Hanna, Christian

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.

Importance Autosomal dominant polycystic kidney disease (ADPKD) is characterized by progressive development of kidney cysts and is the most common inherited kidney disorder worldwide. ADPKD accounts for 5% to 10% of kidney failure in the US and Europe, and its prevalence in the US is 9.3 per 10 000 individuals. Observations ADPKD is typically diagnosed in individuals aged 27 to 42 years and is primarily caused by pathogenic variants in the PKD1 (78%) or PKD2 (15%) genes. Most persons with ADPKD have an affected parent, but de novo disease is suggested in 10% to 25% of families. More than 90% of patients older than 35 years have hepatic cysts, which may cause abdominal discomfort and occasionally require medical or surgical intervention. Hypertension affects 70% to 80% of patients with ADPKD, and approximately 9% to 14% develop intracranial aneurysms, which have a rupture rate of 0.57 per 1000 patient-years. Approximately 50% of individuals with ADPKD require kidney replacement therapy by 62 years of age. The severity of kidney disease can be quantified using the Mayo Imaging Classification (MIC), which stratifies patients based on total kidney volume adjusted for height and age and ranges from 1A to 1E. Patients with MIC 1C to MIC 1E have larger kidneys because of more rapid growth (6%-10% per year) compared with those with MIC 1A and 1B (1%-5% per year) and have earlier progression to kidney replacement therapy, which occurs at a mean age of 58.4 years for MIC 1C, 52.5 years for MIC 1D, and 43.4 years for MIC 1E. Optimal management of ADPKD includes systolic blood pressure lower than 120 mm Hg for most patients, but lower than 110/75 mm Hg for patients with MIC 1C to 1E who have an estimated glomerular filtration rate (eGFR) greater than 60 mL/min/1.73 m 2 and are younger than 50 years, dietary sodium restriction (<2000 mg/d), weight management, and adequate hydration (>2.5 L daily). The vasopressin type 2 receptor antagonist tolvaptan reduces the annual rate of eGFR decline by 0.98 to 1.27 mL/min/1.73 m 2 and is indicated for patients with MIC 1C to 1E or an eGFR decline greater than 3 mL/min/1.73 m 2 per year to slow disease progression and delay the onset of kidney failure. Conclusion ADPKD is the most common genetic kidney disease worldwide and is characterized by progressive development of kidney cysts. Patients typically have hypertension and liver cysts, and 9% to 14% develop intracranial aneurysms. First-line treatment includes blood pressure control, dietary and weight management, and adequate hydration. Tolvaptan reduces the rate of eGFR decline for those at high risk of rapid progression to kidney failure.

Purpose of review Hyponatremia and hypernatremia are commonly encountered electrolyte abnormalities that require timely and careful intervention, as they can be associated with significant morbidity and mortality. Recent findings This review article addresses the etiology, presentation, diagnosis, and management of both hyponatremia and hypernatremia, emphasizing the latest advancements and emerging trends in pediatric care. Summary A methodical approach is needed to accurately assess and treat hyponatremia and hypernatremia. Both conditions continue to rely on serum and urine testing, however newer tests such as copeptin and stimulated testing may hold promise to further refine testing in the future.