Grant Awarded to Study the Nephron Progenitors

Mesenchymal nephron progenitor cells (MNPs) give rise to all nephron tubules in the mammalian kidney. Premature depletion of these cells leads to low nephron numbers, increasing the risk of high blood pressure and various renal diseases. In order to intervene in premature depletion of MNPs, it is important to understand better how maintaining the MNP population occurs during development. To date, the processes required for the maintenance of MNPs in vivo is not fully understood. A research team lead by Joo-Seop Park, PhD, and Eunah Chung, PhD, found that the hedgehog signaling pathway plays important roles in MNP maintenance. Upon binding of hedgehog protein to the patched receptor, a second receptor Smoothened is relieved from Patched-mediated inhibition, initiating the signaling cascade. The team found that MNPs lacking smoothened were prematurely depleted during development, resulting in a 50% reduction in nephron number. Transcription profiling data from MNPs with various smoothened doses not only showed that MNPs do respond to hedgehog signaling but also identified the genes potentially regulated by hedgehog signaling. The team was awarded an R01 grant from the NIH to further investigate how hedgehog signaling determines nephron endowment in the mammalian kidney. Their work will have a high impact on the field by advancing our understanding of the molecular mechanisms underlying nephron endowment.

Pediatric KIDney Stone (PKIDS) Care Improvement Network Multi-Center Study

This prospective cohort study compares stone clearance and the lived experiences for pediatric patients after ureteroscopy, extracorporeal shockwave lithotripsy, and percutaneous nephrolithotomy while also measuring the longitudinal impact of kidney stone disease. Clinical status (stone size, stone location), and patient characteristics (age and sex), determine the effect of the heterogeneity of treatment. The results will provide information that helps patients make individualized decisions about the best surgical approach. The study will also identify surgical techniques specific to URS, SWL, and PCNL that improve stone clearance and patients’ experiences for each procedure. This study will generate knowledge about alternative surgical treatments to remove kidney stones in patients 8 to 21 years of age (at enrollment) at the 22 sites in the PKIDS Care Improvement Network.

Urinary Exosome Analysis to Identify Biomarkers of Bladder Injury in Patients with Posterior Urethral Valves (PUV)

Almost all patients with PUV develop some form of bladder dysfunction with lower urinary tract symptoms. In the more severely affected cases, the ongoing injury can result in progression to chronic kidney disease and end-stage renal disease. Our group undertook a non-invasive study of urine from these patients to improve outcomes by identifying biomarkers associated with exosomes, nano-sized membranous extracellular vesicles (EVs). EVs release from cells lining the urinary tract into urine contain RNA, protein and other metabolites that reflect the status of the cells of origin. We utilize a transcriptome approach to profile the RNA composition of EVs from patients with PUV and from controls. Our preliminary data identifies differential expression of about 20 RNAs in patients with PUV. Analysis of pathological pathways such as fibrosis implicate several of these RNAs. We are currently investigating the expression of these candidate RNAs in a larger patient cohort. Successful completion of the study will provide diagnostic and prognostic biomarkers for PUV-related bladder and kidney disease.

Long-Term Outcomes of Interventions for Reproductive Dysfunction Multi-Center Study

The main objective of this study is to determine the effectiveness of genitoplasty in improving the cosmetic appearance of ambiguous genitalia, if parents are as satisfied with cosmetic outcomes of their child’s genitoplasty as the surgeons who perform the procedures, and which surgical procedures are associated with the lowest complication rates. Children < 2 years of age who have never received previous genitoplasty are eligible to participate if their genital ambiguity is defined as Prader score 3-5 in a genetic female or Quigley score 3-7 in a genetic male. There are currently 12 pediatric hospitals in the US participating in this collaboration.

Enhanced Recovery After Surgery ERAS Multi-Center Study

The hypothesis is that enhanced recovery after surgery (ERAS) peri-operative care principles are implementable at free-standing pediatric hospitals with ≥ 75% adherence to protocol items. We aim to determine if the proposed protocol is optimal to maximize recovery from surgery while minimizing morbidity, characterize protocol deviations by providers and study sites, and define short and long-term outcomes from surgery after application of the ERAS protocol. We aim to broaden exposure of the pediatric urology community to ERAS and demonstrate its application at other medical centers. As ERAS is a multidisciplinary program that requires on-the-ground changes to care delivery by all patient care team members, this study contains a built-in pilot portion to demonstrate that ERAS can be effectively implemented at other centers to attain similar or even better outcomes. Following this will be an exploratory phase where centers enroll patients, and we follow their outcomes over the course of at least one year after surgery. We are currently in the pilot phase at Cincinnati Children’s.

Outcomes of Open and Robotic Assisted Laparoscopic Ureteral Reimplantation Multi-Center Study

As part of a multi-site study, we are evaluating our Cincinnati Children's pediatric urology experience, the associated outcomes, and morbidity of the robotic-assisted laparoscopic (RAL) approach to correct vesicoureteral reflux in children compared to the open approach. The hypotheses to test include: 1) The efficacy of the RAL approach will be comparable to the open approach to correct vesicoureteral reflux; and 2) The length of hospital stay, narcotic drug requirements, and length of post-operative catheterization will decrease compared to the open approach.

This study seeks to compare these two procedures for outcomes. Primary outcomes will be the success of the procedure, measured by a four-month post-operative voiding cystourethrogram (VCUG) and secondary outcomes-length of hospital stay, narcotic requirements, and length of post-operative catheterization, both retrospectively and prospectively. This study follows patients enrolled in this study for 10 years.

Outcomes in Patients with Posterior Urethral Valves

The Division of Urology is currently determining those at increased risk for urinary tract injury by identifying putative miRNA biomarkers in the urine to determine if they correlate with currently accepted measures of the severity of urinary tract injury. We are also prospectively collecting and reviewing clinical data points for this patient population to follow their clinical outcomes and predict their prognosis. We will compare outcomes to reduce variability and standardize the diagnosis, treatment and management of patients with PUV.

Long-Term Outcomes for Renal Replacement Therapy (RRT) and Clean Intermittent Catheterization (CIC) in Patients with Posterior Urethral Valves Multi-Center Study (PUMA)

In a cohort of 274 patients with posterior urethral valves over 20 years, the risk of RRT was significant, with 25% requiring dialysis or transplantation by age 13. Serum nadir creatinine before 1 year of age was strongly predictive of RRT with a risk of 0% for <0.4, 2% for 0.4-0.69, 27% for 0.7-0.99, and 100% for ≥1.0. CIC is something to recommend in many patients, including 50.0% by 14 years of age. The study will allow for better counseling of patients and families on long-term outcomes with posterior urethral valves as well as the identification of those at risk and interventions to preserve their renal function in the future.

Outcomes for Stone Disease

Cincinnati Children’s has experienced a dramatic increase in the number of referrals for stone disease over the past ten years. Many patients have undergone surgical intervention for treatment and removal of these stones. We are evaluating our experience following surgical intervention in patients with pediatric urolithiasis and / or nephrolithiasis and assess diagnosis and treatment to improve the effectiveness and outcomes of clinical care for patients with stone disease.

Outcomes in Robotic Assisted Laparoscopic Pyeloplasty

Ureteropelvic junction obstruction (UPJO) is a fairly common urologic anomaly in the pediatric population. Previous reports indicate the surgical correction of UPJO utilizing the Robotic Assisted Laparoscopic Pyeloplasty (RALP) as an effective alternative to conventional techniques for reconstructive surgery. Data regarding outcomes in this population has generally been limited to the short-term. The purpose of this study is to observe our long-term experience as it relates to outcomes and morbidity utilizing the RALP surgical technique in our patient population.

Testicular Tissue Cryopreservation (TTC) for Fertility Preservation in Patients Facing Infertility-Causing Diseases or Treatment Regimens Multi-Center Study

Many regimens of chemotherapy and / or radiation for cancer and other diseases are gonadotoxic with the potential for permanent azoospermia. With an improving survival due to the advent of more effective multimodal therapies, the late effects on fertility have become increasingly important. In prepubertal patients, there are limits on options for fertility preservation due to a lack of mature sperm and those who cannot provide a semen sample. Through the multi-center study, researchers offer TTC to patients who are undergoing gonadotoxic therapies and cannot provide a semen sample. TTC is currently an investigational protocol, as it is contingent on developing experimental therapies for the maturation of spermatogonial stem cells into sperm. The specific aims are to cryopreserve testicular tissue as a resource for fertility preservation by participants in the future and to develop a biobank of testicular tissue to use for research on optimization of these experimental techniques. Enrollment is ongoing, with a total of 24 participants to date.