Search Results (46)

Congenital Anomalies of the Kidney and Urinary Tract (CAKUT) are among the most common congenital malformations and the leading cause of chronic kidney disease in children. They arise when key steps in kidney development are disrupted, including ureteric bud induction, branching morphogenesis and nephron progenitor differentiation. These processes depend on coordinated transcriptional programs, signaling pathways, ciliary function and proper extracellular matrix (ECM) organization. Advances in whole exome and whole genome sequencing, as well as copy number variation analysis, have expanded the spectrum of known monogenic causes. Pathogenic variants have now been identified in major transcriptional regulators and multiple ciliopathy-related genes. Evidence also points to defects in central signaling pathways and changes in ECM composition as contributors to CAKUT pathogenesis. Clinical presentations vary widely, shaped by modifying effects of genetic background, epigenetic regulation and environmental influences such as maternal diabetes and fetal hypoxia. Emerging tools, including human kidney organoids, gene-editing approaches and single-cell or spatial transcriptomics, allow detailed exploration of developmental mechanisms and validation of candidate pathways. Overall, CAKUT reflects a multifactorial condition shaped by interacting genetic, epigenetic and environmental determinants. Integrating genomic data with experimental models is essential for improving diagnosis, deepening biological insight and supporting the development of targeted therapeutic strategies. Full article

Background/Objectives: KRAS mutations in renal cell carcinoma (RCC) are uncommon and most frequently described in papillary renal neoplasm with reverse polarity (PRNRP). Beyond this entity, the broader clinicopathologic and molecular features of KRAS-mutated RCC remain insufficiently characterized. This study aimed to provide a descriptive assessment of KRAS-mutated RCC. Methods: KRAS-mutant RCC patients were identified from the Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Cancer Targets (MSK-IMPACT) and The Cancer Genome Atlas Kidney Renal Papillary Cell Carcinoma (TCGA-KIRP) cohorts. Copy-number alterations were evaluated using Fraction and allele-specific copy number estimates from tumor sequencing (FACETS). Available samples were used for immunohistochemistry and RNA-sequencing analysis. Results: Seventeen patients were included. Three distinct KRAS-mutant RCC subtypes were identified: KRAS-mutant PRCC (35%), KRAS-mutant URCC (35%), and PRNRP (29%). Seven patients (41%) had metastatic disease; none were PRNRP. RNA-based deconvolution analysis revealed that PRNRP had enrichment in distal nephron components, whereas KRAS-mutant PRCC was enriched in proximal tubule cells (p = 0.02). IHC staining of L1CAM was positive in PRNRP but negative in KRAS-mutant PRCC, supporting their distinct cell-of-origin phenotypes. This study is limited by its cohort size, which influences the availability of tissue samples. Conclusions: PRNRP represents a distinct KRAS-mutant RCC subtype with unique metabolic and genomic features linked to its distal nephron origin. This contrasts with the genomic complexity and aggressive clinical behavior observed in KRAS-mutant PRCC and URCC, highlighting the need for subtype-specific diagnostic criteria and therapeutic strategies. Full article

This review aims to highlight how the study of kidney organoids combined with proteomic analysis can deepen our understanding of renal physiology and disease. Proteomics quantifies proteins in a sample, allowing us to determine which proteins are present, how abundant they are, and how they are modified. These data may reveal the pathways that are active in the kidney organoids and how they change in disease, helping to pinpoint candidate biomarkers. Kidney organoids are three-dimensional structures derived from induced pluripotent stem cells (iPS) that recapitulate many architectural and functional features of the adult organ. Because they can be generated in large numbers under defined conditions, organoids provide a promising platform for testing how genetic mutations, environmental stresses, or drugs affect kidney development and pathology. When proteomic profiles are obtained from mature organoids, researchers can directly link protein-level changes to phenotypic outcomes observed in the model. This integration makes it possible to map disease-related networks at the molecular level and to assess the impact of therapeutic interventions in a system that more closely resembles human kidney tissue than traditional cell lines. A current limitation is that many kidney organoids do not reach the full maturation seen in vivo; they often lack complete segmental differentiation and the functional robustness of adult nephrons. Improving the maturation state of organoids will be essential for accurately modeling chronic kidney diseases and for translating findings into clinically relevant therapies. Full article

Introduction: Available guidelines recommend performing nephron-sparing surgery in selected renal cell carcinoma (RCC) patients. Many studies provided robot-assisted partial nephrectomy (RAPN) functional and oncological outcomes, with most of these including a wide timespan and a number of surgeons with different experiences, which might lead to the heterogeneity of the results. In this study, we aim to provide a contemporary report of RAPN patient outcomes performed at two referral centers by experienced surgeons. Materials and Methods: Overall, 333 RAPN patients treated at two European referral centers between 2019 and 2021 were identified. Continuous and categorical variables were reported using medians and proportions. Multi-variable logistic regression (MLR) models were fitted to test predictors of off-clamp technique use and trifecta achievement. Results: The median age was 65 (IQR: 57–73) years. The clinical stage distribution was as follows: 224 (67%) cT1a vs. 89 (26%) cT1b vs. 20 cT2 (7%). The median warm ischemia time was 14 (10–18) minutes, with trifecta being achieved in 74% (n = 240) of patients. In MLR models predicting off-clamp surgery, an increasing R.E.N.A.L. score was independently associated with a lower chance of attempting such a technique (OR: 0.69, p-value < 0.001). In models predicting trifecta achievement, both a higher R.E.N.A.L. score (OR: 0.78, p-value = 0.007) and the presence of multiple lesions (OR: 0.29, p-value = 0.007) were independently associated with lower chances of reaching the outcome. Significant upstaging of chronic kidney disease (CKD) stage was recorded in 9.4% of patients after one year of follow-up. Conclusions: We reported the contemporary outcomes of patients treated with RAPN by highly experienced surgeons from two referral centers. This report represents a valid benchmark that could be used for individual patient counseling in the decision-making process. Full article

Background: This study aimed to investigate the long-term effects of maternal exposure to fine particulate matter (PM_2.5) with or without vitamin D supplementation on the renal microvasculature in adult rat offspring. Methods: Pregnant Sprague–Dawley rats were exposed to normal saline, PM_2.5, and PM_2.5 with vitamin D for one month during nephrogenesis. Male offspring kidneys were taken for analyses on postnatal day 56. Results: Adult offspring rats exposed to maternal PM_2.5 exhibited lower body weights and greater glomerular and tubular injury scores compared to control rats. Semi-quantitative analysis revealed a significant reduction in glomerular and peritubular capillary endothelial cells, along with a decrease in the number of glomeruli in the PM_2.5 group. Maternal vitamin D supplementation reduced these changes. In offspring rats exposed to maternal PM_2.5, intrarenal expression of renin, angiotensin-converting enzyme (ACE), cytochrome P450 27B1, and vascular endothelial growth factor-A (VEGF-A) increased, while expression of the vitamin D receptor, Klotho, VEGF receptor 2, angiopoietin-1, and Tie-2 decreased. Maternal vitamin D supplementation restored VEGF receptor 2 and angiopoietin-1 activities and reduced ACE and VEGF-A protein expression in adult offspring kidneys. Conclusions: Early-life exposure to PM_2.5 may lead to long-term alterations in renal microvasculature and nephron loss. Maternal vitamin D supplementation during renal development can ameliorate PM_2.5-induced capillary rarefaction and nephron loss in the kidneys of adult offspring. Full article

Down syndrome (DS), the most common survivable autosomal aneuploidy, is associated with a high prevalence of congenital anomalies of the kidney and urinary tract (CAKUT), significantly increasing the risk of chronic kidney disease (CKD). This review examines the diversity of CAKUT phenotypes reported in individuals with DS, focusing on anomalies affecting the kidney, ureter, bladder, and urethra. According to available literature, hydronephrosis is the most common renal anomaly, often secondary to other CAKUT phenotypes, followed by renal hypoplasia and glomerulocystic disease. Furthermore, obstructive uropathies are also frequent but usually lack detailed characterization in the literature. Key features of CAKUT in DS, including reduced kidney size, renal cystic diseases, acquired glomerulopathies, reduced nephron number, and immature glomeruli heighten the risk of CKD. Also, early detection of lower urinary tract dysfunction (LUTD) is critical to prevent progressive upper urinary tract damage and CKD. Despite the prevalence of CAKUT in DS, reported between 0.22% and 21.16%, there is a lack of standardized diagnostic criteria, consistent terminology, and extended follow-up studies. Systematic screening from infancy, including regular renal monitoring via urinalysis and ultrasound, plays a critical role in the timely diagnosis and intervention of CAKUT. To further enhance diagnostic accuracy and develop effective therapeutic strategies, increased awareness and focused research into the genetic factors underlying these anomalies are essential. Moreover, a multidisciplinary approach is indispensable for managing CAKUT and its associated complications, ultimately ensuring better long-term outcomes and an improved quality of life for individuals with DS. Full article

Chronic kidney disease (CKD) is a widespread condition often resulting from multiple factors, including maternal influences. These risk factors not only heighten the likelihood of developing CKD but increase the risk of a preterm birth. Adverse events during nephrogenesis can disrupt kidney development, leading to a reduced number of nephrons. As survival rates for preterm infants improve, more individuals are living into adulthood, thereby elevating their risk of CKD later in life. This review aims to explore the connections between preterm birth, kidney development, and the increased risk of CKD, while proposing practical solutions for the future through a multidisciplinary approach. We examine human studies linking preterm birth to negative kidney outcomes, summarize animal models demonstrating kidney programming and reduced nephron numbers, and consolidate knowledge on common mechanisms driving kidney programming. Additionally, we discuss factors in the postnatal care environment that may act as secondary insults contributing to CKD risk, such as acute kidney injury (AKI), the use of nephrotoxic drugs, preterm nutrition, and catch-up growth. Finally, we outline recommendations for action, emphasizing the importance of avoiding modifiable risk factors and implementing early CKD screening for children born preterm. Together, we can ensure that advancements in kidney health keep pace with improvements in preterm care. Full article

The original UT-1 transporter gene was initially identified in the spiny dogfish (Squalus acanthias), but localization of the UT-1 protein was not determined. Subsequent UT-1 expression was shown to localize to the collecting tubule (CT) of the shark nephron in other shark species, with expression in a closely related chimaera species also located additionally at a lower level in the intermediate-I segment (IS-I) of the nephron. In spiny dogfish, two UT-1 splice variants are known (UT-1 long and short), and there was also a second UT-1 gene described (here termed Brain UT). In this study, a second splice variant of the second Brain UT gene was discovered. Expression profiles (mRNA) of UT-1 long and short and Brain UT were determined in a number of spiny dogfish tissues. Quantitative PCR in kidney samples showed that the level of the short variant of UT-1 was around 100 times higher than the long variant, which was itself expressed around 10 times higher than Brain UT cDNA/mRNA (in kidney). For the long variant, there was a significantly higher level of mRNA abundance in fish acclimatized to 75% seawater. Ultimately, three UT-1 antibodies were made that could bind to both the UT-1 short and long variant proteins. The first two of these showed bands of appropriate sizes on Western blots of around 52.5 and 46 kDa. The second antibody had some additional lower molecular weight bands. The third antibody was mainly bound to the 46 kDa band with faint 52.5 kDa staining. Both the 52.5 and 46 kDa bands were absent when the antibodies were pre-blocked with the peptide antigens used to make them. Across the three antibodies, there were many similarities in localization but differences in subcellular localization. Predominantly, antibody staining was greatest in the intermediate segment 1 (IS-I) and proximal (PIb) segments of the first sinus zone loop of the nephron, with reasonably strong expression also found at the start and middle of the late distal tubule (LDT; second sinus zone loop). While some expression in the collecting tubule (CT) could not be ruled out, the level of staining seemed to be low or non-existent in convoluted bundle zone nephron segments such as the CT. Hence, this suggests that spiny dogfish have a fundamentally different mode of urea absorption in comparison to that found in other shark species, potentially focused more on the nephron sinus zone loops than the CT. Full article

Nephron sparing surgery (NSS) is considered for selected cases of upper tract urothelial carcinoma (UTUC) as it maintains renal function and avoids morbidity associated with radical nephroureterectomy (RNU). The appropriate selection of patients suitable for NSS without compromising oncological outcomes can sometimes be difficult, given the limitations of diagnostic modalities. Recurrence rates for UTUC can be as high as 36 to 54% after NSS. Intraluminal adjuvant therapy can be attempted following NSS to reduce recurrence, but delivery to the upper tract is more challenging than into the bladder. Bacillus Calmette-Guerin (BCG) and chemotherapy such as Mitomycin (MMC) have been administered via nephrostomy or ureteric catheter, which requires invasive/repeated instrumentation of the upper urinary tract. Drug delivery by reflux from bladder instillation along indwelling stents has also been tried but can potentially be unreliable. Recently, a gel formulation of mitomycin has been developed for the controlled exposure of the upper urinary tract to treatment over a number of hours. Drug-eluting stents to deliver chemotherapy to the upper urinary tract have been developed but have not yet entered clinical practice. Endoluminal phototherapy utilising an intravenous photosensitising agent is another novel approach that has recently been described. Intraluminal therapies may be beneficial in decreasing recurrence rates in UTUC, but currently have some limitations in their usage. Full article

Autosomal dominant polycystic kidney disease (ADPKD) is an inherited disorder characterized by renal tubular cystic dilatations. The cysts can develop anywhere along the nephron, and over time the cystic dilatation leads to kidney enlargement. On the other hand, the cysts begin to reduce the number of functional nephrons as a consequence of cystic expansion that further contributes to the decline in renal function over the years. The pressure exerted by the dilated cysts leads to compensatory mechanisms that further contribute to the decline in renal function. These structural changes are responsible of glomerular hyperfiltration states, albuminuria, proteinuria, and hematuria. However, the presentation of ADPKD varies in children, from a completely asymptomatic child with incidental ultrasound detection of cysts to a rapidly progressive disease. There have been reports of early onset ADPKD in children younger than 2 years that showed a more rapid decline in renal function. ADPKD is caused by a mutation in PKD1 and PKD2 genes. Today, the PKD1 gene mutation seems to account for up to 85% of the cases worldwide, and it is associated with worse renal outcomes. Individuals with PKD2 gene mutation seem to present a milder form of the disease, with a more delayed onset of end-stage kidney disease. The cardinal sign of ADPKD is the presence of renal cysts during renal ultrasound. The current guidelines provide clinicians the recommendations for genetic testing in children with a positive family history. Given that the vast majority of children with ADPKD present with normal or supra-normal kidney function, we explored the glomerular filtration rates dynamics and the renal ultrasound-adjusted percentiles. In total, 14 out of 16 patients had kidney percentiles over 90%. The gene mutations were equally distributed among our cohort. In addition, we compared the modified Schwartz formula to the quadratic equation after adjusting the serum creatinine measurements. It seems that even though children with ADPKD have enlarged kidneys, the renal function is more likely normal or near normal when the quadratic estimation of glomerular filtration rate is used (qGFR tended to be lower, 111.95 ± 12.43 mL/min/1.73 m² when compared to Schwartz eGFR 126.28 ± 33.07 mL/min/1.73 m², p = 0.14). Also, when the quadratic equation was employed, not even a single patient reached the glomerular hyperfiltration threshold. The quadratic formula showed that glomerular filtration rates are linear or slightly decreasing after 1 year of follow-up (quadratic ΔeGFR = −0.32 ± 5.78 mL/min/1.73 m²), as opposed to the Schwartz formula that can falsely classify children in a hyperfiltration state (ΔeGFR = 7.51 ± 19.46 mL/min/1.73 m²), p = 0.019. Full article

Background/Objectives: The absence of validated tools to assess the skill transfer from laparoscopy to robotic surgery remains an unsolved issue in the context of robot-assisted partial nephrectomy (RAPN). We aimed to describe and validate a novel proficiency score to critically evaluate the surgical quality of RAPN with the Hugo™ RAS System (Medtronic, Minneapolis, MN, USA). Methods: Between October 2022 and September 2023, 27 consecutive patients underwent off-clamp RAPN for localized renal tumors at our institution. To analyze the learning curve (LC), the cohort was chronologically divided into two phases of 6 months each. Proficiency was defined as the achievement of trifecta while maintaining a comparable intraoperative time in the interquartile range of laparoscopic partial nephrectomy performed by the same surgeon. A logistic binary regression model was built to identify predictors of proficiency achievement. Results: A proficiency score was achieved in 14 patients (74.1%). At univariable analysis, number of consecutive procedures > 12 (OR 13.7; 95%CI 2.05–21.1, p = 0.007), pathological tumor size (OR 0.92; 95%CI 0.89–0.99, p = 0.04) and essential blood hypertension (OR 0.16; 95%CI 0.03–0.82, p = 0.02) were found to be predictors of proficiency score. At multivariable analysis, after adjusting for potential confounding factors, number of consecutive procedures > 12 (OR 8.1; 95%CI 1.44–14.6, p = 0.03) was the only independent predictor of proficiency score achievement. Conclusions: Our results showed that the skills of an experienced laparoscopic surgeon are transferrable to the novel Hugo™ RAS System in the context of nephron-sparing surgery. Improved surgical quality may be expected after completing the first 12 consecutive procedures. Full article

MicroRNAs (miRNAs) and long non-coding RNAs (lncRNAs) are two crucial classes of transcripts that belong to the major group of non-coding RNAs (ncRNAs). These RNA molecules have significant influence over diverse molecular processes due to their crucial role as regulators of gene expression. However, the dysregulated expression of these ncRNAs constitutes a fundamental factor in the etiology and progression of a wide variety of multifaceted human diseases, including kidney diseases. In this context, over the past years, compelling evidence has shown that miRNAs and lncRNAs could be prospective targets for the development of next-generation drugs against kidney diseases as they participate in a number of disease-associated processes, such as podocyte and nephron death, renal fibrosis, inflammation, transition from acute kidney injury to chronic kidney disease, renal vascular changes, sepsis, pyroptosis, and apoptosis. Hence, in this current review, we critically analyze the recent findings concerning the therapeutic inferences of miRNAs and lncRNAs in the pathophysiological context of kidney diseases. Additionally, with the aim of driving advances in the formulation of ncRNA-based drugs tailored for the management of kidney diseases, we discuss some of the key challenges and future prospects that should be addressed in forthcoming investigations. Full article

In diabetes, possibly the most significant site of microvascular damage is the kidney. Due to diabetes and/or other co-morbidities, such as hypertension and age-related nephron loss, a significant number of people with diabetes suffer from kidney diseases. Improved diabetic care can reduce the prevalence of diabetic nephropathy (DN); however, innovative treatment approaches are still required. MicroRNA-21 (miR-21) is one of the most studied multipotent microRNAs (miRNAs), and it has been linked to renal fibrosis and exhibits significantly altered expression in DN. Targeting miR-21 offers an advantage in DN. Currently, miR-21 is being pharmacologically silenced through various methods, all of which are in early development. In this review, we summarize the role of miR-21 in the molecular pathogenesis of DN and several therapeutic strategies to use miR-21 as a therapeutic target in DN. The existing experimental interventions offer a way to rectify the lower miRNA levels as well as to reduce the higher levels. Synthetic miRNAs also referred to as miR-mimics, can compensate for abnormally low miRNA levels. Furthermore, strategies like oligonucleotides can be used to alter the miRNA levels. It is reasonable to target miR-21 for improved results because it directly contributes to the pathological processes of kidney diseases, including DN. Full article

Nephrons are the functional units which comprise the kidney. Each nephron contains a number of physiologically unique populations of specialized epithelial cells that are organized into discrete domains known as segments. The principles of nephron segment development have been the subject of many studies in recent years. Understanding the mechanisms of nephrogenesis has enormous potential to expand our knowledge about the basis of congenital anomalies of the kidney and urinary tract (CAKUT), and to contribute to ongoing regenerative medicine efforts aimed at identifying renal repair mechanisms and generating replacement kidney tissue. The study of the zebrafish embryonic kidney, or pronephros, provides many opportunities to identify the genes and signaling pathways that control nephron segment development. Here, we describe recent advances of nephron segment patterning and differentiation in the zebrafish, with a focus on distal segment formation. Full article