Hanna, Christian

Importance Anhydramnios from fetal kidney failure causes lethal pulmonary hypoplasia. Serial amnioinfusions have shown promise in mitigating pulmonary disease from bilateral renal agenesis, but efficacy and safety for other causes of fetal kidney failure are unproven. Objective To assess the efficacy of serial amnioinfusions initiated before 26 weeks’ gestation to mitigate lethal pulmonary hypoplasia in cases of anhydramnios due to fetal kidney failure. Design, Setting, and Participants Prospective, nonrandomized clinical trial conducted at 13 US fetal therapy centers from December 2018 to February 2025. Outcomes for maternal-fetal pairs with anhydramnios before 22 weeks’ gestation due to fetal kidney failure without bilateral renal agenesis are reported; data collection for surviving infants continued until February 13, 2026. Exposure Thirty-two participants underwent serial amnioinfusions with isotonic fluid beginning before 26 weeks’ gestation. Main Outcomes and Measures The primary end point was neonatal survival for 14 days or longer with dialysis access placement. Secondary outcome measures of survival to discharge home and kidney transplant are reported. Results Twenty-nine of 32 participants (91%) had a live birth, with a median (IQR) gestational age at delivery of 34 weeks 1 day (31 weeks 5 days to 34 weeks 6 days). All participants delivered before 37 weeks’ gestation. No unexpected serious maternal adverse events occurred, and the most common maternal complications were preterm prelabor rupture of membranes in 19 participants (56%) and chorioamniotic separation in 10 (29%). The primary outcome occurred in 19 (65.5%) of 29 live-born neonates (95% CI, 45.7%-82.1%). Factors associated with survival to the primary outcome included receiving more amnioinfusions (median [IQR], 14 [9-18] in survivors vs 7 [4-11] in nonsurvivors; P = .01), longer time interval from first amnioinfusion to preterm prelabor rupture of membranes (63.5 [60.5-74.5] days in survivors vs 29.0 [22.0-56.0] days in nonsurvivors; P = .01), gestational age greater than 32 weeks (79% of survivors vs 38% of nonsurvivors; P = .03), and higher birth weight (2029 [1770-2250] g in survivors vs 1635 [1185-1915] g in nonsurvivors; P = .01). Fourteen live-born infants (48%) survived to hospital discharge at a median (IQR) age of 4.7 (3.4-5.7) months. Of the 11 infants surviving to date, 7 (64%) have undergone kidney transplant between ages 2 years to 5 years. Conclusions and Relevance Serial amnioinfusions mitigated lethal pulmonary hypoplasia in neonates with anhydramnios due to fetal kidney failure. Significant neonatal morbidity and mortality independent of early lung function was noted. Factors associated with survival were consistent with the Renal Anhydramnios Fetal Therapy trial’s bilateral renal agenesis cohort, suggesting common mechanistic pathways for mitigating pulmonary hypoplasia. Trial Registration ClinicalTrials.gov Identifier: NCT03101891

ABSTRACT Background In pediatric kidney transplant recipients, native nephrectomy is sometimes performed to manage conditions such as polyuria, nephrotic syndrome, and recurrent infections. To minimize surgical morbidity, our center adopted a technique from the adult transplant program involving ligation of native ureters at the time of transplantation as an alternative to native nephrectomy in selected patients. Methods This retrospective study describes our center's experience with pediatric patients who underwent ureteral ligation at transplantation between December 2008 and December 2022. Patient selection was based on clinical judgment rather than predefined criteria. Results Sixteen patients underwent ureteral ligation, with polyuria (12/16) and proteinuria associated with focal segmental glomerulosclerosis (4/16) as the primary indications. Ligation was unilateral in 5 patients and bilateral in 11. The average follow‐up was 5.7 years. No operative complications directly attributable to ureteral ligation were observed, including native kidney pyelonephritis or need for reoperation. Although post‐transplant imaging often revealed hydronephrosis of the native kidneys, it had no clinical consequences. Late postoperative hypertension occurred in 31% of the ligation group compared to 47% of controls without ligation, while new‐onset hypertension was more common in the ligation group (18.8% vs. 5.1%). Pain scores postoperatively were comparable between groups. Conclusions This technical report suggests that native ureteral ligation at pediatric kidney transplantation is feasible in selected patients but represents an empirical, non‐standard‐of‐care approach. Prospective comparative studies are needed to refine patient selection and assess long‐term outcomes.

Key Points 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. Background 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. Methods 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. Results 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. Conclusions 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.

We provide the first longitudinal and most comprehensive analysis of the intrarenal microvasculature in a slowly progressive model of autosomal dominant polycystic kidney disease (ADPKD) and integrate the findings with studies in a young cohort of individuals with ADPKD. We identified vasculature-related pathways that could be targeted for therapeutic interventions and contribute promising, noninvasive biomarkers in patients with ADPKD. Alterations of the intrarenal microcirculation may affect drug delivery; a better understanding of its longitudinal changes may aid in treatment management.

Key Points Experimental autosomal dominant polycystic kidney disease is associated with longitudinal changes in the kidney micro-RNA and mRNA profiles. Alterations in cellular transport, a feature of CKD, and a common biological process within polycystic kidney disease models and human autosomal dominant polycystic kidney disease, is present from early stages. Early versus late micro-RNA expression changes in autosomal dominant polycystic kidney disease could be targeted for a more tailored therapeutic intervention in the disease. Background Autosomal dominant polycystic kidney disease (ADPKD) is characterized by the progressive development and enlargement of bilateral kidney cysts, which often leads to kidney failure. This study comprehensively characterized the expression profile of micro-RNAs (miRNAs) and their target genes in Pkd1 RC/RC mice and further compared them with other murine models of polycystic kidney disease (PKD) and a model of CKD and individuals with ADPKD. Methods Pkd1 RC/RC and wild-type (WT) mice ( n =10 each, five males and five females) were studied at 1, 6, and 12 months. At each time point, kidney volume was determined in vivo (magnetic resonance imaging), followed by ex vivo histomorphometric analyses. In randomly selected Pkd1 RC/RC and WT mouse kidneys ( n =5/genotype, at 1 and 12 months), miRNA-sequencing (seq) was performed, followed by mRNA-seq, integrated (miRNA-seq/mRNA-seq analysis), and functional analysis of miRNA target genes. Venn diagrams were constructed to identify overlapping and novel differentially expressed (DE) miRNAs in Pkd1 RC/RC and other commonly used murine models of PKD, diabetic kidney disease, and individuals with ADPKD. Results miRNA-seq analysis identified 41 and 181 miRNAs DE in Pkd1 RC/RC versus WT kidneys at 1 and 12 months, respectively, which were confirmed by quantitative PCR. Target genes of miRNAs DE in Pkd1 RC/RC at early stages encoded for proteins mainly implicated in cell proliferation and α -ketoglutarate ( α -KG) transport, whereas those DE at late stages encoded for transport proteins involved in proinflammatory and metabolic processes. Urine α -KG concentration ( 1 H nuclear magnetic resonance spectroscopy), its fractional excretion, and tissue levels were higher in Pkd1 RC/RC during the entire course of the disease and associated with decreased protein expression of α -KG transporters sodium-coupled dicarboxylate transporter 3 and organic anion transporter 1. We further identified common DE miRNAs among murine models of PKD, diabetic kidney disease, and previous reports in individuals with ADPKD, as well as several novel miRNAs DE in early and late Pkd1 RC/RC kidneys, which have not been previously reported in either other murine models of PKD or patients with ADPKD. Conclusions Our study demonstrates that the renal miRNA expression profile changes longitudinally with the progression of the disease and might suggest that the post-transcriptional regulation of α -KG transport could represent a novel early feature of the disease.