Survival assessment of nephron-sparing surgery or radical nephrectomy in children with unilateral Wilms tumor receiving adjuvant chemotherapy: a retrospective cross-sectional study.

OBJECTIVE: Surgical treatment of unilateral Wilms tumor (WT) in children is controversial. In this study, we aimed to evaluate the survival and prognosis of radical nephrectomy (RN) and nephron-sparing surgery (NSS) in children with unilateral WT receiving adjuvant chemotherapy. PATIENTS AND METHODS: Data on pediatric patients with WT were collected from the Surveillance, Epidemiology, and End Results (SEER) database from 2000 to 2019. Multivariate logistic regression was used to analyze factors influencing the choice of surgical strategy. Cox proportional hazard models were used to assess factors associated with overall survival. RESULTS: We included 1,825 patients with unilateral WT (<14 years) who received adjuvant chemotherapy and surgery. Between 2000 and 2019, the percentage of patients treated with NSS increased from 4% in 2000 to 8% in 2019. There was no significant difference in 10-year overall survival between the two surgical strategies [NSS vs. RN, 93.26% (95% CI, 86.88%-100%) vs. 92.17% (95% CI, 90.75%-93.61%), p=0.98]. Patients with unilateral WTs ≤4 cm were more likely to be treated with NSS. There was no survival benefit for patients treated with RN compared with that for those treated with NSS (HR, 0.74; 95% CI, 0.29-1.86; p=0.5). CONCLUSIONS: The use of NSS in children with unilateral WT has increased over the last two decades. Tumor size is an important influencing factor for the surgical application of NSS. Patients who underwent NSS had an equivalent OS compared with the overall group of patients with unilateral tumors who received RN.

Navigating the kidney organoid: insights into assessment and enhancement of nephron function.

Kidney organoids are three-dimensional structures generated from pluripotent stem cells (PSCs) that are capable of recapitulating the major structures of mammalian kidneys. As this technology is expected to be a promising tool for studying renal biology, drug discovery, and regenerative medicine, the functional capacity of kidney organoids has emerged as a critical question in the field. Kidney organoids produced using several protocols harbor key structures of native kidneys. Here, we review the current state, recent advances, and future challenges in the functional characterization of kidney organoids, strategies to accelerate and enhance kidney organoid functions, and access to PSC resources to advance organoid research. The strategies to construct physiologically relevant kidney organoids include the use of organ-on-a-chip technologies that integrate fluid circulation and improve organoid maturation. These approaches result in increased expression of the major tubular transporters and elements of mechanosensory signaling pathways suggestive of improved functionality. Nevertheless, continuous efforts remain crucial to create kidney tissue that more faithfully replicates physiological conditions for future applications in kidney regeneration medicine and their ethical use in patient care.NEW & NOTEWORTHY Kidney organoids are three-dimensional structures derived from stem cells, mimicking the major components of mammalian kidneys. Although they show great promise, their functional capacity has become a critical question. This review explores the advancements and challenges in evaluating and enhancing kidney organoid function, including the use of organ-on-chip technologies, multiomics data, and in vivo transplantation. Integrating these approaches to further enhance their physiological relevance will continue to advance disease modeling and regenerative medicine applications.

Outcomes of Artificial Intelligence Volumetric Assessment of Kidneys and Renal Tumors for Preoperative Assessment of Nephron-Sparing Interventions.

Background: Renal-cell carcinoma is the most common kidney cancer and the 13th most common cause of cancer death worldwide. Partial nephrectomy and percutaneous ablation, increasingly utilized to treat small renal masses and preserve renal parenchyma, require precise preoperative imaging interpretation. We sought to develop and evaluate a convolutional neural network (CNN), a type of deep learning (DL) artificial intelligence (AI), to act as a surgical planning aid by determining renal tumor and kidney volumes through segmentation on single-phase CT. Materials and Methods: After Institutional Review Board approval, the CT images of 319 patients were retrospectively analyzed. Two distinct CNNs were developed for (1) bounding cube localization of the right and left hemiabdomen and (2) segmentation of the renal parenchyma and tumor within each bounding cube. Training was performed on a randomly selected cohort of 269 patients. CNN performance was evaluated on a separate cohort of 50 patients using Sorensen-Dice coefficients (which measures the spatial overlap between the manually segmented and neural network-derived segmentations) and Pearson correlation coefficients. Experiments were run on a graphics processing unit-optimized workstation with a single NVIDIA GeForce GTX Titan X (12GB, Maxwell Architecture). Results: Median Dice coefficients for kidney and tumor segmentation were 0.970 and 0.816, respectively; Pearson correlation coefficients between CNN-generated and human-annotated estimates for kidney and tumor volume were 0.998 and 0.993 (p < 0.001), respectively. End-to-end trained CNNs were able to perform renal parenchyma and tumor segmentation on a new test case in an average of 5.6 seconds. Conclusions: Initial experience with automated DL AI demonstrates that it is capable of rapidly and accurately segmenting kidneys and renal tumors on single-phase contrast-enhanced CT scans and calculating tumor and renal volumes.

Assessment of nephron number and single-nephron glomerular filtration rate in a clinical setting.

Total nephron counts vary widely between individuals and may affect susceptibility to certain diseases, including hypertension and chronic kidney disease. Detailed analyses of whole kidneys collected from autopsy patients remain the only method for accurately counting nephrons in humans, with no equivalent option in living subjects. Current technological advances have enabled estimations of nephron numbers in vivo, particularly the use of total nephron number and whole-kidney glomerular filtration rate to estimate the mean single-nephron glomerular filtration rate. The use of this method would allow physicians to detect dynamic changes in filtration function at the single-nephron level rather than to simply count the number of nephrons that appear to be functioning. Currently available methods for estimating total nephron number in clinical practice have the potential to overcome limitations associated with autopsy analyses and may therefore pave the way for new therapeutic interventions and improved clinical outcomes.

Kidney functional morphology variations between spring and winter in the Saharan male lizard Uromastyx acanthinura (Sauria, Agamidae), with special reference to body water economy.

To better understand the adaptive mechanisms in Uromastyx acanthinura to the seasonal variations in the arid environment, the present study aimed to explore the kidney functional morphology involved in body water economy. These investigations were carried out by the histological, histochemical and immuno-histochemical methods using conventional light microscopy. The glomeruli number is estimated at 2000 per kidney. The glomeruli size is rather small and decreases significantly in winter. Interestingly, the proximal convoluted tubule (PCT) is long and divided into two different segments which is one of the particularities of this species. Both of the distal convoluted tubule (DCT), connecting tubule (CnT) and collecting duct (CD) epithelium contains mucous cells. The nature and intensity of these mucous secretions vary according to seasons. The evident hypertrophy of the secondary collecting duct (SCD) and tertiary collecting duct (TCD) epithelium is related to the high secretory activity during spring, corresponding to the sexual segment of kidney (SSK). Labeling with anti α-smooth muscle actin-1 showed a thick layer of mucularis surrounded the entire CD. Also, the mesangium of glomeruli contains myofibroblasts. All these renal structural characteristics involved in body water economy may be considered as an adaptive mechanisms of U. acanthinura to resist to dehydration and cope with seasonal variations in the arid environment.

A practical guide to the stereological assessment of glomerular number, size, and cellular composition.

The evaluation of a range of measures in the kidneys, such as developmental stage, rate and success, injury, and disease processes, relies on obtaining information on the three-dimensional structure of the renal corpuscles, and in particular the glomerular capillary tufts. To do this in the most accurate, comprehensive, and unbiased manner depends on a knowledge of stereological methods. In this article, we provide a practical guide for researchers on how to quantitate a number of structures in the kidneys, including the estimation of total glomerular number, glomerular capillary length and filtration surface area, and the cellular composition of individual glomeruli. Guidance is also provided on how to apply these methods to kidneys at different sizes and levels of maturity.

Quality of life outcomes in patients with localised renal cancer: a literature review.

PURPOSE: Patients with localised renal cell carcinoma (RCC) can expect excellent oncologic outcomes. As such, there has been a shift towards maximising health-related quality of life (HRQoL). A greater understanding of HRQoL outcomes associated with different treatment options for RCC can facilitate patient-centred care, shared decision-making and enable cost utility analyses to guide health policies. The aim of this literature review was to evaluate the evidence regarding HRQoL following different management strategies for localised RCC. METHODS: Three databases were searched to identify studies reporting HRQoL in patients with localised renal cancer, including Medline, the Tuft's Medical Centre Cost Effectiveness Analysis registry and the EuroQol website. RESULTS: Considerable methodological heterogeneity was noted. Laparoscopic nephrectomy was associated with significantly better short-term physical function compared to open surgery, although the effect on mental function was inconclusive. Nephron-sparing surgery was associated with better physical function compared to radical surgery. Patients' perception of remaining renal function was a significant independent predictor of HRQoL, rather than surgery type. Tumour size, stage, post-operative complications, age, body mass index, occupational status, educational level and comorbidities were significant predictors of HRQoL. Only three studies were available regarding non-surgical management options and very little data were available regarding the impact of follow-up protocols and long-term effects of "cancer survivorship." CONCLUSION: There is a need for validated and reproducible RCC-specific HRQoL instruments and standardisation amongst studies to enable comparisons. Increased awareness regarding determinants of poor HRQoL may enable high-risk patients to receive tailored support.

The Impact of Preexisting Chronic Kidney Disease on the Severity and Recovery of Acute Kidney Injury.

BACKGROUND: Recent observational studies have shown that in chronic kidney disease (CKD) patients, a significantly smaller percentage of patients with an episode of acute kidney injury (AKI) have full recovery of renal function compared to those without CKD. However, precise mechanisms involved in the incomplete repair after AKI with preexisting CKD have not been completely ascertained. Here, we assessed the impact of preexisting CKD on the severity and recovery of AKI in a mouse model of 5/6 nephrectomy. METHODS: Male CD-1 mice underwent 5/6 nephrectomy (Nx). Six weeks post surgery, ischemia reperfusion injury (IRI) or a sham operation was performed and functional, histological, and various molecular parameters were compared between them. RESULTS: Serum creatinine level on day 1 after IRI was comparable between control and Nx mice. However, serum creatinine remained significantly higher throughout the recovery phase in Nx mice compared to control mice. mRNA and protein expression of the cell cycle regulatory proteins were persistently elevated in Nx mice and this was associated with significantly increased levels of the G1 cell cycle arrest markers. Treatment with a p53 inhibitor following IRI resulted in not only decreased expression of G1 arrest markers but also decreased fibrosis, suggesting that prolonged epithelial G1 cell cycle arrest might be partially responsible for impaired recovery from superimposed AKI on CKD. CONCLUSION: Taken together, reduced nephron mass have a negative effect on the repair process that is partially mediated by the disruption of the cell cycle regulation.

Renal shear wave elastography for the assessment of nephron hypertrophy: a cross-sectional study in chronic kidney disease.

PURPOSE: To investigate the association of renal elasticity to microscopic findings of nephron hypertrophy and nephrosclerosis. METHODS: Patients who underwent renal biopsy were enrolled. Renal elasticity was measured by acoustic radiation force impulse, and nephron size (glomerular volume, non-sclerotic glomerular density, and mean profile tubular area) and nephrosclerosis (globally sclerotic glomeruli and interstitial fibrosis) were estimated. Nephron hypertrophy was indicated by larger glomerular volume, larger tubular area, and lower non-sclerotic glomerular density. Nephrosclerosis was indicated by a higher percentage of globally sclerotic glomeruli and higher severity of fibrosis. RESULTS: Renal elasticity was negatively correlated with glomerular volume (r = - 0.480, P = 0.024) and mean tubular area (r = - 0.469, P = 0.028), but it was not correlated with non-sclerotic glomerular density (r = 0.205, P = 0.359), percentage of globally sclerotic glomeruli (r = 0.057, P = 0.800), and severity of fibrosis (r = 0.014, P = 0.950). In a multiple linear regression analysis, glomerular volume and mean tubular area were independently associated with renal elasticity (std ß = - 0.454, P = 0.015 and std ß = - 0.577, P = 0.007, respectively). CONCLUSION: Renal elasticity was correlated with microstructural findings of nephron hypertrophy. Measuring renal elasticity could help in detecting kidney disease.

A nephron model for study of drug-induced acute kidney injury and assessment of drug-induced nephrotoxicity.

In this study, we developed a multilayer microfluidic device to simulate nephron, which was formed by "glomerulus", "Bowman's capsule", "proximal tubular lumen" and "peritubular capillary". In this microdevice, artificial renal blood flow was circulating and glomerular filtrate flow was single passing through, mimicking the behavior of a nephron. In this dynamic artificial nephron, we observed typical renal physiology, including the glomerular size-selective barrier, glomerular basement membrane charge-selective barrier, glucose reabsorption and para-aminohippuric acid secretion. To demonstrate the capability of our microdevice, we used it to investigate the pathophysiology of drug-induced acute kidney injury (AKI) and give assessment of drug-induced nephrotoxicity, with cisplatin and doxorubicin as model drugs. In the experiment, we loaded the doxorubicin or cisplatin in the "renal blood flow", recorded the injury of primary glomerular endothelial cells, podocytes, tubular epithelial cells and peritubular endothelial cells by fluorescence imaging, and identified the time-dependence, dose-dependence and the death order of four types of renal cells. Then by measuring multiple biomarkers, including E-cadherin, VEGF, VCAM-1, Nephrin, and ZO-1, we studied the mechanism of cell injuries caused by doxorubicin or cisplatin. Also, we investigated the effect of BSA in the "renal blood flow" on doxorubicin-or-cisplatin-induced nephrotoxicity, and found that BSA enhanced the tight junctions between cells and eased cisplatin-induced nephrotoxicity. In addition, we compared the nephron model and traditional tubule models for assessment of drug-induced nephrotoxicity. And it can be inferred that our biomimetic microdevice simulated the complex, dynamic microenvironment of nephron, yielded abundant information about drug-induced-AKI at the preclinical stage, boosted the drug safety evaluation, and provided a reliable reference for clinical therapy.

MRI tools for assessment of microstructure and nephron function of the kidney.

MRI can provide excellent detail of renal structure and function. Recently, novel MR contrast mechanisms and imaging tools have been developed to evaluate microscopic kidney structures including the tubules and glomeruli. Quantitative MRI can assess local tubular function and is able to determine the concentrating mechanism of the kidney noninvasively in real time. Measuring single nephron function is now a near possibility. In parallel to advancing imaging techniques for kidney microstructure is a need to carefully understand the relationship between the local source of MRI contrast and the underlying physiological change. The development of these imaging markers can impact the accurate diagnosis and treatment of kidney disease. This study reviews the novel tools to examine kidney microstructure and local function and demonstrates the application of these methods in renal pathophysiology.

A Case for Nephron Sparing Surgery in the Management of Upper Tract Urothelial Carcinoma.

Upper tract urothelial carcinoma (UTUC) is rare and its management presents many challenges. Outside of distal ureterectomy for select cases, management has been primarily radical nephroureterectomy. Endoscopic nephron sparing management (NSM) is recognized to have some role in UTUC treatment; however, it is yet to gain firm footing in the treatment algorithm. In this review, we discuss the benefits of NSM with regards to oncologic outcomes, renal function preservation, and cost savings. Finally, we propose recognition of endoscopic NSM as a first-line treatment in selected patients with low risk disease.

Parenchymal Volumetric Assessment as a Predictive Tool to Determine Renal Function Benefit of Nephron-Sparing Surgery Compared with Radical Nephrectomy.

PURPOSE: To develop a preoperative prediction model using a computer-assisted volumetric assessment of potential spared parenchyma to estimate the probability of chronic kidney disease (CKD, estimated glomerular filtration rate [eGFR] <60 mL/min/1.73 m(2)) 6 months from extirpative renal surgery (nephron-sparing surgery [NSS] or radical nephrectomy [RN]). PATIENTS AND METHODS: Retrospective analysis of patients who underwent NSS or RN at our institution from January 2000 to June 2013 with a compatible CT scan 6-month renal function follow-up was performed. Primary outcome was defined as the accuracy of 6-month postoperative eGFR compared with actual postoperative eGFR based on root mean square error (RMSE). Models were constructed using renal volumes and externally validated. A clinical tool was developed on the best model after a given surgical procedure using area under the curve (AUC). RESULTS: We identified 130 (51 radical, 79 partial) patients with a median age of 58 years (interquartile range [IQR] 48-67) and preoperative eGFR of 82.1 (IQR 65.9-104.3); postoperative CKD (eGFR <60) developed in 42% (55/130). We performed various linear regression models to predict postoperative eGFR. The Quadratic model was the highest performing model, which relied only on preoperative GFR and the volumetric data for a RMSE of 15.3 on external validation corresponding to a clinical tool with an AUC of 0.89. CONCLUSION: Volumetric-based assessment provides information to predict postoperative eGFR. A tool based on this equation may assist surgical counseling regarding renal functional outcomes before renal tumor surgical procedures.

Surveillance Following Nephron-Sparing Surgery: An Assessment of Recurrence Patterns and Surveillance Costs.

OBJECTIVE: To assess the pattern of renal cell carcinoma (RCC) recurrences in nephron-sparing surgery (NSS) patients, and to determine whether current guidelines for surveillance could be modified based on such patterns. METHODS: Retrospective review of a single-institution NSS database. Pattern of RCC recurrences and factors associated with recurrence were analyzed using univariate and multivariable competing risk regression analyses. Cost of surveillance was estimated based on Medicare charges. RESULTS: A total of 505 patients underwent elective NSS for RCC. Pathologic T stage included 394 pT1a and 79 pT1b lesions. Median follow-up was 38.3 (6-88) months. Recurrence was detected in 26 patients (5.1%) at a median of 18.9 months (2.7% pT1a and 12.7% pT1b). The estimated 5-year cumulative incidence of recurrence for unifocal pT1a lesions was 2.7%. On multivariable analysis, stage higher than pT1a (HR, 5.56 [CI. 2.57-12.0]) and the presence of multifocal or bilateral tumors (HR, 3.32 [CI, 1.45-7.61]) were independent predictors of disease recurrence. For the entire cohort, recurrence was observed in only 10 patients beyond 24 months including only 2 cases with pT1a. CONCLUSION: Current guidelines adequately capture most clinically significant recurrences, and with longer follow-up, it may be possible to confirm that routine surveillance beyond 2 years may have little clinical significance for patients with asymptomatic unifocal pT1a.

Effects of phosphodiesterase-5 inhibitor on ischemic kidney injury during nephron sparing surgery: quantitative assessment by NGAL and KIM-1.

PURPOSE: Interruption of renal blood flow is often necessary during nephron sparing surgery (NSS) and can induce renal injury. This study examines whether tadalafil, a phosphodiesterase-5 (PDE-5) inhibitor and well-known vasodilator, exerts nephroprotective effects in patients undergoing NSS. METHODS: This non-randomized study included 49 patients with enhancing solid renal mass. All patients were subjected to open NSS during which clamping the renal artery was performed. Twenty-two patients were pretreated with tadalafil 1 day prior NSS and 2 days following surgery. The other 27 patients underwent the same surgical procedure but did not receive tadalafil (controls). Urine samples were collected before surgery and following renal pedicle clamp removal. Urine levels of NGAL and KIM-1, two novel biomarkers for acute kidney injury (AKI), were determined. RESULTS: Clamping the renal artery induced kidney dysfunction as reflected by increases in urinary NGAL and KIM-1 in all participants. These increases in urinary NGAL and KIM-1 excretion were evident 1 h after renal ischemia and lasted for 72 and 24 h, respectively. Pretreatment with tadalafil reduced the absolute urinary excretion of KIM-1, but not of NGAL. Although the incidence of AKI was comparable between tadalafil-treated and untreated NSS subjects, the elevation in serum creatinine (SCr) was significantly attenuated in tadalafil-treated group as compared with NSS controls. CONCLUSIONS: Tadalafil exerts nephroprotective effects in AKI following NSS, as was evident by reduced urinary excretion of KIM-1 and attenuation of SCr elevation. Carefully controlled large clinical studies are needed before defining the role of PDE-5 inhibition therapy in these patients.

The association of predonation hypertension with glomerular function and number in older living kidney donors.

The effect of preexisting hypertension on living donor nephron number has not been established. In this study, we determined the association between preexisting donor hypertension and glomerular number and volume and assessed the effect of predonation hypertension on postdonation BP, adaptive hyperfiltration, and compensatory glomerular hypertrophy. We enrolled 51 living donors to undergo physiologic, morphometric, and radiologic evaluations before and after kidney donation. To estimate the number of functioning glomeruli (NFG), we divided the whole-kidney ultrafiltration coefficient (Kf) by the single-nephron ultrafiltration coefficient (SNKf). Ten donors were hypertensive before donation. We found that, in donors ages >50 years old, preexisting hypertension was associated with a reduction in NFG. In a comparison of 10 age- and sex-matched hypertensive and normotensive donors, we observed more marked glomerulopenia in hypertensive donors (NFG per kidney, 359,499±128,929 versus 558,239±205,152; P=0.02). Glomerulopenia was associated with a nonsignificant reduction in GFR in the hypertensive group (89±12 versus 95±16 ml/min per 1.73 m(2)). We observed no difference in the corresponding magnitude of postdonation BP, hyperfiltration capacity, or compensatory renocortical hypertrophy between hypertensive and normotensive donors. Nevertheless, we propose that the greater magnitude of glomerulopenia in living kidney donors with preexisting hypertension justifies the need for long-term follow-up studies.

Assessment of outcomes in partial nephrectomy incorporating detailed functional analysis.

OBJECTIVE: To assess perioperative morbidity and margins after conventional clamped partial nephrectomy (PN) while also using volumetric analysis to differentiate the contributions of parenchymal volume loss and recovery from ischemia. MATERIALS AND METHODS: The study analyzed 163 patients who underwent PN with appropriate studies to allow analysis of function and parenchymal mass specifically in the operated kidney. Recovery from ischemia (glomerular filtration rate saved/volume saved) would be 100% if all nephrons recovered from ischemia. Precision (postoperative parenchymal volume/predicted parenchymal volume, presuming loss of a 5-mm rim of parenchyma related to excision and reconstruction) reflects efforts to optimize the amount of vascularized parenchyma saved with the PN. Trifecta was defined as negative margins, no Clavien grade 3-5 or urologic complications, and both recovery ≥80% and precision ≥80%. RESULTS: An open procedure was performed in 82 patients (50%), and 59 (36%) had a solitary kidney. Warm ischemia was used in 96 patients (59%). The RENAL nephrometry score (radius, exophytic/endophytic properties of the tumor, nearness of tumor deepest portion to the collecting system or sinus, anterior/posterior descriptor, and the location relative to polar lines) was intermediate in 74 (45%) and high complexity in 38 (23%). Median recovery from ischemia was 95% and was ≥80% in 143 patients (88%). Median precision of excision/reconstruction was 93% and was ≥80% in 138 patients (85%). All tumors had negative surgical margins. Perioperative complications occurred in 13 patients (9%). Trifecta was achieved in 113 patients (69%). Multivariable analysis identified solitary kidney as the only significant predictor of trifecta. CONCLUSION: Given careful patient selection and commensurate surgical expertise, excellent outcomes can be obtained with conventional clamped PN. Analysis of parenchymal volumes is necessary to facilitate comprehensive evaluation of functional outcomes after PN, allowing differentiation of nephron loss vs failure to recover from ischemia.