Comparing ECIRS with MPCNL for Complex Renal Calculi: A Retrospective Single-Centre Study on Efficacy and Safety.

BACKGROUND: Kidney stones, a common urinary system ailment, often necessitate surgical intervention. Endoscopic combined intrarenal surgery (ECIRS) and multi-channel percutaneous nephron lithotripsy (MPCNL) are key modalities for treating complex renal stones, prompting the need for a comparative analysis to enhance clinical decision-making. METHODS: Patients undergoing surgical treatment for complex kidney stones from April 2018 to April 2022 were divided into the control (MPCNL) and observation (ECIRS) groups. Propensity score matching was used to balance baseline data, and t-tests and chi-square tests were employed to compare the perioperative indicators between the two groups. RESULTS: A total of 210 patients were enrolled in this study for pre-observational comparison, and they were divided into the control group (110 patients) and observation group (100 patients). Following matching, each group comprised 85 patients. Pre-observational comparison revealed significant differences between the groups in age, disease duration, and stone diameter (p < 0.05). However, after matching, baseline data comparison showed no statistically significant differences (p > 0.05). Surgery-related parameters, including operation time, intraoperative blood loss, postoperative activity duration and hospital stay, did not significantly differ between the groups (p > 0.05). The observation group exhibited a significantly higher stone retention-free rate after initial treatment compared with the control group (p < 0.05), although overall stone clearance rates did not significantly differ between the groups (p > 0.05). We found no significant differences in perioperative complications between the two groups (p > 0.05). Moreover, the observation group experienced significantly lower postoperative pain levels at 6, 24 and 48 h compared with the control group (p < 0.001). CONCLUSIONS: Conclusively, ECIRS and MPCNL are viable options for treating complex renal calculi, with similar operation times, complication rates and stone clearance rates. ECIRS may offer advantages including lower postoperative pain and higher initial stone clearance rates than MPCNL. However, large-scale studies with long follow-up times are needed for validation.

Management of renal sinus angiomyolipoma: modified robotic nephron-sparing surgery in a single center.

BACKGROUND: Renal sinus angiomyolipoma (RSAML) is a rare and typically complex renal tumor. The objective is to present our single-center experience with a modified technique of robotic nephron-sparing surgery (NSS) for treating RSAML. METHODS: We retrospectively evaluated 15 patients with RSAMLs who were treated with robotic NSS at the Department of Urology of Tongji hospital, ranging from November 2018 to September 2022. Renal vessels and ureter were dissected. The outer part of RSAML was resected. The rest of tumor was removed by bluntly grasp, curettage and suction. Absorbable gelatin sponges were filled in the renal sinus. The preoperative parameters, operative measures and postoperative outcomes were all collected. Follow-up was performed by ultrasonography and estimated glomerular filtration rate (eGFR). RESULTS: Robotic NSS was successfully performed in all the patients, without any conversion to open surgery or nephrectomy. The mean operation time was 134.13 ± 40.56 min. The mean warm ischemia time was 25.73 ± 3.28 min. The median estimated blood loss was 100 [50, 270] ml and 1 patient required blood transfusion. The mean drainage duration was 5.77 ± 1.98 days. The median postoperative hospital stay was 6.90 [5.80, 8.70] days. Two patients experienced postoperative urinary tract infection (Clavien-Dindo Grade II). During the median follow-up of 25.53 ± 15.28 months, patients received 91.18% renal function preservation. No local recurrence occurred in all the patients. CONCLUSIONS: Robotic NSS for RSAML is a complicated procedure that demands technical expertise and a well-designed strategy is critical in the operation. Treating RSAML with modified robotic NSS is safe, effective and feasible.

Klotho is highly expressed in the chief sites of regulated potassium secretion, and it is stimulated by potassium intake.

Klotho regulates many pathways in the aging process, but it remains unclear how it is physiologically regulated. Because Klotho is synthesized, cleaved, and released from the kidney; activates the chief urinary K+ secretion channel (ROMK) and stimulates urinary K+ secretion, we explored if Klotho protein is regulated by dietary K+ and the potassium-regulatory hormone, Aldosterone. Klotho protein along the nephron was evaluated in humans and in wild-type (WT) mice; and in mice lacking components of Aldosterone signaling, including the Aldosterone-Synthase KO (AS-KO) and the Mineralocorticoid-Receptor KO (MR-KO) mice. We found the specific cells of the distal nephron in humans and mice that are chief sites of regulated K+ secretion have the highest Klotho protein expression along the nephron. WT mice fed K+-rich diets increased Klotho expression in these cells. AS-KO mice exhibit normal Klotho under basal conditions but could not upregulate Klotho in response to high-K+ intake in the K+-secreting cells. Similarly, MR-KO mice exhibit decreased Klotho protein expression. Together, i) Klotho is highly expressed in the key sites of regulated K+ secretion in humans and mice, ii) In mice, K+-rich diets increase Klotho expression specifically in the potassium secretory cells of the distal nephron, iii) Aldosterone signaling is required for Klotho response to high K+ intake.

Long-term expandable mouse and human-induced nephron progenitor cells enable kidney organoid maturation and modeling of plasticity and disease.

Nephron progenitor cells (NPCs) self-renew and differentiate into nephrons, the functional units of the kidney. Here, manipulation of p38 and YAP activity allowed for long-term clonal expansion of primary mouse and human NPCs and induced NPCs (iNPCs) from human pluripotent stem cells (hPSCs). Molecular analyses demonstrated that cultured iNPCs closely resemble primary human NPCs. iNPCs generated nephron organoids with minimal off-target cell types and enhanced maturation of podocytes relative to published human kidney organoid protocols. Surprisingly, the NPC culture medium uncovered plasticity in human podocyte programs, enabling podocyte reprogramming to an NPC-like state. Scalability and ease of genome editing facilitated genome-wide CRISPR screening in NPC culture, uncovering genes associated with kidney development and disease. Further, NPC-directed modeling of autosomal-dominant polycystic kidney disease (ADPKD) identified a small-molecule inhibitor of cystogenesis. These findings highlight a broad application for the reported iNPC platform in the study of kidney development, disease, plasticity, and regeneration.

Renal artery pseudoaneurysm following robot assisted nephron sparing surgery: two case reports.

BACKGROUND: Renal artery pseudoaneurysm following partial nephrectomy is a rare entity, the incidence of this entity is more common following penetrating abdominal injuries, percutaneous renal interventions such as percutaneous nephrostomy(PCN) or Percutaneous nephrolithotomy (PCNL). Although rare, renal artery pseudoaneurysm can be life threatening if not managed timely, they usually present within two weeks postoperatively with usual presenting complains being gross haematuria, flank pain and/or anaemia. CASE PRESENTATION: We report case of two female patients 34 and 57 year old respectively of South Asian ethnicity, presenting with renal artery pseudoaneurysm following left sided robot assisted nephron sparing surgery for interpolar masses presenting clinically with total, painless, gross haematuria with clots within fifteen days postoperatively and their successful treatment by digital subtraction angiography and coil embolization. CONCLUSION: Renal artery aneurysm is a rare fatal complication of minimally invasive nephron sparing surgery however considering the preoperative and intraoperative risk factors for its development and prompt suspicion at the outset can be life saving with coil embolization of the bleeding arterial aneurysm.

Preoperative three-dimensional modelling and virtual reality planning aids nephron sparing surgery in a child with bilateral Wilms tumour.

Bilateral Wilms tumour (BWT) is a surgically challenging condition. Virtual reality (VR) reconstruction aids surgeons to foresee the anatomy ahead of Nephron Sparing Surgery (NSS). Three-dimensional (3D) visualisation improves the anatomical orientation of surgeons performing NSS. We herewith report a case of BWT where VR planning and 3D printing were used to aid NSS. Conventional imaging is often found to be inadequate while assessing the tumour-organ-vascular anatomy. Advances like VR and 3D printing help surgeons plan better for complex surgeries like bilateral NSS. Next-generation extended reality tools will likely aid robotic-assisted precision NSS and improve patient outcomes.

Preoperative risk calculator for the probability of completing nephron sparing for kidney cancer.

PURPOSE: In absence of predictive models, preoperative estimation of the probability of completing partial (PN) relative to radical nephrectomy (RN) is invariably inaccurate and subjective. We aimed to develop an evidence-based model to assess objectively the probability of PN completion based on patients' characteristics, tumor's complexity, urologist expertise and surgical approach. DESIGN, SETTING AND PARTICIPANTS: 675 patients treated with PN or RN for cT1-2 cN0 cM0 renal mass by seven surgeons at one single experienced centre from 2000 to 2019. OUTCOMES MEASUREMENTS AND STATISTICAL ANALYSES: The outcome of the study was PN completion. We used a multivariable logistic regression (MVA) model to investigate predictors of PN completion. We used SPARE score to assess tumor complexity. We used a bootstrap validation to compute the model's predictive accuracy. We investigated the relationship between the outcomes and specific predictors of interest such as tumor's complexity, approach and experience. RESULTS: Of 675 patients, 360 (53%) were treated with PN vs. 315 (47%) with RN. Smaller tumors [Odds ratio (OR): 0.52, 95%CI 0.44-0.61; P < 0.001], lower SPARE score (OR: 0.67, 95%CI 0.47-0.94; P = 0.02), more experienced surgeons (OR: 1.01, 95%CI 1.00-1.02; P < 0.01), robotic (OR: 10; P < 0.001) and open (OR: 36; P < 0.001) compared to laparoscopic approach resulted associated with higher probability of PN completion. Predictive accuracy of the model was 0.94 (95% CI 0.93-0.95). CONCLUSIONS: The probability of PN completion can be preoperatively assessed, with optimal accuracy relaying on routinely available clinical information. The proposed model might be useful in preoperative decision-making, patient consensus, or during preoperative counselling. PATIENT SUMMARY: In patients with a renal mass the probability of completing a partial nephrectomy varies considerably and without a predictive model is invariably inaccurate and subjective. In this study we build-up a risk calculator based on easily available preoperative variables that can predict with optimal accuracy the probability of not removing the entire kidney.

[Oncological results of repeat partial nephrectomy in patients with recurrence after nephron-sparing procedures].

AIM: To carried out a comparative analysis of the risk of complications and oncological results of repeat partial nephrectomy and radical nephrectomy in patients with local recurrence after previous organ-sparing procedures. MATERIALS AND METHODS: Retrospective and prospective data of 64 patients with local recurrence of kidney cancer after nephron-sparing procedures. who underwent surgical treatment in the department of oncourology of the National Medical Research Center of Oncology named after N.N. Blokhin in the period from 2000 to 2022. A total of 37 (57.8%) patients of the main group underwent repeat partial nephrectomy, while in 27 (42.2%) patients in the control group a radical nephrectomy was done. Median follow-up was 35 (3-131; Q1-Q3: 13-57) months. Both groups were comparable in terms of demographic and clinical characteristics (p>0.05). The median time to detect relapse after previous partial nephrectomy was 24 (2-172) months. RESULTS: Complications were noted in 8 (21.6%) patients after repeat partial nephrectomy, compared to 29.6% in the control group (n=8) (p=0.563). A comparative analysis revealed a significant advantage in overall survival in patients of the main group (p=0.042). There were no significant differences between groups in cancer-specific and disease-free survival (p=0.369 and p=0.537, respectively). CONCLUSION: Repeat partial nephrectomy for local recurrence of kidney cancer leads to an increase in overall survival compared to radical nephrectomy, in the absence of significant differences in cancer-specific and relapse-free survival.

Risk Factors of Open Surgery Conversion in Laparoscopic Partial Nephrectomy to Achieve Nephron Sparing.

OBJECTIVES: We aimed to evaluate the risk factors for the conversion from laparoscopic partial nephrectomy (LPN) to open surgery to achieve partial nephrectomy (PN). METHODS: Data from patients who underwent LPN between June 2020 and September 2023 were analyzed retrospectively. Patients in whom the PN procedure could be completed laparoscopically were recorded as the 'Fully Laparoscopic' (FL) group (n = 97), and those converted to open surgery from laparoscopy were recorded as the 'Conversion to Open' (CTO) group (n = 10). The demographic and pathologic variables were compared between groups. Regression analyses were used to define predictor factors, and receiver operating characteristic analysis was used to define the cut-off value of the surgical bleeding volume. RESULTS: Conversion to open surgery was found in 10/107 patients (9.3%). There was no statistical difference between groups in demographic and pathologic variables. Intraoperative blood loss volume, upper pole localized tumor, and posterior localized tumor were found to be statistically higher in the CTO group (p = 0.001, p = 0.001, and p = 0.043, respectively). Furthermore, these factors were only found to be statistically significant predictors of conversion to open surgery in both univariate and multivariate regression analyses. 235 cc was found to be the cut-off value of intraoperative blood loss volume for predicting conversion to open surgery (p = 0.001). CONCLUSION: Using these predictive factors in clinical practice, treatment planning will lead to the possibility of starting the treatment directly with open surgery instead of minimally invasive options, and it may also provide a chance of being prepared for the possibility of conversion to open surgery peroperatively.

PIEZO1 is a distal nephron mechanosensor and is required for flow-induced K+ secretion.

Ca2+-activated BK channels in renal intercalated cells (ICs) mediate luminal flow-induced K+ secretion (FIKS), but how ICs sense increased flow remains uncertain. We examined whether PIEZO1, a mechanosensitive Ca2+-permeable channel expressed in the basolateral membranes of ICs, is required for FIKS. In isolated cortical collecting ducts (CCDs), the mechanosensitive cation-selective channel inhibitor GsMTx4 dampened flow-induced increases in intracellular Ca2+ concentration ([Ca2+]i), whereas the PIEZO1 activator Yoda1 increased [Ca2+]i and BK channel activity. CCDs from mice fed a high-K+ (HK) diet exhibited a greater Yoda1-dependent increase in [Ca2+]i than CCDs from mice fed a control K+ diet. ICs in CCDs isolated from mice with a targeted gene deletion of Piezo1 in ICs (IC-Piezo1-KO) exhibited a blunted [Ca2+]i response to Yoda1 or increased flow, with an associated loss of FIKS in CCDs. Male IC-Piezo1-KO mice selectively exhibited an increased blood [K+] in response to an oral K+ bolus and blunted urinary K+ excretion following a volume challenge. Whole-cell expression of BKα subunit was reduced in ICs of IC-Piezo1-KO mice fed an HK diet. We conclude that PIEZO1 mediates flow-induced basolateral Ca2+ entry into ICs, is upregulated in the CCD in response to an HK diet, and is necessary for FIKS.

Profiling Cell Heterogeneity and Fructose Transporter Expression in the Rat Nephron by Integrating Single-Cell and Microdissected Tubule Segment Transcriptomes.

Single-cell RNA sequencing (scRNAseq) is a crucial tool in kidney research. These technologies cluster cells based on transcriptome similarity, irrespective of the anatomical location and order within the nephron. Thus, a transcriptome cluster may obscure the heterogeneity of the cell population within a nephron segment. Elevated dietary fructose leads to salt-sensitive hypertension, in part, through fructose reabsorption in the proximal tubule (PT). However, the organization of the four known fructose transporters in apical PTs (SGLT4, SGLT5, GLUT5, and NaGLT1) remains poorly understood. We hypothesized that cells within each subsegment of the proximal tubule exhibit complex, heterogeneous fructose transporter expression patterns. To test this hypothesis, we analyzed rat kidney transcriptomes and proteomes from publicly available scRNAseq and tubule microdissection databases. We found that microdissected PT-S1 segments consist of 81% ± 12% cells with scRNAseq-derived transcriptional characteristics of S1, whereas PT-S2 express a mixture of 18% ± 9% S1, 58% ± 8% S2, and 19% ± 5% S3 transcripts, and PT-S3 consists of 75% ± 9% S3 transcripts. The expression of all four fructose transporters was detectable in all three PT segments, but key fructose transporters SGLT5 and GLUT5 progressively increased from S1 to S3, and both were significantly upregulated in S3 vs. S1/S2 (Slc5a10: 1.9 log2FC, p < 1 × 10-299; Scl2a5: 1.4 log2FC, p < 4 × 10-105). A similar distribution was found in human kidneys. These data suggest that S3 is the primary site of fructose reabsorption in both humans and rats. Finally, because of the multiple scRNAseq transcriptional phenotypes found in each segment, our findings also imply that anatomical labels applied to scRNAseq clusters may be misleading.

Oligonephronia: another piece in the CKDu jigsaw?

Rates of chronic kidney disease of unknown etiology are high in Aguascalientes, Mexico. Kidneys of adolescents are small by ultrasonography, compatible with oligonephronia, whereas proteinuria and higher estimated glomerular filtration rates and blood pressures among those with relatively higher kidney volumes probably flag relatively greater degrees of compensatory hypertrophy. Glomerulomegaly and podocytopathy, and later segmental glomerulosclerosis in biopsies, suggest a cascade driven by nephron deficiency. Better measures of glomerular number and volume should improve understanding, facilitate risk assessment, and guide interventions.

Robotic transperitoneal versus retroperitoneal approach for anterior renal mass nephron-sparing surgery.

Robotic nephron-sparing surgery is traditionally performed via a transperitoneal (TP) approach. However, the retroperitoneal (RP) approach has gained popularity, particularly for posterolateral renal masses. The RP approach is associated with shorter operative time, less blood loss, and shorter length of stay, while preserving oncologic outcomes in selected masses. Here, we aim to assess the feasibility of the RP approach in excising anterior renal masses. Patients ≥ 18 years of age who underwent robotic nephron-sparing surgery for anterior renal masses were retrospectively identified (2008-2022). Baseline demographics, tumor characteristics, and perioperative data were collected and characterized based on TP vs RP approaches. Wilcoxon rank sum test and Pearson's Chi-squared test were used to compare continuous and categorical variables, respectively. Two hundred and sixteen patients were included-178 (82.4%) underwent TP approach and 38 (17.6%) underwent RP approach. Baseline demographics, preoperative tumor size, and renal nephrometry scores were similar. The RP approach was associated with shorter operative (150 vs 203 min, p < 0.001) and warm ischemia time (12 vs 21 min, p < 0.001), and less blood loss (20 vs 100 cc, p = 0.002) (Table 1). The RP approach was associated with shorter length of stay (1 vs 2 days, p < 0.001) and less total complications (5.3% vs 19.1%, p = 0.038). Major complication (Clavien-Dindo Grade > 3) rates were similar. There was no difference in positive surgical margin rates or pathologic characteristics. Robotic RP approach for nephron-sparing surgery is feasible for eligible anterior tumors and is associated with favorable perioperative outcomes with preserved negative surgical margin rates. Table 1 Patient baseline demographics Overall Transperitoneal Retroperitoneal p value Median/N IQR/% Median/N IQR/% Median/N IQR/% N 216 178 82.4% 38 17.6% Age (years) 60.5 (52.1-67.7) 60.4 (52.8-67.7) 61.6 (49.1-69.2) 0.393 Sex Male 126 58.3% 100 56.2% 26 68.4% Female 90 41.7% 78 43.8% 12 31.6% 0.165 Race White 162 75.0% 137 77.0% 25 65.8% Asian 4 1.9% 2 1.1% 2 5.3% Black 21 9.7% 18 10.1% 3 7.9% Hispanic 26 12.0% 18 10.1% 8 21.1% Other 2 0.9% 2 1.1% 0 0.0% 0.197 Body mass index (kg/m2) < 25 32 14.8% 25 14.0% 7 18.4% 25-30 68 31.5% 55 30.9% 13 34.2% 30-35 60 27.8% 50 28.1% 10 26.3% 35 + 56 25.9% 48 27.0% 8 21.1% 0.808 Prior abdominal surgery Yes 118 54.6% 104 58.4% 14 36.8% No 98 45.4% 74 41.6% 24 63.2% 0.015 Prior kidney surgery Yes 10 4.6% 9 5.1% 1 2.6% No 206 95.4% 169 94.9% 37 97.4% 0.518 Chronic kidney disease stage ≥ 3 Yes 45 20.8% 38 21.3% 7 18.4% No 171 79.2% 140 78.7% 31 81.6% 0.687 Charlson comorbidity index 0 138 63.9% 116 65.2% 22 57.9% 1 46 21.3% 38 21.4% 8 21.1% 2 19 8.8% 13 7.3% 6 15.8% ≥ 3 13 6.0% 11 6.2% 2 5.3% 0.412 Tumor size (cm) 2.7 (2-3.6) 2.8 (2-3.5) 2.55 (2-3.7) 0.796 Tumor laterality Left 100 46.3% 78 43.8% 22 57.9% Right 116 53.7% 100 56.2% 16 42.1% 0.114 Clinical T stage cT1a 186 86.1% 152 85.4% 34 89.5% cT1b 30 13.9% 26 14.6% 4 10.5% 0.509 RENAL Nephrometry score Low (4 to 6) 94 43.5% 76 42.7% 18 47.4% Intermediate (7 to 9) 112 51.9% 94 52.8% 18 47.4% High (≥ 10) 19 4.6% 8 4.5% 2 5.3% 0.829 TE tumor enucleation, SPN standard margin partial nephrectomy, IQR interquartile range.

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.

Identification of a core transcriptional program driving the human renal mesenchymal-to-epithelial transition.

During kidney development, nephron epithelia arise de novo from fate-committed mesenchymal progenitors through a mesenchymal-to-epithelial transition (MET). Downstream of fate specification, transcriptional mechanisms that drive establishment of epithelial morphology are poorly understood. We used human iPSC-derived renal organoids, which recapitulate nephrogenesis, to investigate mechanisms controlling renal MET. Multi-ome profiling via snRNA-seq and ATAC-seq of organoids identified dynamic changes in gene expression and chromatin accessibility driven by activators and repressors throughout MET. CRISPR interference identified that paired box 8 (PAX8) is essential for initiation of MET in human renal organoids, contrary to in vivo mouse studies, likely by activating a cell-adhesion program. While Wnt/ß-catenin signaling specifies nephron fate, we find that it must be attenuated to allow hepatocyte nuclear factor 1-beta (HNF1B) and TEA-domain (TEAD) transcription factors to drive completion of MET. These results identify the interplay between fate commitment and morphogenesis in the developing human kidney, with implications for understanding both developmental kidney diseases and aberrant epithelial plasticity following adult renal tubular injury.

Role of paraoxonase 3 in regulating ENaC-mediated Na+ transport in the distal nephron.

Paraoxonase 3 (PON3) is expressed in the aldosterone-sensitive distal nephron, where filtered Na+ is reabsorbed mainly via the epithelial Na+ channel (ENaC) and Na+ -coupled co-transporters. We previously showed that PON3 negatively regulates ENaC through a chaperone mechanism. The present study aimed to determine the physiological role of PON3 in renal Na+ and K+ homeostasis. Pon3 knockout (KO) mice had higher amiloride-induced natriuresis and lower plasma [K+ ] at baseline. Single channel recordings in split-open tubules showed that the number of active channels per patch was significantly higher in KO mice, resulting in a higher channel activity in the absence of PON3. Although whole kidney abundance of ENaC subunits was not altered in Pon3 KOs, ENaC gamma subunit was more apically distributed within the connecting tubules and cortical collecting ducts of Pon3 KO kidneys. Additionally, small interfering RNA-mediated knockdown of PON3 in cultured mouse cortical collecting duct cells led to an increased surface abundance of ENaC gamma subunit. As a result of lower plasma [K+ ], sodium chloride co-transporter phosphorylation was enhanced in the KO kidneys, a phenotype that was corrected by a high K+ diet. Finally, PON3 expression was upregulated in mouse kidneys under dietary K+ restriction, potentially providing a mechanism to dampen ENaC activity and associated K+ secretion. Taken together, our results show that PON3 has a role in renal Na+ and K+ homeostasis through regulating ENaC functional expression in the distal nephron. KEY POINTS: Paraoxonase 3 (PON3) is expressed in the distal nephron of mouse kidneys and functions as a molecular chaperone to reduce epithelial Na+ channel (ENaC) expression and activity in heterologous expression systems. We examined the physiological role of PON3 in renal Na+ and K+ handling using a Pon3 knockout (KO) mouse model. At baseline, Pon3 KO mice had lower blood [K+ ], more functional ENaC in connecting tubules/cortical collecting ducts, higher amiloride-induced natriuresis, and enhanced sodium chloride co-transporter (NCC) phosphorylation. Upon challenge with a high K+ diet, Pon3 KO mice had normalized blood [K+ ] and -NCC phosphorylation but lower circulating aldosterone levels compared to their littermate controls. Kidney PON3 abundance was altered in mice under dietary K+ loading or K+ restriction, providing a potential mechanism for regulating ENaC functional expression and renal Na+ and K+ homeostasis in the distal nephron.

Engineering physiological environments to advance kidney organoid models from human pluripotent stem cells.

During embryogenesis, the mammalian kidney arises because of reciprocal interactions between the ureteric bud (UB) and the metanephric mesenchyme (MM), driving UB branching and nephron induction. These morphogenetic processes involve a series of cellular rearrangements that are tightly controlled by gene regulatory networks and signaling cascades. Here, we discuss how kidney developmental studies have informed the definition of procedures to obtain kidney organoids from human pluripotent stem cells (hPSCs). Moreover, bioengineering techniques have emerged as potential solutions to externally impose controlled microenvironments for organoid generation from hPSCs. Next, we summarize some of these advances with major focus On recent works merging hPSC-derived kidney organoids (hPSC-kidney organoids) with organ-on-chip to develop robust models for drug discovery and disease modeling applications. We foresee that, in the near future, coupling of different organoid models through bioengineering approaches will help advancing to recreate organ-to-organ crosstalk to increase our understanding on kidney disease progression in the human context and search for new therapeutics.