numerous studies have linked MCDK with other genitourinary anomalies, including contralateral ureteropelvic junction
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obstruction and, most commonly, VUR.5-9
Although they are most often diagnosed via antenatal ultrasound, some MCDKs may not be detected until birth, when a palpable abdominal mass triggers an evaluation. The etiology of MCDKs remains unknown but there are two leading theories. The obstruction theory proposes
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that the MCDK results from severe fetal obstructive hydronephrosis due to atresia of the renal pelvis or ureter.10 The finding of an atretic ureter on autopsy specimens is cited as a possible clue. The other theory suggests an abnormal interaction between the ureteric bud and
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metanephric blastema.11 Subsequent development is affected and leads to the MCDK. The observation that ureters that have ectopic insertions are more prone to be associated with
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dysplastic or abnormal renal units bolsters this theory. While both theories have merit, they do not exist in isolation, and the true etiology may be a combination of multiple processes. The course of management has changed over time. Reports from the 1970s stressed
nephrectomy, due to potential harms from the nonfunctioning kidney. 3 Present practice is watchful waiting, based upon natural history studies of MCDK.12-18 Long-term large data series have led many to conclude that the risk of neoplasm and hypertension are not increased in 3
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patients with MCDK and that the trend away from extirpation seems sound.8,13,14,19-23 Currently, the most-common treatment is conservative observation and monitoring patients with MCDK.
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Despite this trend, there is no clear outcome-based clinical algorithm for the management of this anomaly and the question of frequency and duration of clinical and radiological follow-up remains debated and inconsistent within and between institutions. To critically assess the natural
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history of MCDK in children, the present study looked at predictors and probability of
involution, indications for nephrectomy, and associated renal and genitourinary anomalies in a
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large population at a major academic center in order to guide specific management strategies.
Materials and Methods
Pertinent electronic and hardcopy medical records dated from January 01 1980 to January
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30 2013, from the University of Michigan Departments of Urology and Radiology, were searched to identify all unilateral MCDK patients, regardless of age. Available radiological, clinical, and surgical records were reviewed. Antenatal history, demographic information,
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pertinent radiological data from ultrasonography, CT, MRI, and scintigraphy (e.g.laterality,
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baseline size, size at follow-up imaging and associated anomalies), and pertinent clinical history were documented. Institutional Review Board approval was obtained for this retrospective, HIPAA-compliant investigation. Descriptive statistical analysis was performed to present the clinical details of the study
population. Achievement of compensatory hypertrophy was assessed cumulatively at intervals during the first 15 years of life. The log-rank test was used for bivariate analysis to assess the 4
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unadjusted difference in involution probability among patient groups stratified by MCDK predictors. Probability of involution over time was assessed using the Kaplan-Meier method. A Cox proportional hazards regression analysis was used to generate a multivariable model in order
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to determine the important predictors for MCDK involution. Backward model-building
procedures were used to determine the most parsimonious model for MCDK outcome. Subjects with baseline renal imaging from within the first year of life and subsequent follow-up imaging
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at least one year later were included in these analyses. Sixty-eight subjects were excluded from these latter analyses because of missing data. These analyses were performed using SAS
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statistical software (version 9.3; SAS Institute Inc, Cary, NC), and all testing was two-sided. The probability of a type I error was set at 0.05.
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Results
During the sample period, 301 unilateral MCDKs were identified, of which 195 (64.8%) were detected antenatally. In the cohort, 165 (54.8%) MCDKs were boys and 160 (53.2%) were
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right-sided. Mean size at baseline imaging was 5.0 ± 0.2 cm (mean ± SE), with a median age at time of baseline imaging of 0.67 years (0-68.65). Median follow-up time was 4.6 years with a
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mean follow-up time of 14.4 years.
Associated abnormalities and anomalies identified in the subjects included: contralateral
VUR (n = 63; 20.1%); ipsilateral VUR (n = 21; 7.0%); contralateral UPJ obstruction (UPJO) (n = 10; 3.3%); contralateral ureterovesical junction obstruction (UVJO), including primary megaureter (n = 6; 2.0%); and renal fusion anomaly (including horseshoe kidney and cross-fused 5
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ectopia) (n = 4; 1.3%), as shown in Table 1. Additionally, four girls were found to have Müllerian duct (uterine) anomalies.
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Two hundred and thirty nine of the patients underwent a VCUG. Of the 63 patients with contralateral VUR to the functionally solitary kidney, six were lost to follow-up, with respect to their reflux. An additional five were still actively being followed for reflux (oldest age five
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years) and are were currently on antibiotics. Of the remaining 52 patients, 39 had complete resolution of the reflux on VCUG and an additional six were clinically asymptomatic off
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antibiotics and were presumed to have resolved the reflux, making for an 86.5% rate of clinically insignificant reflux. Seven patients underwent surgical correction of their reflux. Of these, two had a known neurogenic bladder and one had a duplicated collecting system, both of which would account for the need for anti-reflux surgery in isolation from the MCDK.
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Involution rates and predictors
Of the 233 subjects who met inclusion criteria, the cumulative probability of involution was 9.8% at one year of age (n = 219), 38.5% at five years of age (n = 146), 53.5% at ten years
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of age (n = 107) and 64.9% at 15 years (n = 91) (Figure 1).
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Baseline MCDK size was the only significant predictor of involution at bivariate (p < 0.0001) and multivariable (p < 0.0001; HR 0.58 [95% CI: 0.49, 0.69]) analyses. The MCDKs that measured less than 5.0 cm at baseline imaging had a mean age at involution of 2.7 years, while those measuring greater than 5.0 cm at baseline imaging had a mean age at involution of 11.0 years. The presence of contralateral VUR as a predictor of involution approached marginal significance (p = 0.06). Patients that experienced involution in the time 6
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frame of the present study had a mean initial MCDK size of 3.8 ± 0.3 cm (mean ± SE), while patients that did not experience involution had a mean initial size of 5.8 ± 0.2 cm (Table 1). Laterality, gender, coexisting renal/genitourinary tract abnormalities, and antenatal vs prenatal
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diagnosis were not found to be significant predictors of involution. No MCDK developed malignancy during the study period.
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Hypertension and compensatory hypertrophy
Nine patients out of the 301-patient cohort developed hypertension throughout the
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follow-up period for a 3% incidence of hypertension. Of these patients, six had either contralateral VUR or a serious comorbid condition (Prune Belly Syndrome, Spina Bifida, cardiac anomalies/subaortic stenosis, and Fraser Syndrome) that could contribute to the development of hypertension, independent of an MCDK.
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Using the 95th percentile as the standard for contralateral compensatory hypertrophy, 49.4% (76/154) of patients with available records reached that level by one year of age; 78.0% (124/159) by five years of age, 89.4% (144/161) by 10 years; and by 15 years of age, 94.9%
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(150/158) reached the 95th percentile. If the 75th percentile is used to define contralateral compensatory hypertrophy, 90.0% (162/180) reached this by five years and 99% (189/191) by 15
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years of age.
Association with cryptorchidism The prevalence of unilateral and bilateral cryptorchidism or undescended testicles (UDT)
in the population of 165 males was found to be 12.7% (n = 21). The majority of the UDTs in the population were right-sided (57.1%; n = 12) or bilateral (33.3%; n = 7). Only two patients (9.5%) 7
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had an isolated left-sided UDT. Almost all of these UDTs were located on the same side as the MCDK (61.9%; n = 13) or were present bilaterally (33.3%; n = 9). Only one UDT presented solely on the contralateral side of the patient’s MCDK, and it was a solitary testicle. Of the
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unilateral UDTs (n = 14), 11 (78.57%) were right-sided and ipsilateral to the patient’s MCDK. A left sided, ipsilateral UDT was much-less common (14.29%; n = 2) (Table 2).
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Surgical management versus time
Pediatric urologists at the institution surgically resected 9, 24 and 15 MCDKs between
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1980–1989, 1990–1999, and 2000–present, respectively. Of these 48 resected kidneys, the mostcommon indications for nephrectomy were failure to involute (18.8%; n = 9), with another 14 presumably removed for the same reason (unclear records), increasing size (18.8%; n = 9) and parental preference (10.4%; n = 5) in order to limit follow-up and perceived risks. Other less-
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common reasons included: flank pain, a concern for cause of hypertension, infection, and one
of its large size.
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Discussion
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child whose MCDK was thought to be contributing to respiratory distress as a newborn because
No consensus exists regarding the appropriate long-term management plan of children
with MCDK. To date, treatment has ranged from early nephrectomy to conservative monitoring of blood pressure and renal contour/size at regular intervals until involution. Given the increasing rate of MCDK detection and widespread use of ultrasonography, the consistency of follow-up has become more important. The present data corroborates previous studies showing that initially 8
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smaller MCDKs are more likely to involute and do so at an earlier age than larger MCDKs.18 As no malignancy was identified in more than 300 children during the longer than 30-year study period, the real risk of this outcome is likely to be very small. This too is consistent with the
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literature that the risk of Wilms’ tumor is negligible and surveillance is not warranted.13,23,24 In addition, the occurrence of hypertension in the present MCDK population was found
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to be consistent with that quoted in the general pediatric population25 and is unlikely to warrant aggressive subspecialty follow-up in the uncomplicated MCDK patient. Multiple studies on
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children with MCDK have revealed similar results15,16,26 and in a 2005 meta-analysis, the risk of hypertension among these children was actually less than that seen in the general population (0.54% vs 1–4.5% between the ages of four and adolescence).22
Interestingly, an increased prevalence of UDT was also found in the male population of
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the present MCDK cohort. The exact etiology of this finding is not clear, but may be related to the embryologic development (abnormal interaction of the ureteric bud with the metanephric mesenchyme) and general proximity of the kidney to the testis/gubernaculum. The review of the
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literature did not identify any prior studies describing an association between MCDK and UDT, and it is believed that this observation warrants further research to determine generalizability and
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embryologic origins.
Whilst the MCDK itself poses virtually no or minimal risk to patients, based on the
present data and other recent investigations,13,15,18,27 it is important that the contralateral and functionally solitary kidney is radiologically assessed for hydronephrosis and size to exclude associated anomalies/abnormalities such as VUR, UPJO, and UVJO. While it is certainly important to preserve the functionally solitary kidney, the present data also reports that for the 9
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majority of patients, reflux is clinically insignificant and requires no additional surgery. This data is consistent with previous literature28 and further supports reduced imaging, VCUG included, in appropriate patients with MCDK. Additionally, the hypertrophy status of the contralateral kidney
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can guide management of the MCDK, as those who have reached the 95th percentile experience higher rates of involution of the MCDKs, as seen in the literature and in the present series.13
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The economic status of health care systems makes it crucial that practices are continually reassessed, including the management of MCDKs. It is important to be certain that the care
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provided is truly medically necessary. After reviewing comprehensive reviews of the medical, radiological and surgical records of 301 MCDK patients, it was noted that the large majority of MCDK follow-up office visits consisted of a physical examination, updating the medical history from the previous encounter, and ultrasonography performed in the Department of Radiology, which most often revealed a stable or involuting MCDK and no associated complications. As a
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result, most patients left their follow-up encounters, which were commonly on an annual basis, with no new useful information or change in MCDK management. In 1998, Perez and colleagues evaluated the cost of nonoperative, ultrasonographic monitoring of MCDKs. This was based on
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serial ultrasound every six months for two years, then annually thereafter to the age eight years;
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they estimated the total national cost in 1000 children was $2.5–3 million dollars.29 This does not include office visit charges or travel costs and time lost from work. Potentially, this is quite a large burden on the health care system. Based on the results of the present study, it is believed that asymptomatic MCDK patients with no contralateral renal or urinary tract abnormality will safely tolerate more limited urological and radiological follow-up, thus potentially saving millions of health care dollars and parental/patient inconvenience. 10
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To address the lack of a clear and standardized management plan for MCDK, a clinical algorithm has been developed for the follow-up of these patients, based on the results of the present study (Figure 2). The proposed algorithm substantially limits the urological and
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radiological follow-up of children with MCDK who are otherwise healthy after undergoing
initial genitourinary clinical and radiological evaluation. Otherwise healthy MCDK patients can be initially counseled on the implications of having a MCDK, and can subsequently be followed
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by their primary care doctor for appropriate care, as well as attention to possible MCDK-related complications, which will be quite rare. The present study and other recent investigations do not
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support routine nephrectomy for MCDKs unless complications arise, such as: recurrent infection, hypertension that is highly likely to be renovascular in etiology, or an enlarging MCDK with pathologic mass-effect or recalcitrant pain.
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Limitations
Limitations of this study are those related to retrospective studies, as there may be missing records that would create recall bias. Some patients had inconsistent imaging follow-up
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and were therefore excluded from the multivariate analysis of this study. The Kaplan-Meier method used for the probability of involution analysis accounted for patients with missing data
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and provided validity to the results.
Conclusion
Multicystic kidney disease is a condition with no vetted algorithm for treatment or urological and radiological follow-up. The present study found that children with initially 11
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smaller MCDKs are more likely to experience involution and experience it at an earlier age, compared to larger MCDKs. By ten years of age, 53.5% of children with MCDK experienced involution of the affected kidney. The present study confirms that malignancy in MCDKs is
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exceedingly rare and that the prevalence of hypertension mirrors that of a general pediatric population. Consequently, there is no absolute indication for nephrectomy in children with
MCDKs. Based on the present data and other recently published studies, it is proposed that
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pediatric MCDK patients can safely tolerate much more limited urological and radiological
physician.
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Conflict of Interest/Funding: None
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follow-up, with MCDK follow-up instead being provided by the patient’s primary care
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References:
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Kalyoussef E, Hwang J, Prasad V, Barone J. Segmental multicystic dysplastic kidney in children. Urology. Nov 2006;68(5):1121 e1129-1111. Cruveilhier J. Anatomie Pathologique du Corps Humain. Paris: J.B. Bailliere Libraire; 1836. Bloom DA, Brosman S. The multicystic kidney. J Urol. Aug 1978;120(2):211-215. Schwartz J. An unusual unilateral multicystic kidney in an infant. J. Urol. 1936;35(259). Heikkinen ES, Herva R, Lanning P. Multicystic kidney. A clinical and histological study of 13 patients. Ann Chir Gynaecol. 1980;69(1):15-22. Atiyeh B, Husmann D, Baum M. Contralateral renal abnormalities in multicystic-dysplastic kidney disease. J Pediatr. Jul 1992;121(1):65-67. Flack CE, Bellinger MF. The multicystic dysplastic kidney and contralateral vesicoureteral reflux: protection of the solitary kidney. J Urol. Dec 1993;150(6):1873-1874. Wacksman J, Phipps L. Report of the Multicystic Kidney Registry: preliminary findings. J Urol. Dec 1993;150(6):1870-1872. al-Khaldi N, Watson AR, Zuccollo J, Twining P, Rose DH. Outcome of antenatally detected cystic dysplastic kidney disease. Arch Dis Child. Jun 1994;70(6):520-522. Felson B, Cussen LJ. The hydronephrotic type of unilateral congenital multicystic disease of the kidney. Semin Roentgenol. Apr 1975;10(2):113-123. Osathanondh V, Potter EL. Pathogenesis of Polycystic Kidneys. Historical Survey. Arch Pathol. May 1964;77:459-465. Wein AJ, Kavoussi LR, Campbell MF. Campbell-Walsh urology / editor-in-chief, Alan J. Wein; [editors, Louis R. Kavoussi ... et al.]. 10th ed. Philadelphia, PA: Elsevier Saunders; 2012. Onal B, Kogan BA. Natural history of patients with multicystic dysplastic kidney-what followup is needed? J Urol. Oct 2006;176(4 Pt 1):1607-1611. Rabelo EA, Oliveira EA, Diniz JS, et al. Natural history of multicystic kidney conservatively managed: a prospective study. Pediatr Nephrol. Oct 2004;19(10):1102-1107. Okada T, Yoshida H, Matsunaga T, et al. Multicystic dysplastic kidney detected by prenatal ultrasonography: natural history and conservative management. Pediatr Surg Int. May 2003;19(3):207-210. Tiryaki S, Alkac AY, Serdaroglu E, Bak M, Avanoglu A, Ulman I. Involution of multicystic dysplastic kidney: is it predictable? J Pediatr Urol. Jun 2013;9(3):344-347. Strife JL, Souza AS, Kirks DR, Strife CF, Gelfand MJ, Wacksman J. Multicystic dysplastic kidney in children: US follow-up. Radiology. Mar 1993;186(3):785-788. Hayes WN, Watson AR. Unilateral multicystic dysplastic kidney: does initial size matter? Pediatr Nephrol. Aug 2012;27(8):1335-1340. Tilemis S, Savanelli A, Baltogiannis D, Cigliano B, Settimi A. Is the risk of hypertension an indication for prophylactic nephrectomy in patients with unilateral multicystic dysplastic kidney? Scand J Urol Nephrol. 2003;37(5):429-432. Sheikh-Hamad D, Cacini W, Buckley AR, et al. Cellular and molecular studies on cisplatin-induced apoptotic cell death in rat kidney. Arch Toxicol. Mar 2004;78(3):147-155. Farnham SB, Adams MC, Brock JW, 3rd, Pope JCt. Pediatric urological causes of hypertension. J Urol. Mar 2005;173(3):697-704. Narchi H. Risk of hypertension with multicystic kidney disease: a systematic review. Arch Dis Child. Sep 2005;90(9):921-924. Narchi H. Risk of Wilms' tumour with multicystic kidney disease: a systematic review. Arch Dis Child. Feb 2005;90(2):147-149. 13
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Psooy K. Multicystic dysplastic kidney in the neonate: the role of the urologist. Can Urol Assoc J. Apr 2010;4(2):95-97. Mitsnefes MM. Hypertension in children and adolescents. Pediatr Clin North Am. Jun 2006;53(3):493-512, viii. Weinstein A, Goodman TR, Iragorri S. Simple multicystic dysplastic kidney disease: end points for subspecialty follow-up. Pediatr Nephrol. Jan 2008;23(1):111-116. Oliveira EA, Diniz JS, Vilasboas AS, Rabelo EA, Silva JM, Filgueiras MT. Multicystic dysplastic kidney detected by fetal sonography: conservative management and follow-up. Pediatr Surg Int. 2001;17(1):54-57. Ismaili K, Avni FE, Alexander M, Schulman C, Collier F, Hall M. Routine voiding cystourethrography is of no value in neonates with unilateral multicystic dysplastic kidney. J Pediatr. Jun 2005;146(6):759-763. Perez LM, Naidu SI, Joseph DB. Outcome and cost analysis of operative versus nonoperative management of neonatal multicystic dysplastic kidneys. J Urol. Sep 1998;160(3 Pt 2):1207-1211; discussion 1216.
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Table 1: Potential Predictors of Involution Over Time
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Involution Predictors
All
Yes
Bivariate Analysis
Multivariable Analysis
No
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n % n % n % Log Rank p HR (95% CI) P HR (95% CI) All Eligible 233 100.0% 87 37.3% 146 62.7% Laterality* Left 106 45.5% 40 37.7% 66 62.3% 0.67 1.10 (0.72, 1.67) Right 127 54.5% 47 37.0% 80 63.0% 1 Sex* Male 129 55.4% 50 38.8% 79 61.2% 0.40 1.20 (0.78, 1.85) Female 104 44.6% 37 35.6% 67 64.4% 1 Initial Size within 1st Year* (missing 89) Mean + SE 144 5.0 + 0.2 55 3.8 + 0.3 89 5.8 + 0.2 < 0.0001 0.58 (0.49, 0.69) < 0.0001 0.58 (0.49, 0.69) Contralateral Abnormalities VUR vs. Others vs. None* (missing 5) VUR 53 23.3% 27 50.9% 26 49.1% 0.06 1.61 (1.02, 2.57) Others 20 8.8% 5 25.0% 15 75.0% 0.67 (0.27, 1.67) No 155 68.0% 54 34.8% 101 65.2% 1 Contralateral Abnormalities Yes vs. No* (missing 5) Yes 73 32.0% 32 43.8% 41 56.2% 0.21 1.32 (0.85, 2.05) No 155 68.0% 54 34.8% 101 65.2% 1 Ipsilateral Abnormalities- VUR vs. Others vs. No* VUR 19 8.2% 6 31.6% 13 68.4% 0.94 0.86 (0.38, 1.97) Others 2 0.9% 1 50.0% 1 50.0% 1.04 (0.15, 7.52)) No 212 91.0% 80 37.7% 132 62.3% 1 Ipsilateral Abnormalities- Yes vs. No* Yes 21 9.0% 7 33.3% 14 66.7% 0.75 0.88 (0.41, 1.91) No 212 91.0% 80 37.7% 132 62.3% 1 Discovered Time* (missing = 52) Prenatal Discovery 153 84.5% 58 37.9% 95 62.1% 0.18 1.66 (0.78, 3.51) Postnatal Discovery 28 15.5% 8 28.6% 20 71.4% 1 * Variables included in the starting multivariable model. Then backward model selection is used to determine the final multivariable model.
Bivariate Analysis
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Predictors
All
Yes % 100.0%
n 87
% 37.3%
n 146
% 62.7%
Left
106
45.5%
40
37.7%
66
62.3%
Right
127
54.5%
47
37.0%
80
63.0%
Male
129
55.4%
50
38.8%
79
Female 104 Initial Size within 1st Year* (missing 89)
44.6%
37
35.6%
67
5.0 + 0.2
55
3.8 + 0.3
144
< 0.0001
0.06
53
23.3%
27
50.9%
26
49.1%
Others
20
8.8%
5
25.0%
15
75.0%
No 155 68.0% Contralateral Abnormalities Yes vs. No* (missing 5)
54
34.8%
101
65.2%
No 155 Ipsilateral Abnormalities- VUR vs. Others vs. No*
32.0%
32
43.8%
41
56.2%
54
34.8%
101
65.2%
6
31.6%
13
68.4%
1
50.0%
1
50.0%
80
37.7%
132
62.3%
9.0%
7
33.3%
14
66.7%
91.0%
80
37.7%
132
62.3%
68.0%
VUR
19
8.2%
Others
2
0.9%
Yes
21
No
212
91.0%
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No 212 Ipsilateral Abnormalities- Yes vs. No*
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73
0.40
5.8 + 0.2
VUR
Yes
0.67
64.4%
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Contralateral Abnormalities VUR vs. Others vs. None* (missing 5)
89
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Mean + SE
61.2%
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Sex*
Log Rank p
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n 233
All Eligible Laterality*
Multivariable Analysis
No
0.21
0.94
0.75
OR (95% CI)
P
OR (95% CI)
1.10 (0.72, 1.67) 1 1.20 (0.78, 1.85) 1 0.58 (0.49, 0.69)
1.61 (1.02, 2.57) 0.67 (0.27, 1.67) 1 1.32 (0.85, 2.05) 1 0.86 (0.38, 1.97) 1.04 (0.15, 7.52)) 1 0.88 (0.41, 1.91) 1
Discovered Time* (missing = 52) 1.66 (0.78, 95 62.1% 58 37.9% 0.18 Prenatal Discovery 153 84.5% 3.51) 28 8 28.6% 20 71.4% Postnatal Discovery 15.5% 1 * Variables included in the starting multivariable model. Then backward model selection is used to determine the final multivariable model.
S1477-5131(14)00169-7
DOI:
10.1016/j.jpurol.2014.06.001
Reference:
JPUROL 1725
To appear in:
Journal of Pediatric Urology
Received Date: 4 March 2014 Accepted Date: 9 June 2014
Please cite this article as: Eickmeyer AB, Casanova NF, Chang He MS, Smith EA, Wan J, Bloom DA, Dillman JR, The natural history of the multicystic dysplastic kidney – is limited follow-up warranted?, Journal of Pediatric Urology (2014), doi: 10.1016/j.jpurol.2014.06.001. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
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The natural history of the multicystic dysplastic kidney – is limited follow-up warranted?
a
The University of Michigan Departments of Urology and Radiology
1500 E Medical Center Drive
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Ann Arbor, MI 48109, USA
Chang He: [email protected] E.A. Smith: [email protected] J. Wan: [email protected]
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D.A. Bloom: [email protected] J.R. Dillman: [email protected]
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Corresponding author:
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A.B. Eickmeyer: [email protected] N.F. Casanova: [email protected]
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A.B. Eickmeyera, N.F. Casanova M.D.a, M.S. Chang Hea, E.A. Smith M.D.a, J. Wan M.D.a, D.A. Bloom M.D.a, J.R. Dillman M.D.a
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Summary
Objective: Imaging of patients with multicystic dysplastic kidney (MCDK) has increased over the past three decades. This increased use of imaging has provided additional insights into the
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natural history of MCDK. The present study looked at this data for predictors of involution and associated anomalies.
Methods and materials: Institutional review board approval was obtained for this retrospective
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study. The University of Michigan Departments of Urology and Radiology records were
searched to identify unilateral MCDK patients during 1980–2012. Available clinical, radiological
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and surgical records were reviewed, and pertinent data were recorded. The log-rank test and a Cox proportional regression analysis were performed to identify predictors of MCDK involution. Probability of involution over time was assessed using Kaplan-Meier methodology.
Results: 301 unilateral MCDKs were identified; 195 (64.8%) were detected antenatally. Of the MCDKs found, 136 (45.2%) were in girls; 160 (53.2%) were right-sided. Mean size at baseline
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was 5.0 ± 0.2 cm (Mean ± SE). Associated abnormalities included: contralateral ureteropelvic junction obstruction (n = 10; 3.3%); contralateral ureterovesical junction obstruction/primary megaureter (n = 6; 2.0%); ipsilateral VUR (n = 21; 7.0%); contralateral VUR (n = 63; 20.1%); and renal fusion anomaly (n = 4; 1.3%). The cumulative probability of involution was: 9.8% at
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one year, 38.5% at five years, and 53.5% at ten years of age. Baseline MCDK size was the only significant predictor of involution at bivariate (p < 0.0001) and multivariate (p < 0.0001; HR
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0.58 [95% CI: 0.49, 0.69]) analyses. No MCDK developed malignancy during the follow-up period.
Conclusion: As many MCDKs eventually involute and the risk of associated malignancy appears to be very low, there is no absolute indication for nephrectomy. Based on the data and other recent studies, it is believed that pediatric MCDK patients with no other urologic abnormalities can safely tolerate more limited urological and radiological follow-up.
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Keywords: Multicystic dysplastic kidney (MCDK); Involution; Wilms’ tumor
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Introduction Multicystic dysplastic kidney (MCDK) is a congenital condition present in approximately
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1 in 1000 to 4000 live births.1 The anomaly was first described by Cruveilhier in 18362 and then reintroduced by Schwartz in 1936.3,4 The condition classically results in a dysmorphic kidney with multiple non-communicating cysts, whose appearance is similar to that of a cluster of
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grapes with little to no identifiable functional renal parenchyma. Numerous studies have linked MCDK with other genitourinary anomalies, including contralateral ureteropelvic junction
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obstruction and, most commonly, VUR.5-9
Although they are most often diagnosed via antenatal ultrasound, some MCDKs may not be detected until birth, when a palpable abdominal mass triggers an evaluation. The etiology of MCDKs remains unknown but there are two leading theories. The obstruction theory proposes
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that the MCDK results from severe fetal obstructive hydronephrosis due to atresia of the renal pelvis or ureter.10 The finding of an atretic ureter on autopsy specimens is cited as a possible clue. The other theory suggests an abnormal interaction between the ureteric bud and
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metanephric blastema.11 Subsequent development is affected and leads to the MCDK. The observation that ureters that have ectopic insertions are more prone to be associated with
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dysplastic or abnormal renal units bolsters this theory. While both theories have merit, they do not exist in isolation, and the true etiology may be a combination of multiple processes. The course of management has changed over time. Reports from the 1970s stressed
nephrectomy, due to potential harms from the nonfunctioning kidney. 3 Present practice is watchful waiting, based upon natural history studies of MCDK.12-18 Long-term large data series have led many to conclude that the risk of neoplasm and hypertension are not increased in 3
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patients with MCDK and that the trend away from extirpation seems sound.8,13,14,19-23 Currently, the most-common treatment is conservative observation and monitoring patients with MCDK.
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Despite this trend, there is no clear outcome-based clinical algorithm for the management of this anomaly and the question of frequency and duration of clinical and radiological follow-up remains debated and inconsistent within and between institutions. To critically assess the natural
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history of MCDK in children, the present study looked at predictors and probability of
involution, indications for nephrectomy, and associated renal and genitourinary anomalies in a
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large population at a major academic center in order to guide specific management strategies.
Materials and Methods
Pertinent electronic and hardcopy medical records dated from January 01 1980 to January
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30 2013, from the University of Michigan Departments of Urology and Radiology, were searched to identify all unilateral MCDK patients, regardless of age. Available radiological, clinical, and surgical records were reviewed. Antenatal history, demographic information,
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pertinent radiological data from ultrasonography, CT, MRI, and scintigraphy (e.g.laterality,
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baseline size, size at follow-up imaging and associated anomalies), and pertinent clinical history were documented. Institutional Review Board approval was obtained for this retrospective, HIPAA-compliant investigation. Descriptive statistical analysis was performed to present the clinical details of the study
population. Achievement of compensatory hypertrophy was assessed cumulatively at intervals during the first 15 years of life. The log-rank test was used for bivariate analysis to assess the 4
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unadjusted difference in involution probability among patient groups stratified by MCDK predictors. Probability of involution over time was assessed using the Kaplan-Meier method. A Cox proportional hazards regression analysis was used to generate a multivariable model in order
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to determine the important predictors for MCDK involution. Backward model-building
procedures were used to determine the most parsimonious model for MCDK outcome. Subjects with baseline renal imaging from within the first year of life and subsequent follow-up imaging
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at least one year later were included in these analyses. Sixty-eight subjects were excluded from these latter analyses because of missing data. These analyses were performed using SAS
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statistical software (version 9.3; SAS Institute Inc, Cary, NC), and all testing was two-sided. The probability of a type I error was set at 0.05.
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Results
During the sample period, 301 unilateral MCDKs were identified, of which 195 (64.8%) were detected antenatally. In the cohort, 165 (54.8%) MCDKs were boys and 160 (53.2%) were
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right-sided. Mean size at baseline imaging was 5.0 ± 0.2 cm (mean ± SE), with a median age at time of baseline imaging of 0.67 years (0-68.65). Median follow-up time was 4.6 years with a
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mean follow-up time of 14.4 years.
Associated abnormalities and anomalies identified in the subjects included: contralateral
VUR (n = 63; 20.1%); ipsilateral VUR (n = 21; 7.0%); contralateral UPJ obstruction (UPJO) (n = 10; 3.3%); contralateral ureterovesical junction obstruction (UVJO), including primary megaureter (n = 6; 2.0%); and renal fusion anomaly (including horseshoe kidney and cross-fused 5
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ectopia) (n = 4; 1.3%), as shown in Table 1. Additionally, four girls were found to have Müllerian duct (uterine) anomalies.
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Two hundred and thirty nine of the patients underwent a VCUG. Of the 63 patients with contralateral VUR to the functionally solitary kidney, six were lost to follow-up, with respect to their reflux. An additional five were still actively being followed for reflux (oldest age five
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years) and are were currently on antibiotics. Of the remaining 52 patients, 39 had complete resolution of the reflux on VCUG and an additional six were clinically asymptomatic off
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antibiotics and were presumed to have resolved the reflux, making for an 86.5% rate of clinically insignificant reflux. Seven patients underwent surgical correction of their reflux. Of these, two had a known neurogenic bladder and one had a duplicated collecting system, both of which would account for the need for anti-reflux surgery in isolation from the MCDK.
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Involution rates and predictors
Of the 233 subjects who met inclusion criteria, the cumulative probability of involution was 9.8% at one year of age (n = 219), 38.5% at five years of age (n = 146), 53.5% at ten years
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of age (n = 107) and 64.9% at 15 years (n = 91) (Figure 1).
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Baseline MCDK size was the only significant predictor of involution at bivariate (p < 0.0001) and multivariable (p < 0.0001; HR 0.58 [95% CI: 0.49, 0.69]) analyses. The MCDKs that measured less than 5.0 cm at baseline imaging had a mean age at involution of 2.7 years, while those measuring greater than 5.0 cm at baseline imaging had a mean age at involution of 11.0 years. The presence of contralateral VUR as a predictor of involution approached marginal significance (p = 0.06). Patients that experienced involution in the time 6
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frame of the present study had a mean initial MCDK size of 3.8 ± 0.3 cm (mean ± SE), while patients that did not experience involution had a mean initial size of 5.8 ± 0.2 cm (Table 1). Laterality, gender, coexisting renal/genitourinary tract abnormalities, and antenatal vs prenatal
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diagnosis were not found to be significant predictors of involution. No MCDK developed malignancy during the study period.
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Hypertension and compensatory hypertrophy
Nine patients out of the 301-patient cohort developed hypertension throughout the
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follow-up period for a 3% incidence of hypertension. Of these patients, six had either contralateral VUR or a serious comorbid condition (Prune Belly Syndrome, Spina Bifida, cardiac anomalies/subaortic stenosis, and Fraser Syndrome) that could contribute to the development of hypertension, independent of an MCDK.
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Using the 95th percentile as the standard for contralateral compensatory hypertrophy, 49.4% (76/154) of patients with available records reached that level by one year of age; 78.0% (124/159) by five years of age, 89.4% (144/161) by 10 years; and by 15 years of age, 94.9%
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(150/158) reached the 95th percentile. If the 75th percentile is used to define contralateral compensatory hypertrophy, 90.0% (162/180) reached this by five years and 99% (189/191) by 15
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years of age.
Association with cryptorchidism The prevalence of unilateral and bilateral cryptorchidism or undescended testicles (UDT)
in the population of 165 males was found to be 12.7% (n = 21). The majority of the UDTs in the population were right-sided (57.1%; n = 12) or bilateral (33.3%; n = 7). Only two patients (9.5%) 7
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had an isolated left-sided UDT. Almost all of these UDTs were located on the same side as the MCDK (61.9%; n = 13) or were present bilaterally (33.3%; n = 9). Only one UDT presented solely on the contralateral side of the patient’s MCDK, and it was a solitary testicle. Of the
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unilateral UDTs (n = 14), 11 (78.57%) were right-sided and ipsilateral to the patient’s MCDK. A left sided, ipsilateral UDT was much-less common (14.29%; n = 2) (Table 2).
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Surgical management versus time
Pediatric urologists at the institution surgically resected 9, 24 and 15 MCDKs between
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1980–1989, 1990–1999, and 2000–present, respectively. Of these 48 resected kidneys, the mostcommon indications for nephrectomy were failure to involute (18.8%; n = 9), with another 14 presumably removed for the same reason (unclear records), increasing size (18.8%; n = 9) and parental preference (10.4%; n = 5) in order to limit follow-up and perceived risks. Other less-
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common reasons included: flank pain, a concern for cause of hypertension, infection, and one
of its large size.
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Discussion
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child whose MCDK was thought to be contributing to respiratory distress as a newborn because
No consensus exists regarding the appropriate long-term management plan of children
with MCDK. To date, treatment has ranged from early nephrectomy to conservative monitoring of blood pressure and renal contour/size at regular intervals until involution. Given the increasing rate of MCDK detection and widespread use of ultrasonography, the consistency of follow-up has become more important. The present data corroborates previous studies showing that initially 8
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smaller MCDKs are more likely to involute and do so at an earlier age than larger MCDKs.18 As no malignancy was identified in more than 300 children during the longer than 30-year study period, the real risk of this outcome is likely to be very small. This too is consistent with the
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literature that the risk of Wilms’ tumor is negligible and surveillance is not warranted.13,23,24 In addition, the occurrence of hypertension in the present MCDK population was found
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to be consistent with that quoted in the general pediatric population25 and is unlikely to warrant aggressive subspecialty follow-up in the uncomplicated MCDK patient. Multiple studies on
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children with MCDK have revealed similar results15,16,26 and in a 2005 meta-analysis, the risk of hypertension among these children was actually less than that seen in the general population (0.54% vs 1–4.5% between the ages of four and adolescence).22
Interestingly, an increased prevalence of UDT was also found in the male population of
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the present MCDK cohort. The exact etiology of this finding is not clear, but may be related to the embryologic development (abnormal interaction of the ureteric bud with the metanephric mesenchyme) and general proximity of the kidney to the testis/gubernaculum. The review of the
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literature did not identify any prior studies describing an association between MCDK and UDT, and it is believed that this observation warrants further research to determine generalizability and
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embryologic origins.
Whilst the MCDK itself poses virtually no or minimal risk to patients, based on the
present data and other recent investigations,13,15,18,27 it is important that the contralateral and functionally solitary kidney is radiologically assessed for hydronephrosis and size to exclude associated anomalies/abnormalities such as VUR, UPJO, and UVJO. While it is certainly important to preserve the functionally solitary kidney, the present data also reports that for the 9
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majority of patients, reflux is clinically insignificant and requires no additional surgery. This data is consistent with previous literature28 and further supports reduced imaging, VCUG included, in appropriate patients with MCDK. Additionally, the hypertrophy status of the contralateral kidney
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can guide management of the MCDK, as those who have reached the 95th percentile experience higher rates of involution of the MCDKs, as seen in the literature and in the present series.13
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The economic status of health care systems makes it crucial that practices are continually reassessed, including the management of MCDKs. It is important to be certain that the care
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provided is truly medically necessary. After reviewing comprehensive reviews of the medical, radiological and surgical records of 301 MCDK patients, it was noted that the large majority of MCDK follow-up office visits consisted of a physical examination, updating the medical history from the previous encounter, and ultrasonography performed in the Department of Radiology, which most often revealed a stable or involuting MCDK and no associated complications. As a
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result, most patients left their follow-up encounters, which were commonly on an annual basis, with no new useful information or change in MCDK management. In 1998, Perez and colleagues evaluated the cost of nonoperative, ultrasonographic monitoring of MCDKs. This was based on
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serial ultrasound every six months for two years, then annually thereafter to the age eight years;
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they estimated the total national cost in 1000 children was $2.5–3 million dollars.29 This does not include office visit charges or travel costs and time lost from work. Potentially, this is quite a large burden on the health care system. Based on the results of the present study, it is believed that asymptomatic MCDK patients with no contralateral renal or urinary tract abnormality will safely tolerate more limited urological and radiological follow-up, thus potentially saving millions of health care dollars and parental/patient inconvenience. 10
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To address the lack of a clear and standardized management plan for MCDK, a clinical algorithm has been developed for the follow-up of these patients, based on the results of the present study (Figure 2). The proposed algorithm substantially limits the urological and
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radiological follow-up of children with MCDK who are otherwise healthy after undergoing
initial genitourinary clinical and radiological evaluation. Otherwise healthy MCDK patients can be initially counseled on the implications of having a MCDK, and can subsequently be followed
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by their primary care doctor for appropriate care, as well as attention to possible MCDK-related complications, which will be quite rare. The present study and other recent investigations do not
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support routine nephrectomy for MCDKs unless complications arise, such as: recurrent infection, hypertension that is highly likely to be renovascular in etiology, or an enlarging MCDK with pathologic mass-effect or recalcitrant pain.
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Limitations
Limitations of this study are those related to retrospective studies, as there may be missing records that would create recall bias. Some patients had inconsistent imaging follow-up
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and were therefore excluded from the multivariate analysis of this study. The Kaplan-Meier method used for the probability of involution analysis accounted for patients with missing data
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and provided validity to the results.
Conclusion
Multicystic kidney disease is a condition with no vetted algorithm for treatment or urological and radiological follow-up. The present study found that children with initially 11
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smaller MCDKs are more likely to experience involution and experience it at an earlier age, compared to larger MCDKs. By ten years of age, 53.5% of children with MCDK experienced involution of the affected kidney. The present study confirms that malignancy in MCDKs is
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exceedingly rare and that the prevalence of hypertension mirrors that of a general pediatric population. Consequently, there is no absolute indication for nephrectomy in children with
MCDKs. Based on the present data and other recently published studies, it is proposed that
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pediatric MCDK patients can safely tolerate much more limited urological and radiological
physician.
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Conflict of Interest/Funding: None
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follow-up, with MCDK follow-up instead being provided by the patient’s primary care
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References:
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20. 21. 22. 23.
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Kalyoussef E, Hwang J, Prasad V, Barone J. Segmental multicystic dysplastic kidney in children. Urology. Nov 2006;68(5):1121 e1129-1111. Cruveilhier J. Anatomie Pathologique du Corps Humain. Paris: J.B. Bailliere Libraire; 1836. Bloom DA, Brosman S. The multicystic kidney. J Urol. Aug 1978;120(2):211-215. Schwartz J. An unusual unilateral multicystic kidney in an infant. J. Urol. 1936;35(259). Heikkinen ES, Herva R, Lanning P. Multicystic kidney. A clinical and histological study of 13 patients. Ann Chir Gynaecol. 1980;69(1):15-22. Atiyeh B, Husmann D, Baum M. Contralateral renal abnormalities in multicystic-dysplastic kidney disease. J Pediatr. Jul 1992;121(1):65-67. Flack CE, Bellinger MF. The multicystic dysplastic kidney and contralateral vesicoureteral reflux: protection of the solitary kidney. J Urol. Dec 1993;150(6):1873-1874. Wacksman J, Phipps L. Report of the Multicystic Kidney Registry: preliminary findings. J Urol. Dec 1993;150(6):1870-1872. al-Khaldi N, Watson AR, Zuccollo J, Twining P, Rose DH. Outcome of antenatally detected cystic dysplastic kidney disease. Arch Dis Child. Jun 1994;70(6):520-522. Felson B, Cussen LJ. The hydronephrotic type of unilateral congenital multicystic disease of the kidney. Semin Roentgenol. Apr 1975;10(2):113-123. Osathanondh V, Potter EL. Pathogenesis of Polycystic Kidneys. Historical Survey. Arch Pathol. May 1964;77:459-465. Wein AJ, Kavoussi LR, Campbell MF. Campbell-Walsh urology / editor-in-chief, Alan J. Wein; [editors, Louis R. Kavoussi ... et al.]. 10th ed. Philadelphia, PA: Elsevier Saunders; 2012. Onal B, Kogan BA. Natural history of patients with multicystic dysplastic kidney-what followup is needed? J Urol. Oct 2006;176(4 Pt 1):1607-1611. Rabelo EA, Oliveira EA, Diniz JS, et al. Natural history of multicystic kidney conservatively managed: a prospective study. Pediatr Nephrol. Oct 2004;19(10):1102-1107. Okada T, Yoshida H, Matsunaga T, et al. Multicystic dysplastic kidney detected by prenatal ultrasonography: natural history and conservative management. Pediatr Surg Int. May 2003;19(3):207-210. Tiryaki S, Alkac AY, Serdaroglu E, Bak M, Avanoglu A, Ulman I. Involution of multicystic dysplastic kidney: is it predictable? J Pediatr Urol. Jun 2013;9(3):344-347. Strife JL, Souza AS, Kirks DR, Strife CF, Gelfand MJ, Wacksman J. Multicystic dysplastic kidney in children: US follow-up. Radiology. Mar 1993;186(3):785-788. Hayes WN, Watson AR. Unilateral multicystic dysplastic kidney: does initial size matter? Pediatr Nephrol. Aug 2012;27(8):1335-1340. Tilemis S, Savanelli A, Baltogiannis D, Cigliano B, Settimi A. Is the risk of hypertension an indication for prophylactic nephrectomy in patients with unilateral multicystic dysplastic kidney? Scand J Urol Nephrol. 2003;37(5):429-432. Sheikh-Hamad D, Cacini W, Buckley AR, et al. Cellular and molecular studies on cisplatin-induced apoptotic cell death in rat kidney. Arch Toxicol. Mar 2004;78(3):147-155. Farnham SB, Adams MC, Brock JW, 3rd, Pope JCt. Pediatric urological causes of hypertension. J Urol. Mar 2005;173(3):697-704. Narchi H. Risk of hypertension with multicystic kidney disease: a systematic review. Arch Dis Child. Sep 2005;90(9):921-924. Narchi H. Risk of Wilms' tumour with multicystic kidney disease: a systematic review. Arch Dis Child. Feb 2005;90(2):147-149. 13
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Psooy K. Multicystic dysplastic kidney in the neonate: the role of the urologist. Can Urol Assoc J. Apr 2010;4(2):95-97. Mitsnefes MM. Hypertension in children and adolescents. Pediatr Clin North Am. Jun 2006;53(3):493-512, viii. Weinstein A, Goodman TR, Iragorri S. Simple multicystic dysplastic kidney disease: end points for subspecialty follow-up. Pediatr Nephrol. Jan 2008;23(1):111-116. Oliveira EA, Diniz JS, Vilasboas AS, Rabelo EA, Silva JM, Filgueiras MT. Multicystic dysplastic kidney detected by fetal sonography: conservative management and follow-up. Pediatr Surg Int. 2001;17(1):54-57. Ismaili K, Avni FE, Alexander M, Schulman C, Collier F, Hall M. Routine voiding cystourethrography is of no value in neonates with unilateral multicystic dysplastic kidney. J Pediatr. Jun 2005;146(6):759-763. Perez LM, Naidu SI, Joseph DB. Outcome and cost analysis of operative versus nonoperative management of neonatal multicystic dysplastic kidneys. J Urol. Sep 1998;160(3 Pt 2):1207-1211; discussion 1216.
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Table 1: Potential Predictors of Involution Over Time
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Involution Predictors
All
Yes
Bivariate Analysis
Multivariable Analysis
No
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n % n % n % Log Rank p HR (95% CI) P HR (95% CI) All Eligible 233 100.0% 87 37.3% 146 62.7% Laterality* Left 106 45.5% 40 37.7% 66 62.3% 0.67 1.10 (0.72, 1.67) Right 127 54.5% 47 37.0% 80 63.0% 1 Sex* Male 129 55.4% 50 38.8% 79 61.2% 0.40 1.20 (0.78, 1.85) Female 104 44.6% 37 35.6% 67 64.4% 1 Initial Size within 1st Year* (missing 89) Mean + SE 144 5.0 + 0.2 55 3.8 + 0.3 89 5.8 + 0.2 < 0.0001 0.58 (0.49, 0.69) < 0.0001 0.58 (0.49, 0.69) Contralateral Abnormalities VUR vs. Others vs. None* (missing 5) VUR 53 23.3% 27 50.9% 26 49.1% 0.06 1.61 (1.02, 2.57) Others 20 8.8% 5 25.0% 15 75.0% 0.67 (0.27, 1.67) No 155 68.0% 54 34.8% 101 65.2% 1 Contralateral Abnormalities Yes vs. No* (missing 5) Yes 73 32.0% 32 43.8% 41 56.2% 0.21 1.32 (0.85, 2.05) No 155 68.0% 54 34.8% 101 65.2% 1 Ipsilateral Abnormalities- VUR vs. Others vs. No* VUR 19 8.2% 6 31.6% 13 68.4% 0.94 0.86 (0.38, 1.97) Others 2 0.9% 1 50.0% 1 50.0% 1.04 (0.15, 7.52)) No 212 91.0% 80 37.7% 132 62.3% 1 Ipsilateral Abnormalities- Yes vs. No* Yes 21 9.0% 7 33.3% 14 66.7% 0.75 0.88 (0.41, 1.91) No 212 91.0% 80 37.7% 132 62.3% 1 Discovered Time* (missing = 52) Prenatal Discovery 153 84.5% 58 37.9% 95 62.1% 0.18 1.66 (0.78, 3.51) Postnatal Discovery 28 15.5% 8 28.6% 20 71.4% 1 * Variables included in the starting multivariable model. Then backward model selection is used to determine the final multivariable model.
Bivariate Analysis
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Predictors
All
Yes % 100.0%
n 87
% 37.3%
n 146
% 62.7%
Left
106
45.5%
40
37.7%
66
62.3%
Right
127
54.5%
47
37.0%
80
63.0%
Male
129
55.4%
50
38.8%
79
Female 104 Initial Size within 1st Year* (missing 89)
44.6%
37
35.6%
67
5.0 + 0.2
55
3.8 + 0.3
144
< 0.0001
0.06
53
23.3%
27
50.9%
26
49.1%
Others
20
8.8%
5
25.0%
15
75.0%
No 155 68.0% Contralateral Abnormalities Yes vs. No* (missing 5)
54
34.8%
101
65.2%
No 155 Ipsilateral Abnormalities- VUR vs. Others vs. No*
32.0%
32
43.8%
41
56.2%
54
34.8%
101
65.2%
6
31.6%
13
68.4%
1
50.0%
1
50.0%
80
37.7%
132
62.3%
9.0%
7
33.3%
14
66.7%
91.0%
80
37.7%
132
62.3%
68.0%
VUR
19
8.2%
Others
2
0.9%
Yes
21
No
212
91.0%
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No 212 Ipsilateral Abnormalities- Yes vs. No*
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73
0.40
5.8 + 0.2
VUR
Yes
0.67
64.4%
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Contralateral Abnormalities VUR vs. Others vs. None* (missing 5)
89
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Mean + SE
61.2%
SC
Sex*
Log Rank p
RI PT
n 233
All Eligible Laterality*
Multivariable Analysis
No
0.21
0.94
0.75
OR (95% CI)
P
OR (95% CI)
1.10 (0.72, 1.67) 1 1.20 (0.78, 1.85) 1 0.58 (0.49, 0.69)
1.61 (1.02, 2.57) 0.67 (0.27, 1.67) 1 1.32 (0.85, 2.05) 1 0.86 (0.38, 1.97) 1.04 (0.15, 7.52)) 1 0.88 (0.41, 1.91) 1
Discovered Time* (missing = 52) 1.66 (0.78, 95 62.1% 58 37.9% 0.18 Prenatal Discovery 153 84.5% 3.51) 28 8 28.6% 20 71.4% Postnatal Discovery 15.5% 1 * Variables included in the starting multivariable model. Then backward model selection is used to determine the final multivariable model.
