Dataset Information

Activated Hedgehog-GLI Signaling Causes Congenital Ureteropelvic Junction Obstruction.

ABSTRACT: Intrinsic ureteropelvic junction obstruction is the most common cause of congenital hydronephrosis, yet the underlying pathogenesis is undefined. Hedgehog proteins control morphogenesis by promoting GLI-dependent transcriptional activation and inhibiting the formation of the GLI3 transcriptional repressor. Hedgehog regulates differentiation and proliferation of ureteric smooth muscle progenitor cells during murine kidney-ureter development. Histopathologic findings of smooth muscle cell hypertrophy and stroma-like cells, consistently observed in obstructing tissue at the time of surgical correction, suggest that Hedgehog signaling is abnormally regulated during the genesis of congenital intrinsic ureteropelvic junction obstruction. Here, we demonstrate that constitutively active Hedgehog signaling in murine intermediate mesoderm-derived renal progenitors results in hydronephrosis and failure to develop a patent pelvic-ureteric junction. Tissue obstructing the ureteropelvic junction was marked as early as E13.5 by an ectopic population of cells expressing Ptch2, a Hedgehog signaling target. Constitutive expression of GLI3 repressor in Ptch1-deficient mice rescued ectopic Ptch2 expression and obstructive hydronephrosis. Whole transcriptome analysis of isolated Ptch2+ cells revealed coexpression of genes characteristic of stromal progenitor cells. Genetic lineage tracing indicated that stromal cells blocking the ureteropelvic junction were derived from intermediate mesoderm-derived renal progenitors and were distinct from the smooth muscle or epithelial lineages. Analysis of obstructive ureteric tissue resected from children with congenital intrinsic ureteropelvic junction obstruction revealed a molecular signature similar to that observed in Ptch1-deficient mice. Together, these results demonstrate a Hedgehog-dependent mechanism underlying mammalian intrinsic ureteropelvic junction obstruction.

SUBMITTER: Sheybani-Deloui S

PROVIDER: S-EPMC5791051 | biostudies-literature | 2018 Feb

REPOSITORIES: biostudies-literature

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Activated Hedgehog-GLI Signaling Causes Congenital Ureteropelvic Junction Obstruction.

Sheybani-Deloui Sepideh S Chi Lijun L Staite Marian V MV Cain Jason E JE Nieman Brian J BJ Henkelman R Mark RM Wainwright Brandon J BJ Potter S Steven SS Bagli Darius J DJ Lorenzo Armando J AJ Rosenblum Norman D ND

Journal of the American Society of Nephrology : JASN 20171106 2

Intrinsic ureteropelvic junction obstruction is the most common cause of congenital hydronephrosis, yet the underlying pathogenesis is undefined. Hedgehog proteins control morphogenesis by promoting GLI-dependent transcriptional activation and inhibiting the formation of the GLI3 transcriptional repressor. Hedgehog regulates differentiation and proliferation of ureteric smooth muscle progenitor cells during murine kidney-ureter development. Histopathologic findings of smooth muscle cell hypertro ...[more]

PMID: 29109083

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Project description:Introduction stating the aim of the study: Robot-assisted laparoscopic pyeloplasty (RALP) is gaining acceptance among pediatric urologists. Few studies have evaluated the retroperitoneal approach for RALP. We share our experience from the first 2 years of a multidisciplinary pediatric robotic program in our center. Patients (or Materials) and Methods: We performed a retrospective analysis of prospectively collected data of children undergoing RALP for ureteropelvic junction obstruction (n = 50). Diagnosis was confirmed by ultrasound and Tc-99m mercaptoacetyltriglycine renal scan or MRI; the same criteria were used to evaluate outcome. Surgical approach was chosen according to a specific algorithm. Transperitoneal approach (n = 13) was reserved for horseshoe kidney, ectopic kidney, and redo surgery. We analyzed the 37 cases performed by a lateral retroperitoneal approach. Dismembered pyeloplasty was done for all cases and anastomosis was performed using a running monofilament 6/0 absorbable suture. All were drained by double J stent. Patient data, operating room parameters and postoperative course were recorded. Results: The median age was 7.9 years (5.1-13.8); the youngest was 2 years old. The median weight was 23 kg (17-41) with the smallest weighing 12.4 kg. Aberrant crossing vessels were present in 18 children. Median set-up time, from skin incision until the end of the 4-port insertion, was 33 min (29-48). Median surgeon's console time was 151 min (136-182). No conversion to an open procedure was necessary. The postoperative course was free of complications, except urinary tract infection in 6 children. All but 4 patients were discharged on day one. Median follow-up was 9 months (5-13). Redo pyeloplasty was not required. Practical training of other colleagues was possible after 10 cases performed by the same surgeon. Conclusion: These preliminary results suggest that retroperitoneal RALP in children is feasible, safe and effective. It is an excellent option with ideal anatomical exposure. Longer term results as well as continued practice will identify and overcome any challenges and enable surgical mastery of this procedure which is still evolving.

Project description:BackgroundMultiple surgical treatment options are available for the treatment of ureteropelvic junction obstruction (UPJO). The aim of this study is to compare the most frequently used technics in a comprehensive network approach.MethodsA systematic literature search of the EMBASE, MEDLINE and COCHRANE libraries was conducted in January 2018. Publications were included that evaluated at least two of the following surgical techniques: open pyeloplasty (OP), endopyelotomy (EP), laparoscopic (LP) and robot assisted pyeloplasty (RP). Main outcomes were operative success, complications, urinary leakage, re-operation, transfusion rate, operating time, and length of stay. Network meta-analyses with random effects models simultaneously assessed effectiveness of all surgical techniques.ResultsA total of 26 studies including 3143 patients were analyzed. Compared with RP, EP and LP showed lower operative success rates (EP: OR?=?0.09, 95%CI:0.05-0.19; p <?0.001; LP: OR?=?0.51, 95%CI:0.31-0.84; p =?0.008). Compared with OP, LP and RP had lower risk for complications (LP: OR?=?0.62; 95%CI:0.41-0.95; p =?0.027; RP: OR?=?0.41; 95%CI:0.22-0.79; p =?0.007). Compared with RP, no significant differences were detected for urinary leakage or re-operation, transfusion rates. Compared with EP, RP yielded longer operating time (mean?=?102.87?min, 95%CI:41.79?min-163.95?min, p =?<?0.001). Further significant differences in operating times were detected when comparing LP to EP (mean?=?115.13?min, 95%CI:65.63?min-164.63?min, p =?<?0.001) and OP to EP (mean?=?91.96?min, 95%CI:32.33?min-151.58?min, p =?0.003).ConclusionsMultiple surgical techniques are available for treatment of UPJO. RP has the highest rates of operative success and as well as LP lower complication rates than OP. Although surgical outcomes are worse for EP, its operating time is shorter than OP, RP, and LP. Surgeons should consider these findings when selecting the optimal treatment method for individual patients.

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Dataset Information

Activated Hedgehog-GLI Signaling Causes Congenital Ureteropelvic Junction Obstruction.

Publications

Activated Hedgehog-GLI Signaling Causes Congenital Ureteropelvic Junction Obstruction.

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