Urinary Exosome analysis to identify biomarkers of bladder injury in patients with posterior urethral valves (PUV)
Almost all patients with posterior urethral valves (PUV) develop some form of bladder dysfunction with lower urinary tract symptoms. In more severely affected cases, the ongoing injury can result in progression to chronic kidney disease and end-stage renal disease. In a non-invasive study, our group studies urine from these patients with the goal of improving outcomes by identifying biomarkers associated with exosomes, nano-sized membranous extracellular vesicles (EVs). Cells lining the urinary tract release EV's into urine and 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. Implication of several of these RNAs is in the regulation of pathological pathways, such as fibrosis. Successful completion of the study will provide diagnostic and prognostic biomarkers for PUV-related bladder and kidney disease.
Long-Term Outcomes in Patients with Bladder Exstrophy—Multi-Center Study (Pediatric Urology Midwest Alliance-PUMA)
A multi-center cohort study of over 200 patients with bladder exstrophy over a 36-year period, illustrates the risk of bladder augmentation or urinary diversion and the need for clean intermittent catheterization (CIC) was significant after primary closure of the bladder. This need increased over time. The risk of bladder augmentation or urinary diversion was 52.0% by 10 years of age and increased to 72.1% by 18 years of age. A majority of patients also required CIC, including 65.7% of the entire cohort and 86.0% of adults at last follow-up. The study demonstrates the feasibility of such a collaborative model for clinical research and will allow for better counseling of patients and families on long-term outcomes with bladder exstrophy in the future.
Long-Term Outcomes for Renal Replacement Therapy (RRT) and Clean Intermittent Catheterization (CIC) in Patients with Posterior Urethral Valves—Multi-Center Study (PUMA)
A multi-center cohort study of 274 patients with posterior urethral valves over 20 years shows the risk of RRT was significant with 25% requiring dialysis or transplantation by the age of 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 allows 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.
Discovery of renal proximal tubule progenitors
Proximal tubule cells are the most abundant cell type in the kidney and they perform the bulk of the renal reabsorption of water, salt, and nutrients. Despite the importance of these cells in kidney function, understanding how they form during development is not well known. A research team led by
Joo-Seo Park, PhD, recently made a breakthrough discovery on how this process regulates in the mammalian kidney. In this study, they found that Cadherin-6-expressing cells are proximal tubule progenitors in the mouse kidney and the requirement of the transcription factor Hnf4a for these immature cells to develop into mature proximal tubule cells. Genomic analyses showed that Hnf4a directly regulates the expression of genes required for renal reabsorption, such as transmembrane transporter genes and metabolism genes. The
Journal of the American Society of Nephrology published this landmark
study. The team recently received an NIH R01 grant to further pursue this important area of research.
Enhanced Recovery After Surgery (ERAS)—Multi-Center Study
The hypothesis that enhanced recovery after surgery (ERAS) peri-operative care principles is something free-standing pediatric hospitals can implement with ≥ 75% adherence to protocol items. Our aim is to determine if proposing this is optimal to maximize recovery from surgery while minimizing morbidity, to characterize protocol deviations by providers and study sites, and to define short and long- term outcomes from surgery after application of the ERAS protocol. Broadening exposure of the pediatric urology community to ERAS and demonstrating its application at other medical centers is our goal. As ERAS is a multidisciplinary program requiring on-the-ground changes to how members of the patient care team deliver care, this study contains a built-in pilot portion to demonstrate the effective implementation of ERAS at other centers attains similar or even better outcomes. Following this will be an exploratory phase where centers enroll patients that we follow for their outcomes over the course of at least one year after surgery. We are currently in the exploratory phase at Cincinnati Children’s.
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 (URS), extracorporeal shockwave lithotripsy (SWL), and percutaneous nephrolithotomy (PCNL) 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 the time of enrollment) at the 22 sites in the PKIDS Care Improvement Network.
Testicular Tissue Cryopreservation 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 improving survival due to the advent of more effective multimodal therapies, the late effects on fertility are becoming increasingly important. There is a limit to the options for fertility preservation in prepubertal patients due to a lack of mature sperm as well as those who cannot provide a semen sample. This multi-center study offers testicular tissue cryopreservation (TTC) to patients who are undergoing gonadotoxic therapies who cannot provide a semen sample. TTC is currently an investigational protocol as it is contingent on the development of 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 use by participants in the future and to develop a biobank of testicular tissue for use in research on optimization of these experimental techniques. Enrollment is ongoing with a total of 58 participants to date here at Cincinnati Children’s.
