Compared with cancers of other organs, precursor lesions of renal cell neoplasms are rarely discussed. However, there are specific scenarios where cysts or microscopic solid lesions are thought to precede tumor formation. In 2024, the International Society of Urological Pathology (ISUP) held a consensus meeting on precursor lesions of urologic neoplasms in Florence, Italy. This report details the findings of Working Group 3-Precursor Lesions of the Kidney. Papillary adenoma is likely the best-established precursor lesion in the kidney, thought to be an incipient form of papillary renal cell carcinoma (RCC) with shared morphology, immunohistochemistry, and genetics. Likewise, in patients with VHL disease, the kidney often contains multiple small nodules of clear cells and/or cysts lined by one or more layers of clear cells, likely representing early tumor or precursor lesions. Interestingly, a precursor counterpart for clear cell RCC in the sporadic setting is not well established. In other scenarios, cysts are considered potential precursors of neoplasia, such as those in acquired cystic kidney disease (ACKD) and possibly in some hereditary renal tumor syndromes. The consensus panel proposes the following terms "cyst with epithelial proliferation" for tufted/hyperplastic/cribriform cyst lining in ACKD without solid tumor, and "papillary hyperplasia" for tufting of cyst lining in autosomal dominant polycystic kidney. Terms such as "tumorlet," "microtumor," or "incipient tumor" are acceptable for incidental unencapsulated microscopic lesions in hereditary syndrome patients. There is insufficient evidence for the diagnosis of "tubular dysplasia" as a precursor to RCC at the present time.

Renal pathology is common in childhood. Imaging plays a critical role in the diagnosis of kidney diseases and encompasses a range of modalities. Advanced imaging is typically performed in specialised paediatric hospitals, where experienced paediatric radiologists are familiar with the relevant techniques, protocols, indications, and limitations. However, children are often first admitted to general hospitals, where radiologists may have more limited experience in paediatric imaging. Renal cysts in children differ from those in adults, most commonly presenting as cystic kidney diseases. In the majority of cases, ultrasound (US) is the sole diagnostic modality required. Imaging is not necessary for the diagnosis of urinary tract infection (UTI), but it is essential for detecting underlying anomalies and potential complications. Urinary tract dilatation is a common finding in children; however, only up to 30% of cases require further evaluation to diagnose urinary tract obstruction or vesicourinary reflux. Urolithiasis is relatively uncommon in children and is primarily diagnosed with US, although computed tomography (CT) may occasionally be necessary. Solid renal lesions identified on US should be further evaluated in highly specialised paediatric centres. Mild to moderate renal trauma can be diagnosed and monitored using US, whereas CT remains the modality of choice for assessing severe trauma. CLINICAL RELEVANCE STATEMENT: This review provides general radiologists with a comprehensive overview of the normal renal appearance across paediatric age groups, including normal variants and imaging pathways for the most common renal pathologies in children. It also highlights scenarios where referral to specialised paediatric centres is necessary. KEY POINTS: US is the first-line imaging modality for diagnosing most renal pathologies in children. MRI is used in a variety of situations (e.g. complex congenital anomalies of the kidney and urinary tract, or focal lesions) when US is not sufficient. CT is reserved for emergencies and in selected cases of urolithiasis. Knowledge of normal renal features, including normal anatomical and morphological variants across different age groups, is essential.

Accumulating evidence supports a direct contribution of abnormalities in phosphate homeostasis to progression of polycystic kidney disease (PKD); however, the mechanisms for these relationships remain undefined. A universal feature of nephron loss in all forms of kidney disease is increased urinary phosphate excretion by residual functional nephrons that helps to maintain systemic phosphate balance. To date, no studies have examined the direct contribution of urinary phosphate to kidney pathology in PKD. We first examined the impact of dietary phosphate on kidney outcomes in Pkd1RC/RC mice, an orthologous murine model of PKD. Next, to more specifically delineate the direct contribution of urinary phosphate to kidney pathology, we characterized kidney phenotypes in phosphaturic Slc34a1-/- mice. We then investigated how increasing urinary phosphate excretion through Slc34a1 deletion impacted cystic kidney disease progression in Pkd1RC/RC mice. Finally, to define the relevance of our findings to human PKD, we conducted high-resolution imaging and trace mineral analysis of human PKD and control kidney specimens to assess the prevalence and composition of sub-clinical mineral deposition. Pkd1RC/RC mice fed a high phosphate diet exhibited kidney injury with activation of early fibrosis pathways, accelerated cyst growth, and phosphate-based crystal deposition that spatially colocalized with macrophages. Slc34a1-/- mice demonstrated extensive nephrocalcinosis, tubular microcyst formation, and evidence of early kidney injury, inflammation, and fibrosis. Moreover, compound mutant Pkd1RC/RC, Slc34a1-/- mice had increased kidney cyst burden accompanied by reduced kidney function compared to Pkd1RC/RC, Slc34a1+/+ controls. Finally, µCT and trace mineral analyses of human kidneys revealed consistent deposition of calcium-phosphate microcrystals in PKD kidneys. Increased urinary phosphate excretion directly contributes to kidney injury, cyst formation/growth, inflammation, and fibrosis. Urinary phosphate excretion and tubular mineral solubility may represent novel therapeutic targets for slowing PKD progression in humans.

BACKGROUND Renal cysts and diabetes syndrome (RCAD), caused by heterozygous variants or whole-gene deletions in the HNF1B gene, is a rare, multisystem disorder often detected prenatally by ultrasound findings of bilateral cystic or hyperechogenic kidneys. CASE REPORT We present the case of a 21-year-old woman (G3P2) at 19 weeks of gestation referred for detailed fetal evaluation due to bilateral hyperechogenic, polycystic kidneys and severe oligohydramnios. After counselling, an amnioinfusion was performed to enable amniocentesis and cytogenetic testing. Chromosomal microarray analysis identified a 1.4 Mb interstitial deletion at 17q12 (arr 17q12(34,850,785_36,248,926)x1), encompassing the HNF1B gene and consistent with RCAD syndrome. Family history revealed maternal renal cysts and paternal early-onset diabetes. Despite conservative management and monitoring, the pregnancy was complicated by intrauterine infection, leading to fetal death. CONCLUSIONS This case report expands the spectrum of prenatal findings associated with RCAD and emphasizes the importance of integrating ultrasonographic, genetic, and familial data in the diagnostic pathway. Chromosomal microarray analysis remains a pivotal tool for prenatal detection of HNF1B deletions and for differentiating RCAD from other cystic kidney diseases, such as autosomal recessive polycystic kidney disease (ARPKD) and autosomal dominant polycystic kidney disease (ADPKD), which require targeted gene sequencing. Recognition of RCAD in the prenatal setting enables precise counselling, recurrence risk assessment, and postnatal follow-up planning for affected families.

Pathogenic variants in the HNF1B gene cause a multi system disorder encompassing organ abnormalities-primarily affecting the kidneys and pancreas-as well as metabolic disturbances, collectively referred to as HNF1B-related disease. While maturity-onset diabetes of the young type 5 is a well-recognized manifestation, neonatal diabetes mellitus (NDM) associated with HNF1B is exceedingly rare, and has only been reported in patients harboring single nucleotide variants. We describe two unrelated female children presenting with transient NDM caused by a complete HNF1B gene deletion. Both developed hyperglycemia within the first days of life requiring short-term insulin therapy, followed by spontaneous normalization of glycemia. However, their subsequent phenotypes diverged significantly. The first patient exhibited bilateral renal dysplasia while maintaining normal neurodevelopment. In contrast, the second patient developed later-onset cystic kidney disease, neurodevelopmental delay, and dysmorphic features, consistent with a broader 17q12 deletion syndrome spectrum. Although, in both cases, kidney abnormalities and extra-renal features (NDM, hypomagnesemia, hyperuricemia) were observed, both patients experienced a delay in diagnosis. On follow-up, serial oral glucose tolerance tests (OGTT), HbA1c assessments, and glucagon stimulation tests to date demonstrated preserved β-cell function, with the exception of hyperglycemia in 30-60 min of the extended OGTT in one patient. These two cases represent the first report of transient NDM due to HNF1B deletion. Our findings broaden the molecular and clinical spectrum of HNF1B-related diabetes, and emphasize the importance of considering HNF1B defects in children with transient neonatal hyperglycemia.

Chronic kidney disease (CKD) increases the risk of renal cell carcinoma (RCC), particularly with long-term dialysis exposure and acquired cystic kidney disease (ACKD). At the same time, CKD-related architectural distortion and hypoperfusion reduce lesion conspicuity on ultrasound and weaken enhancement-based interpretation on CT and MRI. In advanced CKD, restrictions on iodinated and gadolinium-based contrast agents further increase the proportion of renal masses that remain indeterminate after conventional imaging. Contrast-enhanced ultrasound (CEUS) addresses the key unmet need in this setting: a safe, direct assessment of microvascular perfusion. Microbubble agents are purely intravascular and non-nephrotoxic, enabling use across all CKD stages and in dialysis patients. By showing real-time enhancement of septa, wall thickening and mural nodules, CEUS distinguishes vascular tumour components from avascular hemorrhagic or proteinaceous material that can mimic enhancement on CT/DECT or signal abnormalities on non-contrast MRI. This capability supports a CEUS-adapted Bosniak approach: lesion categorization is driven by enhancement of septa, wall and nodules rather than by attenuation or T1 hyperintensity of cyst contents, helping avoid misclassification in ACKD. We propose a structured workflow that integrates the triad of CKD stage/eGFR, dialysis status and ACKD with pre- and post-CEUS Bosniak assessment to guide follow-up versus biopsy or nephron-sparing treatment. This article is a narrative review of the literature, complemented by an illustrative clinical case which demonstrates how CEUS can resolve ambiguity when CT/DECT and non-contrast MRI remain inconclusive.

In a cohort of children, 79% of families with kidney cysts had a monogenic diagnosis. Resolved cases were more likely to have a family history of kidney cysts and unresolved cases more often had unilateral cysts. Broad genetic testing revealed genetic diversity and informed prognosis and clinical management in childhood kidney cysts. Pediatric kidney cysts may indicate an underlying genetic disorder, yet the full spectrum of causes remains incompletely defined. With advances in genetic testing enabling broader evaluation, this study assessed the diagnostic utility of comprehensive genetic testing in a broad pediatric cohort with kidney cysts and characterized the underlying etiological diversity. This observational cohort study included patients younger than 18 years enrolled between January 2020 and June 2024 at a single tertiary center. Genetic testing used targeted multigene or custom curated exome/genome sequencing panels, with segregation analysis when available. Eligible participants had at least two cysts without family history, one cyst with positive family history, or enlarged echogenic kidneys on prenatal ultrasound; those with congenital anomalies of the kidney and urinary tract associated with cysts were excluded. Clinical presentation was categorized as symptomatic, incidental, prenatal, or family screening. Primary outcomes were diagnostic yield and distribution of pathogenic variants. Among 109 patients (median age 7.6 years, 53% female), genetic testing identified a definitive diagnosis in 81 of 100 tested patients (81%) from 72 families (79%; 14 disorders). PKD1 variants were most common (45%), while PKD2 accounted for 7%. Other causes included HNF1B or 17q12 deletions (13%), minor autosomal dominant polycystic kidney disease genes (11%; GANAB, NEK8, IFT140 ), monoallelic PKHD1 (3%), and biallelic PKHD1 (8%), while syndromic ciliopathy genes accounted for 5%. A positive family history of cystic kidney disease was more common among patients with a genetic diagnosis (54% versus 11%; P = 0.008). Patients without an identified genetic diagnosis more often had unilateral cysts (26% versus 4%; P = 0.53). Diagnosis by clinical symptoms was the most genetically diverse category. Comprehensive genetic testing in pediatric kidney cysts achieved high diagnostic yield in a selected cohort and identified diverse causes beyond major autosomal dominant polycystic kidney disease/autosomal recessive polycystic kidney disease genes, supporting early evaluation to improve diagnostic accuracy, inform prognosis, and guide management, even in the absence of family history.

Background: Monoallelic pathogenic variants in GANAB cause autosomal dominant cystic kidney and liver disease, but quantitative imaging phenotypes remain incompletely defined. Methods: We performed a retrospective study of 16 individuals with GANAB variants and available abdominal imaging. Deep learning-based cyst segmentation quantified kidney and liver volumes and cyst metrics, including height-adjusted total kidney volume (htTKV), height-adjusted total liver volume, total cyst number (TCN), and height-adjusted total cyst volume. Results: Hepatic involvement was common, with polycystic liver disease present in most individuals with varying severity (liver TCN range 22–219). Kidney involvement was more heterogeneous (htTKV range 153–858 mL/m; kidney TCN range 3–42). Individuals with kidney TCN <20 had preserved kidney function and slower annual estimated glomerular filtration rate (eGFR) decline (median −1.68 mL/min/1.73 m2) compared with those with kidney TCN ≥20 (−2.8 mL/min/1.73 m2/year); no individual progressed to kidney failure during follow-up. Hypertension occurred in 50%. Intracranial aneurysms were identified in 3 of 6 screened individuals, including two from a family with known aneurysmal disease. Conclusions: Quantitative imaging reveals a phenotypic spectrum in ADPKD-GANAB, ranging from liver-predominant cystic disease with minimal kidney involvement to a phenotype with higher kidney cyst burden and faster eGFR decline. Establishing robust genotype-phenotype relationships in this rare disease will require larger, aggregated cohorts with standardized imaging and systemic extrarenal screening.

In this issue, Takahashi, Tanaka, and colleagues provide a comprehensive genomic, transcriptomic, and spatial analysis of renal cell carcinomas (RCC) associated with end-stage renal disease. They demonstrate that the clonal expansion of a subset of proximal tubule cells, supported by an inflammatory microenvironment, gives rise to the cysts of acquired cystic kidney disease as well as to acquired cystic disease-associated RCC. See related article by Takahashi et al., p. 478.

Genetic testing in kidney transplantation and living kidney donor risk assessment.

This study investigates the biomechanical properties of primary cilia in healthy kidneys and an early-stage cystic kidney model (CKM), focusing on their role in flow-mediated mechanosensation. Morphological analysis showed that CKM cilia are longer, more curved, and exhibit disrupted axonemal integrity compared with normal cilia. To evaluate the effect of such structural changes on bending and stiffness, which may affect the drag force, shear stress and PC1/PC2 complex activation, we developed a mathematical model simulating urine-flow-induced drag. The model predicts that longer and curved cilia experience only one-fourth of the drag force of shorter and straight cilia under identical flow conditions. Remarkably, addition of 5% glucose to drinking water, which was reported to increase water intake, was predicted by the model to elevate urine flow to levels sufficient to partially normalize ciliary length and tubular morphology in CKM kidneys. These findings indicate that ciliary deformation impairs mechanosensation, contributing to cystogenesis, and that restoring mechanical stimulation may mitigate disease progression. Beyond estimating the urine volume required for therapeutic effect, the model offers a framework for developing interventions targeting ciliary mechanotransduction, which could be particularly useful when fluid-loading strategies are not feasible. This approach highlights the potential of combining morphological analysis, biophysical modeling, and mechanobiology to better understand and treat early cystic kidney disease.

Glomerulocystic renal disease has numerous etiologies, including HNF1B mutations. In addition to cysts, morphologic renal findings in a setting of HNF1B mutations include cystic renal dysplasia, solitary functioning kidney, horseshoe kidney, and oligomeganephronia. Embryonal hyperplasia resembling nephrogenic rests has been reported in rare cases of glomerulocystic disease, but none have been genetically characterized. We report a case of bilateral glomerulocystic kidney disease (GCKD) showing extensive embryonal hyperplasia in a setting of germline HNF1B mutation with progressive renal failure. Explant showed numerous epithelial proliferations throughout the intervening stroma. GCKD may be seen in a setting of HNF1B mutation; however, the additional finding of extensive embryonal hyperplasia in a case with a known mutation has never been reported. Reports of similar embryonal hyperplasia, associated with either cystic kidney disease or other disease processes, appear to represent a heterogeneous population of presentations and etiologies, though there is sufficient evidence to suggest that this is a finding, that is, recurrently associated with cystic kidney diseases. The underlying pathobiology of embryonal hyperplasia and the neoplastic potential in this setting is unknown. We report this case to highlight a novel combination of morphologic and genetic findings in GCKD and to raise awareness of this rare finding.

Polycystic kidney disease (PKD) is a Mendelian renal disease characterised by the development of cysts and progressive decline in kidney function, leading to kidney failure. Although genetic testing can provide a precise molecular diagnosis of PKD in the majority of cases, 6-13% of patients remain unsolved. Copy number variants (CNVs) are an established pathogenic mechanism in PKD, however detection typically relies on multiplex ligation-dependent probe amplification (MLPA) which is resource intensive and separate to next-generation sequencing (NGS) pipelines. Here, a bioinformatics tool ClinCNV was used to call CNVs from NGS data of 371 people with PKD who had previously undergone short nucleotide variant (SNV) analysis with a standard NGS pipeline. Diagnostic CNVs were confirmed in 13 patients across 7 families, increasing the diagnostic yield from 86.5 to 90.0%. We also tested CNVs as potential disease modifiers. Regression models indicated an association of cystic gene duplication burden to worse kidney survival (HR = 1.56, 95% CI: 1.26, 1.93, adj-p = 0.0004). These models also revealed that duplication burden in genes unrelated to cystic kidney disease associated with the absence of liver cysts, possibly driven by a region containing LRP5L. These results demonstrate the utility of targeted gene panel and exome sequencing for the detection of CNVs in key PKD genes.

Genomic investigation is playing an increasing role in the management of cystic kidney diseases, reflecting a broader shift towards precision medicine in Nephrology. Recent updates to the KDIGO Clinical Practice Guideline emphasize diagnostic genomics as a core component of Autosomal Dominant Polycystic Kidney Disease (ADPKD) care in particular, recognizing its utility across a range of clinical scenarios. Traditionally, diagnosis of ADPKD has been clinical, using age-dependent imaging criteria for at risk individuals via ultrasound and Magnetic Resonance Imaging (MRI). While these imaging modalities have good sensitivity, there are pitfalls in clinical diagnosis, particularly in patients with atypical clinical features, those without family history or those at a young age. A confirmed genetic diagnosis can guide screening of at-risk family members, inform reproductive decisions, support safe selection of living-related kidney donors and provide the opportunity to utilize genotype-specific prognostication tools. In addition, as genotype-specific therapies enter the landscape, accurate genotyping will become essential for identifying which patients will benefit from treatment. This narrative review aims to provide a practical approach for the general Nephrologist of when to offer genetic testing to patients with cystic kidney disease and outline the technical and genetic counselling considerations in the provision of patient-centered genetic investigation.

Cystic kidney disease and related ciliopathies are caused by pathogenic variants in genes that commonly result in ciliary dysfunction. For a substantial number of individuals affected by those cilia-related diseases, the causative gene remains unknown. Using massively parallel sequencing, we here identified a pathogenic bi-allelic variant in the gene encoding PALS1-associated tight junction protein ([PATJ] also known as inactivation-no-afterpotential D-like, INADL) in an individual with ciliopathy. The affected fetus carried the homozygous truncating PATJ nonsense variant c.830delC (p.Pro277fsX), and presented with a syndromic phenotype mainly characterized by polycystic kidney disease and hydrocephalus. Using zebrafish (Danio rerio) as a vertebrate in vivo model organism, we could validate our patient findings and demonstrated a ciliopathy phenotype. In addition, we were able to address a hitherto not described role of Patj for cilia formation and function. Taken together, with the Crumbs cell polarity complex member PATJ, we add a new member to the large family of ciliopathy-related human disease proteins that is different from the classical ciliopathy protein classes, and may offer new perspectives for drug development.

Renal transplantation (RTx) is the preferred treatment for end-stage renal disease (ESRD), reducing mortality and improving quality of life. However, long-term immunosuppression increases the risk of malignancy, with renal cell carcinoma (RCC) occurring in approximately 0.6%-0.7% of renal transplant recipients, most commonly arising in the native kidneys. Bilateral RCC is rare and is typically associated with papillary histology and acquired cystic kidney disease (ACKD). A 16-year-old male with ESRD secondary to diffuse mesangial hypercellularity underwent living-related renal transplantation from his mother. Fourteen months posttransplant, routine ultrasonography revealed bilateral renal masses in the native kidneys. Contrast-enhanced computed tomography confirmed multiple lesions in both kidneys. The patient underwent bilateral laparoscopic nephrectomy. Histopathology revealed bilateral clear cell renal cell carcinoma, confined to the kidneys with negative surgical margins. Multiple benign cortical cysts suggested early acquired cystic kidney disease. At 1-year follow-up, the patient showed no evidence of recurrence, with normal serum creatinine and stable graft function. Bilateral RCC after renal transplantation is rare and is usually associated with papillary histology and acquired cystic kidney disease. The early occurrence of bilateral clear cell RCC in a pediatric transplant recipient is unusual and may indicate an underlying predisposition. Early detection through routine imaging allowed timely surgical management with preservation of graft function. This case highlights the rare occurrence of early bilateral clear cell RCC in a pediatric renal transplant recipient. Careful surveillance of native kidneys in transplant recipients may facilitate early diagnosis and favorable outcomes.

Introduction: The prevalence of acquired cystic kidney disease (ACKD) varies according to the duration of dialysis. Few studies are available on this subject in sub-Saharan Africa. The objective of this study was to determine its prevalence, define its clinical profiles and ultrasound characteristics, and identify factors associated with its development. Patients and Methods: This was a multicenter, cross-sectional, descriptive, and analytical study conducted over seven months in three hospitals in Dakar. Included were chronic hemodialysis patients aged 18 years or older, with a duration of dialysis exceeding three years, and in whom renal ultrasound revealed at least three acquired cysts in each kidney. Results: The prevalence of ACKD was 30.37%. The mean age of the patients was 51.49 ± 13.4 years, with a male-to-female ratio of 2.15. Hypertensive nephropathy was the most common nephropathy, accounting for 39.03% of cases. The average session duration was 3.93 ± 0.26 hours, and the frequency was 3 or 4 times per week. Lower back pain was present in 34.3% of patients, while no patient experienced episodes of macroscopic hematuria. The mean hemoglobin level was 10 ± 1.9 g/dL. Corticomedullary cysts were the most frequent, occurring in 46.34% of cases, followed by medullary cysts in 31.71%, with 21.95% of patients having cortical cysts. The mean number of cysts in the right kidney was 6.93 ± 3.72, and in the left kidney, the mean was 6.27 ± 3.03. The mean cyst size was 22 ± 8.06 mm. Factors associated with the development of ACKD included male sex, duration of dialysis (over 60 months), low diastolic blood pressure, low dose dialysis, and a hemoglobin level greater than 10 ± 1.9 g/dL. Conclusion: This study identified factors associated with the development of acquired cystic kidney disease in hemodialysis patients in our setting. Regular screening is necessary for patients on hemodialysis for more than 3 years to prevent certain complications, particularly renal cell carcinoma.

Acquired cystic kidney disease-associated renal cell carcinoma (ACKD-RCC) can develop in the kidneys of patients with chronic kidney disease, particularly those on long-term dialysis, and displays morphologic diversity. We present a 70-year-old man with acquired cystic disease who developed 3 discrete tumors, each with different morphology. The patient had been on hemodialysis for 22 years and underwent right nephrectomy for a newly detected kidney mass. Histopathology and immunohistochemistry revealed 3 discrete tumors: a superior polar tumor displaying classic ACKD-RCC architecture with PAX8, AMACR, and KRT7 expression; an inferior polar tumor displaying ACKD-RCC morphology combined with a high-grade sarcomatoid component with PAX8 expression without AMACR and KRT7, consistent with dedifferentiation; and a midkidney tumor consisting mainly of bland spindle cells in fascicles with PAX8 and focal KRT7 expression confirming its epithelial origin, and negative mesenchymal and melanocytic markers excluding mimics, leading to a diagnosis of renal cell carcinoma (RCC), not otherwise specified (NOS). The patient developed pulmonary and bone metastases postoperatively and died of the disease 3 months later. The synchronous occurrence of conventional ACKD-RCC, a dedifferentiated sarcomatoid form, and a spindle cell RCC, NOS demonstrate the marked morphological heterogeneity of neoplasia in ACKD. The presence of both sarcomatoid and spindle cell histologic patterns is associated with an aggressive clinical course, highlighting the importance of intensive surveillance and thorough pathological evaluation of kidney masses in patients on long-term dialysis.

Abstract Introduction Studies on the prevalence of urologic conditions in the transgender population undergoing hormonal treatment are limited. Non-communicable conditions are especially underrepresented in the literature, with most existing research focusing on mental health and infectious diseases. Objective This study leverages the All of Us (AoU) Controlled Tier Dataset v7, a large-scale database designed to capture diverse health data, to examine whether transgender individuals undergoing hormonal gender-affirming care exhibit urological outcomes distinct from their cisgender counterparts. Methods Participants in the AoU database with self-reported gender identity of “Transgender”, sex assigned at birth (SAB) of “male” or “female”, and at least one record of gender-affirming hormonal treatment were included. Nearest neighbor propensity score matching was performed to create a matched cisgender control group by age, race/ethnicity, SAB, and smoking status. Standardized mean differences (SMDs) assessed covariate balance, and all-time prevalence rates of urological disorders (grouped by SNOMED CT codes) were compared between groups using Pearson’s chi-squared test. Stratified comparisons based on SAB used pairwise Fisher's exact test with Benjamini-Hochberg correction. Results SMDs for all matched variables were &amp;lt; 0.01. Mean ages for both groups were 46.6 ± 16.3 years. Transgender participants (n=157) were more likely than cisgender participants (n=471) to have a record of cystic kidney disorders (p=0.025). Subgroup analysis showed individuals assigned female at birth had a higher prevalence of urinary tract infections (UTIs) in both cisgender (p&amp;lt;0.001) and transgender (p=0.002) groups, while individuals assigned male at birth were more likely to exhibit obstructive symptoms across both cisgender (p&amp;lt;0.001) and transgender (p=0.043) groups. Conclusions These findings suggest that gender-affirming hormonal therapy, in isolation, does not substantially modify the urologic disease profile of transgender individuals relative to matched cisgender controls. The observed differences-such as increased prevalence of cystic kidney disease and sex-based patterns in UTI and obstructive symptoms-likely reflect underlying biological or sociodemographic factors rather than effects of hormonal treatment alone. The dataset's limited documentation of gender-affirming surgeries constrains broader interpretation. Continued investigation is warranted to clarify the interplay between hormonal, surgical, and psychosocial factors shaping urologic outcomes in transgender populations. Disclosure No

Rationale & ObjectiveMounting evidence supports that identifying the specific molecular etiology for individuals with cystic kidney disease (CyKD) is important for prognostication, surveillance, identifying related living donors, and defining familial risk, even in cases in which a clinical diagnosis appears straightforward. In this study, we aimed to investigate the yield of genetic findings and the unique variant characteristics using multigene panel testing (MGPT) in a referral laboratory setting for an unselected population of patients with an indication of CyKD.Study DesignCross-sectional study.Setting & ParticipantsA retrospective analysis of 1,235 genetic testing reports from patients with suspected CyKD who pursued MGPT was performed.FindingsA positive result in a gene associated with CyKD was identified in 49.4% (610/1235) of patient reports, identifying 468 unique variants classified as pathogenic or likely pathogenic in 20 unique genes. Variants in PKD1, a gene complicated by homology to 6 different pseudogenes, contributed to 65.6% (400/610) of positive results. Copy number variants (CNVs) were identified in 9.5% (58/610) of positive results, with 30.4% (17/56) of deletions consisting of 4 exons or less. Variants of uncertain significance that were suspicious for being pathogenic (susVUS) were identified in 57.0% (94/165) of patients with inconclusive results.LimitationsGenetic analysis was targeted to the genes included on the panel at the time of testing. As new evidence emerges supporting additional gene-disease associations, there is potential for additional positive results.ConclusionsThoughtful selection of carefully curated MGPT optimized to detect technically challenging variants can identify the molecular etiology in individuals presenting with CyKD. Further investigation of susVUS through segregation analysis in families may contribute to additional positive results.