Association Between Multicystic Dysplastic Kidney and the Local Renin-Angiotensin-Aldosterone System: A Pilot Study of a New Biomarker.

Serial Followup of the Contralateral Renal Size In Children With Multicystic Dysplastic Kidney

Unilateral Multicystic Dysplastic Kidney With Progressive Infundibular Stenosis in the Contralateral Kidney: Experience at 1 Center and Review of Literature

Natural History of Patients With Multicystic Dysplastic Kidney—What Followup is Needed?

HYPERTENSION ASSOCIATED WITH MULTICYSTIC DYSPLASTIC KIDNEY IN CHILDREN

Multicystic dysplastic kidney (MCDK) is a common form of congenital cystic kidney disease in children. The etiology of MCDK remains unclear. Given an important role of the renin-angiotensin system in normal kidney development, we explored whether MCDK in children is associated with variants in the genes encoding renin-angiotensin system components by Sanger sequencing. The coding regions of renin (REN), angiotensinogen (AGT), ACE, and angiotensin 1 receptor (AGTR1) genes were amplified by PCR. The effect of DNA sequence variants on protein function was predicted with PolyPhen-2 software. 3 novel and known AGT variants were found. 1 variant was probably damaging, 1 was possibly damaging and one was benign. Out of 7 REN variants, 4 were probably damaging and 3 were benign. Of 6 ACE variants, 3 were probably damaging and 3-benign. 3 AGTR1 variants were found. 2 variants were possibly damaging, and one was benign. We report novel associations of sequence variants in REN, AGT, ACE, or AGTR1 genes in children with isolated MCDK in the United States. Our findings suggest a recessive disease model and support the hypothesis of multiple renin-angiotensin system gene involvement in MCDK. Discovery of novel gene variants in renin-angiotensin genes in children with MCDK. Novel possibly damaging gene variants discovered. Multiple renin-angiotensin system gene variants are involved in MCDK.

RENIN CONTAINING CELLS ARE PRESENT PREDOMINANTLY IN SCARRED AREAS BUT NOT IN DYSPLASTIC REGIONS IN MULTICYSTIC DYSPLASTIC KIDNEY

We retrospectively studied our cases of Multicystic Dysplastic Kidney (MCDK). The review was aimed at identifying the pattern of the disease in Indian Scenario and the required management thereof. We studied the clinical, radiological and nuclear scan findings of 22 patients with unilateral MCDK. They were diagnosed and/or treated in our unit from 1999 to 2007. The diagnosis was achieved by Ultrasound and further confirmed by DMSA scans. Other ancillary investigations like Micturating cystourethrogram were done if indicated. These patients were followed and followup investigations consisted of renal ultrasound, blood pressure measurement, and urinalysis and blood biochemistry A total of 22 patients (18 boys and 4 girls) with unilateral MCDK were investigated and followed for a mean period of 41 months. MCDK was detected on antenatal ultrasound only in 12(55%) and postnatally in 10(45%) babies. Mean age for postnatal diagnosis was 20 months. Follow up ultrasound revealed complete involution of MCDK in 3 patients and partial regression in 11 patients. The size of dysplastic kidney was unchanged in 4 patients and a further 4 patients underwent nephrectomy. Indications of nephrectomy were parental anxiety in 2, hypertension in 1 and palpable mass in 1. Large proportion (45%) of patients in presented series are diagnosed post natally contrary to western world where more than 80% are diagnosed antenatally. Uncomplicated isolated MCDK carry good prognosis with nephrectomy required in only a few patients. Association with other urological anomalies in ipsilateral/contralateral genitourinary tract is important to identify as they have worse outcome in terms of ultimate renal function. All patients with simple/complex unilateral MCDK should be advised long term follow up for the possible development of hypertension and/or hyper infiltration injury.

Background and Aims Congenital anomalies of the kidney and urinary tract (CAKUT) are the major cause of chronic kidney disease and end-stage kidney disease in childhood. Solitary functioning kidney (SFK) is part of the spectrum of CAKUT. Congenital SFK is mainly due to unilateral renal agenesis (URA) and multi-cystic dysplastic kidney (MCDK). With the implementation of routine fetal ultrasound screening, SFK is increasingly recognized before birth, significantly raising the number of patients referred to paediatric nephrology units for clinical monitoring during childhood. Understanding the pathophysiology of SFK is pivotal for guiding the clinical management and informing long-term outcome. However, observational studies performed in children with SFK are controversial, especially about the need, methodology and timing of functional assessment. This may be at least in part due to the fact that different models of SFK, including congenital and acquired after unilateral nephrectomy, are often grouped together. The aim of this study was to assess the clinical, laboratory and functional features of congenital SFK caused by URA and MCDK in children, with a particular focus on the role of renal scintigraphy in estimating kidney function during childhood and adolescence. Method We retrospectively collected clinical, laboratory and instrumental records of all consecutive pediatric patients (aged 0-18 years) affected by congenital SFK caused by URA or MCDK referred to the Nephrology and Dialysis Unit of Meyer Children’s Hospital of Florence (Italy) from 1992 to 2019. Patients with unilateral kidney hypodysplasia were excluded. In particular, we reviewed data from ultrasound scanning and sequential renal scintigraphy over time. URA and MCDK were compared for clinical features, long-term course and outcome. Results A total of 155 patients with congenital SFK were included in the study and divided in two groups according to the cause of SFK (URA, n=100; MCDK, n=55). The median length of follow-up was 47 and 45 months, respectively. Male sex and ethnicity were equally distributed in the two groups. Prenatal diagnosis was more frequent in MCDK group. We did not observe either preterm birth or low birth weight in patients enrolled. Overall, the clinical features were not statistically different between the two groups. In particular, SFK associated CAKUT, including vesicoureteral reflux, occurred at a comparable frequency. Also, measurement of kidney length by ultrasound scanning, which is often considered suggestive of compensatory hypertrophy, did not differ between groups. Although renal clearance from sequential renal scintigraphy appeared not statistically different between URA and MCDK, the latter seems to reach complete functional adaptation more rapidly and earlier in the first two years of life. Conclusion The clinical course and long-term outcome of SFK has been a topic of extensive debate. Due to poor-quality of data (unclear inclusion/exclusion criteria, lack of uniformity in data collection and outcome definition), generalization of findings from observational studies to all patients with SFK could be inappropriate. Congenital SFK could represent the most unbiased group to analyze and this study provides a thorough clinical characterization of a large and strictly selected cohort. Insights from sequential renal scintigraphy suggest a different trend in reaching single kidney complete functional adaptation in URA and MCDK. These results could potentially reveal significant differences in the pathophysiologic mechanisms of reaching compensatory hypertrophy and functional adaptation by the solitary kidney in the two models. Whether confirmed in larger cohorts, these findings could provide important implications for follow-up planning, informing the need, methodology and timing for function assessment, tailoring the clinical management and understanding long-term prognosis.

The purpose of this study was to evaluate the clinical course and outcome for children with multicystic dysplastic kidney (MCDK) disease and to non-invasively predict which of these patients are at significant risk for developing urinary tract infection (UTI) and renal insufficiency. Patients were divided, on the basis of postnatal physical examination and renal ultrasonography, into simple or complex MCDK. Simple MCDK was defined as unilateral renal dysplasia without additional genitourinary (GU) abnormalities. Complex MCDK included patients with bilateral renal dysplasia or unilateral renal dysplasia with other GU abnormalities. The designation as simple or complex MCDK was independent of reflux, since routine voiding cystourethrography (VCUG) was not performed. The charts of all patients with the diagnosis of MCDK disease seen from August 1995 to March 1999 at Yale University School of Medicine were examined to determine: (1) if UTI had occurred and (2) the level of renal function at last follow-up. Thirty-five patients were evaluated: 28 (80%) patients had unilateral MCDK, 7 (20%) were bilateral, and 14 (40%) had associated GU anomalies. Overall, 21 patients had unilateral MCDK without GU abnormalities (simple MCDK), while 14 had complex MCDK. The final outcome for patients with simple MCDK was quite good, with normal renal function and compensatory hypertrophy of the contralateral kidney in all patients. Although the patients with simple MCDK did not have routine VCUG or prophylactic antibiotics, the development of UTI was infrequent, damage to the contralateral kidney did not occur, and renal function was well preserved. In contrast, patients with bilateral disease or associated GU anomalies had a higher incidence of UTI and progression to renal failure. Complex MCDK was associated with a worse outcome (50% chronic renal insufficiency or failure).

We read with interest the article entitled “Natural history of multicystic kidney conservatively managed: a prospective study” by Rabelo et al. [1] in this journal and would like to describe our current approach for the management of multicystic dysplastic kidneys (MCDK) with laparoscopic nephrectomy. Rabelo et al. [1] postulated that the long-term conservative management of children with unilateral MCDK is a safe option because its natural history is benign with a small number of complications and a low rate of contralateral kidney abnormalities. According to their calculation, it takes nearly 10 years (122 months) for the MCDK to involute completely. Recently, however, management has been based on cost-effectiveness [2]. In addition, it should be noted that long-term follow-up of the seemingly asymptomatic child does not only result in significant clinic non-attendance but also induces long-term parental anxiety [3]. Recent advances in laparoscopic nephrectomy have enabled us to apply this procedure to infants [4]. The benefit of this less invasive approach is based on improved cosmetic results and shorter convalescence compared with open surgery. We have recently performed laparoscopic nephrectomy in ten infants with MCDK. This option was chosen by the parents’ families after being informed of the risks of laparoscopic nephrectomy and the potential morbidity associated with conservative management. As a result, they were fully satisfied after the nephrectomy. Furthermore, based on our calculation of the cumulative cost of management of children with unilateral MCDK, laparoscopic nephrectomy is less expensive than conservative follow-up if it takes more than 3 years for natural involution (Table 1, [5]). The cost for conservative management is based on the charge of the outpatient clinic visit where the physical examination, measurements of blood pressure, and ultrasound examination were performed. The frequency of the clinic attendance is monthly during the first 3 months, trimonthly between 3 months and 12 months of age, at 6 months’ intervals between 1 and 2 years of age, and yearly thereafter [5]. Thus, we currently favor a less invasive laparoscopic nephrectomy for unilateral MCDK over long-term conservative management because of its cost-effectiveness and avoidance of complications. However, the final decision should be made by the family after being fully informed. K. Kaneko Department of Pediatrics, Juntendo University Urayasu Hospital, Chiba, Japan

Multicystic dysplastic kidneys (MCDK) are commonly detected on prenatal ultrasound examinations, occurring in 1 in 1,000 to 4,300 live births. This study focuses on neonatal outcomes in fetuses with MCDK, with particular attention to the presence of additional anomalies. Retrospective data of fetuses diagnosed with MCDK at Charité University Hospital between 2005 and 2022 were collected and analyzed. Rates of termination of pregnancy (TOP), intrauterine fetal demise (IUFD) and live birth were evaluated. Outcome parameters, including APGAR score, survival, neonatal ventilation therapy or respiratory adjustment disorder, were examined. A total of 103 fetuses with MCDK were identified. Eight exhibited bilateral MCDK (7.8%). 92.2% showed unilateral MCDK (n = 95), of which 43 revealed additional anomalies (45.3%). Fetuses with additional anomalies displayed significantly fewer live births, more prematurity, lower APGAR scores and lower gestational ages at birth. The expected outcome of fetuses with MCDK is contingent upon the presence of additional anomalies. Bilateral MCDK, as well as unilateral MCDK with additional anomalies, are associated with an unfavorable postnatal outcome. To consult parents on the potential postnatal well-being of their offspring with MCDK, it is crucial to search for additional anomalies. Genetic counseling and invasive genetic testing should be offered.

To establish the diagnostic accuracy of obstetric ultrasound at a tertiary fetal medicine center in the prenatal detection of unilateral and bilateral multicystic dysplastic kidney (MCDK) in fetuses in which this condition was suspected, and to undertake a systematic review of the relevant literature. This was a retrospective observational study of all cases referred to a regional tertiary fetal medicine unit due to suspicion of either unilateral or bilateral MCDK between 1997 and 2015. Diagnosis was confirmed by postnatal ultrasound reports or postmortem examination. The accuracy of prenatal ultrasound in the diagnosis of MCDK was calculated. Using a systematic search strategy we also performed a review of the literature regarding the prenatal diagnosis and diagnostic accuracy of MCDK. We included 144 women in our analysis; 37 (25.7%) opted for pregnancy termination (TOP) (due to unilateral MCDK with additional abnormalities, suspected bilateral MCDK or severe obstructive uropathy). Complete pre- and postnatal data were available in 126 pregnancies, including 104 livebirths, 19 TOPs with postmortem findings available and three intrauterine fetal deaths. Two infants died shortly after birth (due to known bilateral MCDK or known cranial vault defect). The overall number of cases of MCDK confirmed postnatally was 100; of these, 98 were diagnosed prenatally (true positive), while two were thought to be hydronephrosis prenatally (false negative) and the diagnosis of MCDK was made after birth. In nine cases, the initial antenatal diagnosis of suspected MCDK was revised, either later in pregnancy (n = 2) or postnatally (n = 7) (false positive). Overall, the diagnostic accuracy in our population for the use of antenatal ultrasound to detect MCDK was 91.3%, while that reported in the existing literature was found to range from 53.3% to 100%. MCDK was isolated in the majority (71%) of cases, while in 29% of cases it was found to be associated with other renal and extrarenal fetal abnormalities. Antenatal ultrasound had a diagnostic accuracy of about 91% in the prediction of postnatal MCDK and can therefore be used to guide antenatal counseling. However, prenatal or postnatal revision of the diagnosis occurred in about 7% of cases and parents should be counseled appropriately. Copyright © 2016 ISUOG. Published by John Wiley & Sons Ltd.

Comparison of Ultrasound and Magnetic Resonance Urography for Evaluation of Contralateral Kidney in Patients With Multicystic Dysplastic Kidney Disease

Many papers are published on cohorts with unilateral multicystic dysplastic kidney (MCDK) patients, but show variable results as to the incidence of associated urinary tract abnormalities. The objective of this study was to describe the status of the urinary tract, including contralateral hypertrophy and malformations, in patients with unilateral MCDK based on a meta-analysis of the literature, taking into account the timing of diagnosis (pre- versus postnatal) as a possible source of bias. A systematic review of the scientific literature in English was conducted using PubMed and Embase. A meta-analysis was performed with the studies that were identified using our reproducible search. Based on analysis of the data in 19 populations, the overall incidence of unilateral MCDK is 1 in 4300 with an increasing trend over the years. A total of 67 cohorts with over 3500 patients with unilateral MCDK were included in the meta-analysis. Fifty-nine percent of patients were male and the MCDKs were significantly more often found on the left side (53.1%). Associated anomalies in the solitary functioning kidney were found in 1 in 3 patients, mainly vesicoureteric reflux (VUR, in 19.7%). In patients with VUR, 40% have severe contralateral VUR, defined as grade III-V. Contralateral hypertrophy, present in 77% of patients after a follow-up of at least 10 years, showed a trend to be less pronounced in patients with VUR. Timing of the diagnosis of MCDK did not essentially influence the results. These aggregate results provide insight into the incidence, demographic data and associated anomalies in patients with unilateral MCDK. One in three patients with unilateral MCDK show anomalies in the contralateral, solitary functioning kidney. However, studies into the long-term consequences of these anomalies are scarce.

<h3>Background</h3> Follow-up for unilateral MCDK is recommended due to its risk of contralateral kidney abnormalities and long-term sequelae. However, there is currently no national or international consensus on management strategies for this group of children and young people. Varying practice between and within departments may have negative consequences including performance of unnecessary investigations, parental anxiety or late recognition of chronic kidney disease progression in those at risk. <h3>Objectives</h3> To review the current evidence and explore variation in management strategies amongst paediatricians looking after children and young people with unilateral MCDK. <h3>Methods</h3> A nationwide online survey was performed using a 10-item survey with multiple choice and free text between August 2020 to December 2020. The survey was open to tertiary paediatric nephrology and general paediatric consultants who care for these patients. <h3>Results</h3> A total of 60 responses were obtained, two-thirds of whom were paediatric nephrologists. 62% routinely perform a DMSA scan to confirm the diagnosis (Paediatric Nephrologists(58%); SPIN paediatricians(67%); Non-SPIN paediatricians(80%)). 8% routinely perform an MCUG to investigate for contralateral vesico-ureteric reflux (VUR) (Paediatric Nephrologists(13%); SPIN paediatricians(0%); Non-SPIN paediatricians(0%)). Thematic analysis of free-text answers supported these findings. A total of 62% of respondents stated the need for routine renal function assessment even in the absence of indication. The frequency of blood sampling ranged from once only(62%) to ‘every two years’ until transfer to adult services. Referral to assess for nephrectomy for lack of involution was stated by 7%. Thresholds quoted were: ‘still present at 3/4 years’; ‘still present at 5 years’; ‘3cm at 5 years’; and ‘6cm at 6 years’. 25% of respondents recalled nephrectomy of an MCDK in the previous five years. Quoted indications for nephrectomy of the MCDK were: hypertension(5), large size(4, 1 with symptoms), lack of involution(3), urinary tract infections (1), surgical decision (1), previous sibling died from malignancy (1). The survey also revealed divergent opinions over creation and implementation of a national guidance for management of MCDK, mainly due to concerns around overcautious management. However an evidence-based national guidance that could (1) balance between consensus and safe variation and (2) offer families both choice and reassurance, was cited as potentially beneficial. Estimated costs from birth to adulthood(18 years) in those with uncomplicated MCDK were calculated from the respondents’ free-text answers. 53 (88%) respondents’ answers were detailed enough and suitable for this analysis. Mean estimated costs were £1,962 (range: £258 - £3,854). Although the average costs were greater for general paediatricians compared to paediatric nephrologists, this was not statistically significant (£1,950 SD± £871 versus £1,485 SD± £829). <h3>Conclusions</h3> Management of children and young people with unilateral MCDK varies nationally. Review of current evidence suggests this variation extends globally. There is increasing consensus for avoiding invasive testing and taking a more pragmatic approach, but the risks of hypertension and progression to chronic kidney disease remain a concern in some, highlighting the need for a clear pathway to ensure those at high-risk of renal sequelae are recognised early and followed-up appropriately.