Epoxyeicosatrienoic acid administration or soluble epoxide hydrolase inhibition attenuates renal fibrogenesis in obstructive nephropathy.

Epoxyeicosatrienoic acids (EETs) are arachidonic acid metabolites with biological effects, including antiapoptotic, anti-inflammatory, and antifibrotic functions. Soluble epoxide hydrolase (sEH)-mediated hydrolysis of EETs to dihydroxyeicosatrienoic acids (DHETs) attenuates these effects. Recent studies have demonstrated that inhibition of sEH prevents renal tubulointerstitial fibrosis and inflammation in the chronic kidney disease model. Given the pathophysiological role of the EET pathway in chronic kidney disease, we investigated if administration of EET regioisomers and/or sEH inhibition will promote antifibrotic and renoprotective effects in renal fibrosis following unilateral ureteral obstruction (UUO). EETs administration abolished tubulointerstitial fibrogenesis, as demonstrated by reduced fibroblast activation and collagen deposition after UUO. The inflammatory response was prevented as demonstrated by decreased neutrophil and macrophage infiltration and expression of cytokines in EET-administered UUO kidneys. EET administration and/or sEH inhibition significantly reduced M1 macrophage markers, whereas M2 macrophage markers were highly upregulated. Furthermore, UUO-induced oxidative stress, tubular injury, and apoptosis were all downregulated following EET administration. Combined EET administration and sEH inhibition, however, had no additive effect in attenuating inflammation and renal interstitial fibrogenesis after UUO. Taken together, our findings provide a mechanistic understanding of how EETs prevent kidney fibrogenesis during obstructive nephropathy and suggest EET treatment as a potential therapeutic strategy to treat fibrotic diseases.NEW & NOTEWORTHY Epoxyeicosatrienoic acids (EETs) are cytochrome P-450-dependent antihypertensive and anti-inflammatory derivatives of arachidonic acid, which are highly abundant in the kidney and considered renoprotective. We found that EET administration and/or soluble epoxide hydrolase inhibition significantly attenuates oxidative stress, renal cell death, inflammation, macrophage differentiation, and fibrogenesis following unilateral ureteral obstruction. Our findings provide a mechanistic understanding of how EETs prevent kidney fibrogenesis during obstructive nephropathy and suggest that EET treatment may be a potential therapeutic strategy to treat fibrotic diseases.

Hepatic and proximal tubule angiotensinogen play distinct roles in kidney dysfunction, glomerular and tubular injury, and fibrosis progression.

Components of the renin-angiotensin system, including angiotensinogen (AGT), are critical contributors to chronic kidney disease (CKD) development and progression. However, the specific role of tissue-derived AGTs in CKD has not been fully understood. To define the contribution of liver versus kidney AGT in the CKD development, we performed 5/6 nephrectomy (Nx), an established CKD model, in wild-type (WT), proximal tubule (PT)- or liver-specific AGT knockout (KO) mice. Nx significantly elevated intrarenal AGT expression and elevated blood pressure (BP) in WT mice. The increase of intrarenal AGT protein was completely blocked in liver-specific AGT KO mice with BP reduction, suggesting a crucial role for liver AGT in BP regulation during CKD. Nx-induced glomerular and kidney injury and dysfunction, as well as fibrosis, were all attenuated to a greater extent in liver-specific AGT KO mice compared with PT-specific AGT KO and WT mice. However, the suppression of interstitial fibrosis in PT- and liver-specific AGT KO mouse kidneys was comparable. Our findings demonstrate that liver AGT acts as a critical contributor in driving glomerular and tubular injury, renal dysfunction, and fibrosis progression, whereas the role of PT AGT was limited to interstitial fibrosis progression in chronic renal insufficiency. Our results provide new insights for the development of tissue-targeted renin-angiotensin system intervention in the treatment of CKD.NEW & NOTEWORTHY Chronic kidney disease (CKD) is a major unmet medical need with no effective treatment. Current findings demonstrate that hepatic and proximal tubule angiotensinogen have distinct roles in tubular and glomerular injury, fibrogenesis, and renal dysfunction during CKD development. As renin-angiotensin system components, including angiotensinogen, are important targets for treating CKD in the clinic, the results from our study may be applied to developing better tissue-targeted treatment strategies for CKD and other fibroproliferative diseases.

Proximal tubule cyclophilin D regulates fatty acid oxidation in cisplatin-induced acute kidney injury.

Regardless of the etiology, acute kidney injury involves aspects of mitochondrial dysfunction and ATP depletion. Fatty acid oxidation is the preferred energy source of the kidney and is inhibited during acute kidney injury. A pivotal role for the mitochondrial matrix protein, cyclophilin D in regulating overall cell metabolism is being unraveled. We hypothesize that mitochondrial interaction of proximal tubule cyclophilin D and the transcription factor PPARα modulate fatty acid beta-oxidation in cisplatin-induced acute kidney injury. Cisplatin injury resulted in histological and functional damage in the kidney with downregulation of fatty acid oxidation genes and increase of intrarenal lipid accumulation. However, proximal tubule-specific deletion of cyclophilin D protected the kidneys from the aforementioned effects. Mitochondrial translocation of PPARα, its binding to cyclophilin D, and sequestration led to inhibition of its nuclear translocation and transcription of PPARα-regulated fatty acid oxidation genes during cisplatin-induced acute kidney injury. Genetic or pharmacological inhibition of cyclophilin D preserved nuclear expression and transcriptional activity of PPARα and prevented the impairment of fatty acid oxidation and intracellular lipid accumulation. Docking analysis identified potential binding sites between PPARα and cyclophilin D. Thus, our results indicate that proximal tubule cyclophilin D elicits impaired mitochondrial fatty acid oxidation via mitochondrial interaction between cyclophilin D and PPARα. Hence, targeting their interaction may be a potential therapeutic strategy to prevent energy depletion, lipotoxicity and cell death in cisplatin-induced acute kidney injury.

Clinical Outcome and Biological Predictors of Relapse After Nephrectomy Only for Very Low-risk Wilms Tumor: A Report From Children's Oncology Group AREN0532.

OBJECTIVE: To determine if observation alone after nephrectomy in very low-risk Wilms tumor (defined as stage I favorable histology Wilms tumors with nephrectomy weight <550g and age at diagnosis <2 years) results in satisfactory event-free survival and overall survival, and to correlate relapse with biomarkers. PATIENTS AND METHODS: The AREN0532 study enrolled patients with very low-risk Wilms tumor confirmed by central review of pathology, diagnostic imaging, and surgical reports. After nephrectomy, patients were followed without adjuvant chemotherapy. Evaluable tumors were analyzed for WT1mutation, 1p and 16q copy loss, 1q copy gain, and 11p15 imprinting. The study was powered to detect a reduction in 4-year EFS from 87% to 75% and overall survival from 95% to 88%. RESULTS: A total of 116 eligible patients enrolled with a median follow up of 80 months (range: 5-97 months). Twelve patients relapsed. Estimated 4-year event-free survival was 89.7% (95% confidence interval 84.1-95.2%) and overall survival was 100%. First sites of relapse were lung (n = 5), tumor bed (n = 4), and abdomen (n = 2), with one metachronous tumor in the contralateral kidney (n = 1) at a median time of 4.3 months for those who relapsed (range 2.3-44 months). The presence of intralobar (P = 0.46) or perilobar rests (P = 1.0) were not associated with relapse (P = 0.16). 1q gain, 1p and 16q loss, and WT1 mutation status were not associated with relapse. 11p15 methylation status was associated relapse (20% relapse with loss of heterozygosity, 25% with loss of imprinting, and 3.3% relapse with retention of the normal imprinting (P = 0.011)). CONCLUSIONS: Most patients meeting very low-risk criteria can be safely managed by nephrectomy alone with resultant reduced exposure to chemotherapy. Expansion of an observation alone strategy for low-risk Wilms tumor incorporating both clinical features and biomarkers should be considered.

Patterns of Performance of Oncologic Surgery by North American Pediatric Urologists: A Report from the Pediatric Urologic Oncology Working Group of the Society for Pediatric Urology.

PURPOSE: Objective data on patterns of oncology practice among pediatric urologists are lacking. We reviewed surgical case logs submitted to the American Board of Urology by those self-reporting as pediatric urologists. We hypothesized that logs would reveal a low oncology volume (fewer than 5 cases) and identify orchiectomy as the most common oncology cases, and that less than 25% of logs would show nephrectomy for renal tumor. MATERIALS AND METHODS: Case logs submitted for American Board of Urology certification, recertification or pediatric subspecialty certification were reviewed and standardized to represent 12-month practice. Data were collected on pediatric oncologic surgeries as noted by procedure codes linked with oncologic diagnosis codes for patients up to age 30 years. RESULTS: We identified 281 case logs meeting study criteria. A total of 364 oncology cases were logged and 131 logs (46.6%) listed at least 1 oncology case, while 150 (53.4%) contained no oncology cases. The 75th, 90th and 95th percentiles of oncology volume were represented by reporting 2, 3 and 4 cases, respectively. A total of 13 logs (4.6%) accounted for more than a third of all oncology cases (35.9%). The most frequent oncology case logged was orchiectomy, which was documented in 83 logs (29.5%). On Poisson regression surgeon variables associated with higher oncology volume included male gender (IRR 2.8, 95% CI 2.1-3.9), 2010 log year (IRR 2.4, 95% CI 1.3-4.4), 2015 log year (IRR 3.7, 95% CI 2.1-6.4) and nonpediatric subspecialty certification log (IRR 1.6, 95% CI 1.2-2.3). CONCLUSIONS: Few pediatric urologists perform a high volume of oncologic surgeries based on surgical case logs submitted to the American Board of Urology. A small cohort of pediatric urologists logged the majority of such cases.

A Society for Pediatric Urology Workforce Survey on the Current Perceptions of Oncology Care by Pediatric Urologists: A Report from the Pediatric Urologic Oncology Working Group of the Society for Pediatric Urology.

PURPOSE: Data are lacking on the current perception of oncology care among pediatric urologists. Thus, we developed, pilot tested and administered a survey on this topic to SPU (Society for Pediatric Urology) members. MATERIALS AND METHODS: Approval for this proposal was granted by SPU leadership prior to developing or distributing the survey instrument. The survey was developed and pilot tested by the PUOWG (Pediatric Urologic Oncology Working Group). Response data were collected and descriptive statistics were used for analysis. Logistic regression analysis was performed to correlate surgeon reported factors with higher volumes of reported oncology surgery. RESULTS: A total of 426 surveys were distributed via email to SPU members and 212 individual surveys (49.8%) were returned with the background/introduction section completed. Of these surveys 200 (94.3%) were completed by practicing pediatric urologists. Overall, 155 respondents (77.5%) reported performing 5 or fewer oncology related surgeries per year and 74.9% reported that less than 25% of renal tumor surgery at their institution was performed through the pediatric urology service. On multivariate analysis the self-reported factors significantly associated with increased oncology surgical volume (more than 5 cases per year) were greater than 50% attendance at institutional tumor board meetings (OR 4.8, 95% CI 1.4-16.9) and practicing at a hospital with a higher volume of renal tumor surgery (OR 2.6, 95% CI 1.2-5.8). CONCLUSIONS: Few surveyed pediatric urologists reported performing a high volume of oncology surgery. Respondents expressed interest in ways to increase pediatric urology involvement in oncology care, including opportunities for increased education. Self-reported factors that correlated with higher volume were regular attendance at the institutional pediatric tumor board and practice at a higher volume institution.

Treatment with the immunomodulator FTY720 (fingolimod) significantly reduces renal inflammation in murine unilateral ureteral obstruction.

PURPOSE: The S1P signaling pathway represents an important potential target for the modulation of tissue inflammation/injury. The immunomodulator FTY720, also known as fingolimod, is a potent agonist for multiple S1P receptors that was approved by the Food and Drug Administration to treat multiple sclerosis. We examined the therapeutic role of FTY720 for renal injury secondary to unilateral ureteral obstruction. MATERIALS AND METHODS: CB57BL/6 mice underwent a sham procedure or unilateral ureteral obstruction and were treated with FTY720 by gavage for 1, 3 and 5 days. Control groups received vehicle. Ligated and unligated renal tissue was examined for histopathological changes, inflammatory and fibrotic markers, TGF-ß1, α-SMA, and macrophage infiltration by Western blot and immunohistochemistry. Proinflammatory and profibrotic cytokines were profiled by quantitative reverse transcriptase-polymerase chain reaction. RESULTS: Pathological evaluation revealed that FTY720 treatment resulted in a significant reduction in inflammatory infiltration in obstructed kidneys compared to controls. Immunohistochemical and Western blot showed that TGF-ß1 and α-SMA protein levels were similarly decreased, as was macrophage infiltration into the renal interstitial space, compared to untreated mice. In agreement with these observations quantitative reverse transcriptase-polymerase chain reaction revealed that inflammatory and fibrotic cytokines (MCP-1, IL-1ß, CXCL1, TNF-α and TGF-ß1) were also significantly decreased in the FTY720 group. CONCLUSIONS: This study suggests that in a murine ureteral obstruction model FTY720 significantly inhibited the production of inflammatory cytokines and factors regulating interstitial fibrosis and extracellular matrix accumulation. These findings were associated with decreased evidence of renal injury on pathological examination, suggesting that FTY720 or related compounds may be valuable modulators of obstruction induced renal injury.

Contemporary disparities in progression to orchiopexy for cryptorchidism as reported in the Pediatric Health Information System (PHIS) database.

INTRODUCTION: When evaluating the timeliness of orchiopexy for cryptorchidism, health disparities are apparent among Hispanic and African American males and those with public insurance. Since the publication of these data, the COVID-19 pandemic has stressed our healthcare system and significantly affected the provision of pediatric urology care. OBJECTIVE: We sought to assess if certain groups were disproportionately affected in progression to orchiopexy after the diagnosis of cryptorchidism during and after the pandemic in US freestanding children's hospitals. STUDY DESIGN: Using the PHIS database, pediatric patients ≤5 years who underwent orchiopexy between January 2018 and December 2022 were retrospectively analyzed. Exclusion criteria included prematurity, retractile testes, and testicular torsion. Primary outcomes were age at orchiopexy and the proportion of individuals undergoing timely orchiopexy for cryptorchidism. RESULTS: Over the study period 3140 patients ≤5 years old underwent orchiopexy for cryptorchidism. Non-Hispanic Blacks and Hispanics were significantly less likely to have timely orchiopexy and underwent orchiopexy 2.13 and 3.60 months later compared to whites (p < 0.01). As compared to pre-COVID-19, during the pandemic the proportion of patients who had timely surgery was higher and the median age was significantly lower (p = 0.01 and p < 0.01, respectively) in white patients only. Over the study period, patients with public insurance were less likely to have timely orchiopexy and underwent orchiopexy 2.94 months later (p < 0.01) than patients with private insurance. Compared to during the pandemic, post-pandemic a significantly lower proportion of publicly insured patients have since undergone timely orchiopexy (p = 0.04). Patients in the West were less likely to have timely orchiopexy and had a higher age at time of orchiopexy (p < 0.01) than other regions. However, in the West during the pandemic, the proportion of children who had timely surgery was higher compared to pre-and post-COVID-19 (p < 0.01). DISCUSSION: Overall, regardless of insurance status, race, or location, a significant proportion of patients did not undergo timely orchiopexy. During the pandemic white patients had a lower median age and an increased proportion underwent timely orchiopexy, despite the number of orchiopexies remaining constant. Disparities in the post-COVID-19 era have been further exacerbated for publicly insured patients, who a significantly lower proportion of have since undergone timely orchiopexy. Specific efforts are required across the United States to increase timely orchiopexy for all boys. CONCLUSIONS: Progression to timely orchiopexy remains low for all boys in the era surrounding COVID-19; certain groups appear to be more adversely affected.

Does KUB play a role in the diagnosis of bladder bowel dysfunction?

INTRODUCTION: Kidney ureter bladder radiography (KUB) is widely used for the evaluation of constipation in children with bladder and bowel dysfunction (BBD); however, there is varying evidence to support its routine diagnostic use. One drawback to KUB is radiation exposure. The dangers of radiation in children are well-documented, and per As Low As Reasonably Achievable, non-beneficial radiation should be avoided. This risk is especially high in children who undergo repeated imaging in the follow up of constipation treatment. OBJECTIVE: We sought to assess the utility of KUB in diagnosing children with BBD by comparing it to four diagnostic tests and/or validated instruments: the Dysfunctional Voiding Symptom Score (DVSS), Rome IV criteria, rectal diameter on ultrasound (RD), and the Bristol Stool Form Score (BSFS). STUDY DESIGN: We prospectively enrolled a cohort of patients presenting to an academic pediatric urology practice with symptoms of BBD. Severity of stool burden on KUB (mild, moderate, or severe), RD on ultrasound (≥3.4 cm), DVSS, Rome IV, and BSFS were obtained for each patient. All imaging was interpreted by a pediatric radiologist and pediatric urologist. Primary outcomes were the association between the four diagnostic tests and KUB stool burden. Bivariate analysis of all individual variables versus KUB was performed, as well as multivariate regressions to determine if multiple measures were predictive of KUB stool burden when combined. RESULTS: Between October 2020 and May 2022, 50 patients were enrolled. All children were under the age of 18, with a median age of 8 years (IQR 3-13). 38 % were male. Median BMI-for-age-percentile was 80.8 (IQR 50.3-98.3). When comparing individual variables to KUB in bivariate analyses, it was found that RD on ultrasound is predictive of significant stool burden on KUB (p = 0.03). No other individual variables were predictive. In the multivariate analyses, no combination of tests was found to be predictive of KUB. DISCUSSION: We compared the effectiveness of four commonly used diagnostic tests in children with BBD to validate the use of KUB. In conclusion, our results support the use of RD on ultrasound as a non-radiating alternative to KUB to assess stool burden. Data also suggest that KUB for fecal load does not correlate with urinary (DVSS) or bowel (Rome IV, BSFS) symptoms in BBD, and that symptoms scores should still be used independently for diagnosis and monitoring of treatment response. CONCLUSION: In conclusion, KUB has a limited role in the diagnosis of BBD.

Inter-disciplinary provider development of an online, interactive adolescent varicocele decision aid prototype.

BACKGROUND: Decision-making regarding varicocele management can be a complex process for patients and families. However, to date, no studies have presented ways to mitigate the decisional conflict surrounding varicoceles. OBJECTIVE: To facilitate a discussion among physicians in order to develop a framework of the decision-making process regarding adolescent varicocele management, which will inform the development of the first online, interactive decision aid. MATERIALS AND METHODS: Semi-structured interviews with pediatric urologists and interventional radiologists were conducted to discuss their rationale for varicocele decision-making. Interviews were audio recorded, transcribed, and coded. Key themes were identified, grouped, and then qualitatively analyzed using thematic analysis. Utilizing the common themes identified and the Ottawa Decision Support Framework, a decision aid prototype was developed and transformed into a user-friendly website: varicoceledecisionaid.com. RESULTS: Pediatric urologists (n = 10) and interventional radiologists (n = 2) were interviewed. Key themes identified included: (1) definition/epidemiology; (2) observation as an appropriate management choice; (3) reasons to recommend repair; (4) types of repair; (5) reasons to recommend one repair over another; (6) shared decision-making; and (7) appropriate counseling. With this insight, a varicocele decision aid prototype was developed that engages patients and parents in the decision-making process. DISCUSSION AND CONCLUSIONS: This is the first interactive and easily accessible varicocele decision aid prototype developed by inter-disciplinary physicians for patients. This tool aids in decision-making surrounding varicocele surgery. It can be used before or after consultation to help families understand more about varicoceles and their repair, and why intervention may or may not be offered. It also considers a patient and family's personal values. Future studies will incorporate the patient and family perspective into the decision-making aid as well as implement and test the usability of this decision aid prototype in practice and in the wider urologic community.