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Editorial ARTICLE

Front. Pediatr., 26 June 2020 | https://doi.org/10.3389/fped.2020.00348

Editorial: Developmental Disorders of the Kidney and Urinary Tract: Recent Insights From Clinical and Molecular Studies

  • 1Pediatric Nephrology Unit, Department of Pediatrics, Federal University of Minas Gerais, Belo Horizonte, Brazil
  • 2Division of Pediatric Nephrology, Rady Children's Hospital San Diego, University of California, San Diego, La Jolla, CA, United States
  • 3National Institute of Science and Technology (INCT) of Molecular Medicine, Belo Horizonte, Brazil

Outstanding advances have been obtained in basic and clinical research on congenital anomalies of the kidney and urinary tract (CAKUT) over the past decade. From the molecular point of view, new generation sequencing has made crucial contributions to our understanding of the biology and pathophysiology of disrupted renal development, including the identification of associated genes and insights into the cellular pathophysiology (1, 2). Approximately 40 different monogenic causes for human CAKUT have so far been identified. Nevertheless, at present only about 20% of CAKUT cases can be explained by these established monogenic causes (35). Therefore, it is probably that several additional monogenic causes of human CAKUT have yet to be identified. In this Research Topic, Woolf et al. have demonstrated several rare diseases among the CAKUT complex with defined genetic causes. These studies are indicating that the implicated genes encode smooth muscle, neural or urothelial molecules, or master transcription factors that regulate their expression. However, variants in these same genes do not appear to explain the more common human non-syndromic urinary tract malformations such as primary vesicoureteral reflux. Of note, studies with whole exome sequencing, a technology that seeks variants in the protein coding regions of all genes, is being applied to seek likely pathogenic mutation in clinical cohorts of children born with a range of kidney malformations (6). Such researches have yielded useful genetic information in 10–14% of cases tested (Woolf et al.). Taroni et al. reported, on this Research topic, a case of a 2 years old child with Hypotonia-Cystinuria syndrome (HCS). HCS is a rare disease, caused by a mutation in two contiguous genes (SLC3A1 and PREPL), localized on chromosome 2p21, and it is characterized by both renal involvement with cystine stones and nervous involvement with hypotonia. Interestingly, the case reported had HCS associated with other clinical features of CAKUT, primary obstructed megaureter (POM), cryptorchidism and cardiac involvement. Some clinical features showed in this case report, like cryptorchidism and POM, have never been reported before in patients with HCS.

From the clinical point of the view, CAKUT encompass a wide range of structural malformations, including a complex spectrum of abnormalities that occur at the level of the kidney (e.g., hypoplasia and dysplasia), ureter (e.g., hydronephrosis and megaureter), bladder (e.g., ureterocele and vesicoureteral reflux), and urethra (e.g., posterior urethral valves) (7). CAKUT are estimated to be implicated in 30–60% of cases of childhood-onset chronic kidney disease (CKD) in different populations (810). CAKUT are a heterogeneous and complex group of congenital disorders which can lead to long-term health risks of hypertension, recurrent urinary tract infection (UTI), CKD, and end stage renal disease (ESRD) in children (1114).

Due to the recognized role played by CAKUT as primary causes in a sizeable proportion of pediatric CKD, it is of crucial importance that early diagnosis and tailored management are enacted to minimize renal damage and especially with respect to prevent or delay the onset of CKD. In this regard, over the last decade, pediatric disciplines have been markedly influenced by fetal screening ultrasonography, notably pediatric nephrology, and urology. An increasing number of renal anomalies are currently detected at antenatal stage in otherwise uncomplicated pregnancies. As a matter of fact, the majority of CAKUT is currently detected by antenatal ultrasonography; although still many cases remain undiagnosed until adulthood. Prenatal detection has permitted a refinement of the management of these conditions. A multidisciplinary team approach, including obstetrics, neonatology, pediatric nephrology, and pediatric urology is clearly required to diagnose and treat these complex disorders (15, 16). Consistent clinical information regarding diagnosis and prognosis should be provided during pregnancy and after birth. The calculated prognosis regarding the severity of the disease, survival and quality of life will have a major impact on decision-making during both pregnancy and postnatal period. In this regard, Katsoufis et al. presented on this Research Topic, a cohort of 42 subjects followed prospectively from birth for an average of 6.1 ± 2.8 years. The authors showed that a neonatal CysC >3.0 mg/L predicted progression to ESRD, while a nadir serum creatine >0.6 mg/dL predicted progression to CKD 3–5 with the highest specificity and sensitivity by ROC-AUC analysis (P < 0.0001). Interestingly, Vasconcelos et al. (14) developed a clinical predictive model to assess individualized risk of post-natal surgical intervention in patients with antenatal detected CAKUT. Predictors of the surgical intervention in the model were: baseline glomerular filtration rate, associated hydronephrosis, presence of renal damage and the severity of renal pelvic dilatation. Concerning the selection of infants with CAKUT for surgical intervention, Damasio et al. compare functional magnetic resonance (MR) urography with dynamic renal (DRS) scintigraphy in measuring volumetric split renal function (SRF) and in the classification of drainage curves. The authors showed that there were no significant differences between functional MR urography and DRS in measuring volumetric SRF and in the classification of drainage curves in patients with CAKUT.

The long-term impact of the earlier diagnosis and management of CAKUT needs to be addressed by longitudinal studies, including significant clinical outcomes, such as proteinuria, hypertension, and renal survival. In this regard, Chiodini et al. presented on this Research Topic, a comprehensive review of the clinical outcomes of the most frequently discovered by post-natal screening, including uretero-pelvic junction stenosis (UPJS), primary vesicoureteral reflux (VUR), megaureter, duplex kidney, and posterior urethral valves (PUV). Interestingly, Gabriele and Koch Nogueira have shown that hypertension is an independent risk factor for kidney disease progression and should be promptly managed for renal protection, especially among patients with CAKUT, the most common cause of CKD in the pediatric population.

In summary, CAKUT are responsible for 20–30% of all prenatally detected anomalies and are the most common cause of CKD in infants. A multidisciplinary team approach is optimal to diagnose and manage these complex disorders. The long-term impact of the data-based management of these renal abnormalities needs to be addressed by future studies, including significant clinical outcomes, such as proteinuria, hypertension, and CKD. Advances in prenatal diagnosis, genetic testing, fetal surgery, organ transplantation, and surgical treatment of CAKUT have improved the prognosis and quality of life of affected patients. CAKUT have significant impact in clinical medicine and across various subspecialties. Regardless of current difficulties and limitations, molecular genetic diagnoses may offer hopeful advances to the clinical management of patients with CAKUT. For instance, identification of causative mutations perhaps will contribute to relevant aspects of pediatric care including prognostic prediction of renal survival and the likelihood for the development of extrarenal complications. Nevertheless, in spite of this outstanding progress, many issues remain to be solved in order to integrate these approaches into clinical practice.

Author Contributions

EO, RM, and AS: conceptualization and writing—review and editing. EO: writing—original draft preparation. All authors contributed to the article and approved the submitted version.

Funding

This study was partially supported by CNPq (Brazilian National Research Council, Grant 430246/2018-8, Grant 460334/2014-0), FAPEMIG (Fundação de Amparo à Pesquisa do Estado de Minas Gerais, Grant APQ-02304-10, Grant PPM-00228-15, Grant PPM-00555-15, and Grant PPM-00435-18). EO and AS were receiving a productivity research grant from CNPq.

Conflict of Interest

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

References

1. Renkema KY, Winyard PJ, Skovorodkin IN, Levtchenko E, Hindryckx A, Jeanpierre C, et al. Novel perspectives for investigating congenital anomalies of the kidney and urinary tract (CAKUT). Nephrol Dial Transplant. (2011) 26:3843–51. doi: 10.1093/ndt/gfr655

PubMed Abstract | CrossRef Full Text | Google Scholar

2. Verbitsky M, Westland R, Perez A, Kiryluk K, Liu Q, Krithivasan P, et al. The copy number variation landscape of congenital anomalies of the kidney and urinary tract. Nat Genet. (2019) 51:117–27. doi: 10.1038/s41588-018-0281-y

PubMed Abstract | CrossRef Full Text | Google Scholar

3. van der Ven AT, Vivante A, Hildebrandt F. Novel insights into the pathogenesis of monogenic congenital anomalies of the kidney and urinary tract. J Am Soc Nephrol. (2018) 29:36–50. doi: 10.1681/ASN.2017050561

PubMed Abstract | CrossRef Full Text | Google Scholar

4. Sanna-Cherchi S, Westland R, Ghiggeri GM, Gharavi AG. Genetic basis of human congenital anomalies of the kidney and urinary tract. J Clin Invest. (2018) 128:4–15. doi: 10.1172/JCI95300

PubMed Abstract | CrossRef Full Text | Google Scholar

5. Vivante A, Kohl S, Hwang DY, Dworschak GC, Hildebrandt F. Single-gene causes of congenital anomalies of the kidney and urinary tract (CAKUT) in humans. Pediatr Nephrol. (2014) 29:695–704. doi: 10.1007/s00467-013-2684-4

PubMed Abstract | CrossRef Full Text | Google Scholar

6. van der Ven AT, Connaughton DM, Ityel H, Mann N, Nakayama M, Chen J, et al. Whole-exome sequencing identifies causative mutations in families with congenital anomalies of the kidney and urinary tract. J Am Soc Nephrol. (2018) 29:2348–61. doi: 10.1681/ASN.2017121265

PubMed Abstract | CrossRef Full Text | Google Scholar

7. Song R, Yosypiv IV. Genetics of congenital anomalies of the kidney and urinary tract. Pediatr Nephrol. (2011) 26:353–64. doi: 10.1007/s00467-010-1629-4

PubMed Abstract | CrossRef Full Text | Google Scholar

8. Soares CM, Diniz JS, Lima EM, Oliveira GR, Canhestro MR, Colosimo EA, et al. Predictive factors of progression to chronic kidney disease stage 5 in a predialysis interdisciplinary programme. Nephrol Dial Transplant. (2009) 24:848–55. doi: 10.1093/ndt/gfn547

PubMed Abstract | CrossRef Full Text | Google Scholar

9. Soares CM, Diniz JS, Lima EM, Silva JM, Oliveira GR, Canhestro MR, et al. Clinical outcome of children with chronic kidney disease in a pre-dialysis interdisciplinary program. Pediatr Nephrol. (2008) 23:2039–46. doi: 10.1007/s00467-008-0868-0

PubMed Abstract | CrossRef Full Text | Google Scholar

10. Warady BA, Abraham AG, Schwartz GJ, Wong CS, Munoz A, Betoko A, et al. Predictors of rapid progression of glomerular and nonglomerular kidney disease in children and adolescents: the chronic kidney disease in children (CKiD) cohort. Am J Kidney Dis. (2015) 65:878–88. doi: 10.1053/j.ajkd.2015.01.008

PubMed Abstract | CrossRef Full Text | Google Scholar

11. Coelho GM, Bouzada MC, Lemos GS, Pereira AK, Lima BP, Oliveira EA. Risk factors for urinary tract infection in children with prenatal renal pelvic dilatation. J Urol. (2008) 179:284–9. doi: 10.1016/j.juro.2007.08.159

PubMed Abstract | CrossRef Full Text | Google Scholar

12. Coelho GM, Bouzada MC, Pereira AK, Figueiredo BF, Leite MR, Oliveira DS, et al. Outcome of isolated antenatal hydronephrosis: a prospective cohort study. Pediatr Nephrol. (2007) 22:1727–34. doi: 10.1007/s00467-007-0539-6

PubMed Abstract | CrossRef Full Text | Google Scholar

13. Poggiali IV, Simoes ESAC, Vasconcelos MA, Dias CS, Gomes IR, Carvalho RA, et al. A clinical predictive model of renal injury in children with congenital solitary functioning kidney. Pediatr Nephrol. (2019) 34:465–74. doi: 10.1007/s00467-018-4111-3

PubMed Abstract | CrossRef Full Text | Google Scholar

14. Vasconcelos MA, Simões E Silva AC, Gomes IR, Carvalho RA, Pinheiro SV, Colosimo EA, et al. A clinical predictive model of chronic kidney disease in children with posterior urethral valves. Pediatr Nephrol. (2019) 34:283–94. doi: 10.1007/s00467-018-4078-0

PubMed Abstract | CrossRef Full Text | Google Scholar

15. Oliveira EA, Oliveira MC, Mak RH. Evaluation and management of hydronephrosis in the neonate. Curr Opin Pediatr. (2016) 28:195–201. doi: 10.1097/MOP.0000000000000321

PubMed Abstract | CrossRef Full Text | Google Scholar

16. Quirino IG, Diniz JS, Bouzada MC, Pereira AK, Lopes TJ, Paixao GM, et al. Clinical course of 822 children with prenatally detected nephrouropathies. Clin J Am Soc Nephrol. (2012) 7:444–51. doi: 10.2215/CJN.03400411

PubMed Abstract | CrossRef Full Text | Google Scholar

Keywords: congenital anomalies of the kidney and urinary tract, chronic kidney disease, prenatal diagnosis, fetal hydronephrosis, renal hypodysplasia, genetics, molecular mechanisms, gene polymorphism

Citation: Oliveira EA, Mak RH and Simões e Silva AC (2020) Editorial: Developmental Disorders of the Kidney and Urinary Tract: Recent Insights From Clinical and Molecular Studies. Front. Pediatr. 8:348. doi: 10.3389/fped.2020.00348

Received: 02 May 2020; Accepted: 26 May 2020;
Published: 26 June 2020.

Edited and reviewed by: Michael L. Moritz, University of Pittsburgh, United States

Copyright © 2020 Oliveira, Mak and Simões e Silva. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

*Correspondence: Eduardo A. Oliveira, eduolive812@gmail.com