多発性嚢胞腎

BACKGROUND: Native nephrectomy in patients with autosomal dominant polycystic kidney disease (ADPKD) undergoing kidney transplantation remains controversial, particularly regarding indications, timing, and laterality. This study evaluated surgical strategies and outcomes of native nephrectomy in ADPKD kidney transplant candidates. METHODS: We retrospectively analyzed adult patients with ADPKD who underwent kidney transplantation at a single center between 1999 and 2021. Demographic, transplant-related, nephrectomy-related, surgical, complication, and histopathological data were compared between patients who underwent native nephrectomy and those managed without nephrectomy. RESULTS: Among 109 patients with ADPKD, 79 (72%) underwent native nephrectomy and 30 (28%) did not. Patients undergoing nephrectomy had significantly higher body weight and were more frequently on dialysis before transplantation. Most nephrectomies were performed before transplantation, predominantly as bilateral procedures. The leading indication was lack of intra-abdominal space for graft implantation, followed by cyst infection, chronic pain, and hemorrhagic cysts. Post-transplant nephrectomy was uncommon and mainly performed for persistent or delayed native kidney-related complications. Postoperative complications, including bleeding requiring transfusion, fluid collections, incisional hernias, and surgical reinterventions, with no statistically significant differences in complication rates between nephrectomy strategies. No malignancy was identified in the available histopathological specimens. CONCLUSIONS: Native nephrectomy was frequently performed in ADPKD kidney transplant candidates, most often before transplantation and primarily to create sufficient space for graft implantation. Bilateral pre-transplant nephrectomy was the predominant strategy but was associated with most postoperative complications. These findings highlight the variability of current practice and support individualized, anatomy- and symptom-based decision-making.

Autosomal Dominant Polycystic Kidney Disease (ADPKD) is a progressive kidney disorder with limited therapeutic options, highlighting an urgent need for safer, long-term treatments. This study presents a multi-step computational and experimental approach to identify and assess target-based hypotheses for mechanisms underlying the cAMP-dependent cyst swelling. We analyzed phenotypic screening data from a 3D mIMCD3-Pkd1-/- forskolin-induced, cAMP-driven cyst swelling (CS) assay, classifying compounds based on their CS activity. These compounds were cross-referenced with the Papyrus database to identify known biological targets, which were then prioritized by considering their expression in the screened cell model and by deprioritizing targets associated with antineoplastic activity. Four prioritized targets, P2X purinoceptor 7 (P2RX7), Glucose Transporter 1 (GLUT1), Mineralocorticoid Receptor (MR), and Adenosine A1 Receptor (A1AR), were experimentally evaluated by testing known ligands in the phenotypic assay. While P2RX7 modulation showed no effect, GLUT1 inhibitors significantly reduced cyst swelling. For A1AR, known agonists reduced CS while the inverse agonist DPCPX enhanced it. In contrast, MR modulation showed compound-specific effects, with the antagonist Esaxerenone uniquely reducing CS among tested MR antagonists. Quantitative structure-activity relationship (QSAR) models for A1AR and MR were used to select structural analogues of known active compounds within chemical vendor catalogues to further confirm identified target-ADPKD activity space. Radioligand displacement assays were conducted to confirm the QSAR-predicted A1AR binding affinities and selectivity among adenosine receptor subtypes. A1AR affinity and subtype selectivity was a common denominator among ligands with CS-reducing activity, with the A1AR positive allosteric modulator MIPS521 showing the strongest effect. The workflow therefore generated a coherent A1AR-linked hypothesis and identified Esaxerenone as a compound-specific phenotypic hit; both require mechanistic confirmation and evaluation in additional disease models.

Autosomal dominant polycystic kidney disease (ADPKD), mainly driven by pathogenic variants in PKD1 and PKD2, is the most common inherited cause of kidney failure. Details of ADPKD pathogenesis are incompletely resolved, but primary cilia are an integral component. There is also evidence for changes to the tubular basement membrane (TBM) in early disease. In this issue of the JCI, Mazloum and colleagues link cilia-dependent, PKD1-mediated regulation of the TBM to ADPKD pathogenesis. Using in vivo, ex vivo, tubule-on-chip, and cellular models of ADPKD, they connect cilia-dependent tubule dilation and TBM thinning to early-stage cystogenesis. Moreover, they identify a cilia-dependent TBM remodeling expression signature in affected tubules and suggest that PC1 loss compromises TBM stiffness. By integrating roles for cilia at the apical membrane and extracellular matrix at the basolateral membrane in cystogenesis, this work highlights the TBM as an additional area for investigation of therapeutic and biomarker discovery in ADPKD.

BACKGROUND: Classic hairy cell leukemia (HCL) is a rare, indolent B-cell lymphoproliferative disorder characterized by bone marrow fibrosis causing pancytopenia, splenomegaly, and a near-universal BRAF V600E mutation. Purine nucleoside analogs (PNAs) are the standard first-line therapy but are contraindicated in patients with significantly advanced chronic kidney disease (CKD) or end-stage renal disease (ESRD) due to renal excretion and risk of prolonged myelosuppression. Data on the use of targeted therapies, such as BRAF inhibitors, in dialysis-dependent HCL patients are lacking. CASE: We present a novel case of a 43-year-old man on chronic hemodialysis secondary to suspected autosomal dominant polycystic kidney disease diagnosed with classic BRAF V600E-mutated HCL, treated with low-dose vemurafenib in combination with anti-CD20 therapy. The patient achieved hematologic remission without significant renal or infectious complications. Notably, this case is further distinguished by the development of reactive macrocytic polycythemia with normal erythropoietin levels and no alternative identifiable cause, highlighting an unusual hematologic manifestation in the setting of treated HCL and end-stage renal disease. DISCUSSION: This report highlights the feasibility and efficacy of BRAF-targeted therapy combined with an anti-CD20 antibody in a young dialysis-dependent HCL patient, expanding therapeutic options for this high-risk population. Further prospective studies and case series are needed to guide management in this unique clinical context.

Background/Objectives: KDIGO supports molecular testing in selected autosomal dominant polycystic kidney disease (ADPKD) scenarios and targeted next-generation sequencing panels when broader evaluation is warranted; however, gene inclusion alone establishes neither analytical completeness nor clinical reportability. Methods: We designed and evaluated a 28-gene ADPKD-spectrum hybrid-capture panel in a 16-sample, two-configuration pilot using 694 analytical target intervals per sample. Multiplex ligation-dependent probe amplification assessed dosage in suspected PKD1-related disease or TSC2/PKD1 contiguous-gene deletion, and whole-exome sequencing selectively supported short-read reidentification. Results: In the primary eight-sample dataset, 4592/5552 observations (82.7%) had interval mean depth ≥20×, 4256/5552 (76.7%) had interval minimum depth ≥20×, and 89.6% of interval-record bases reached ≥10×. Nine genes (FLCN, GANAB, HNF1B, PRKCSH, REN, SEC61A1, TSC2, UMOD and VHL) met mean depth ≥20× throughout; six also met the minimum-depth criterion. For PKD1, 45/46 intervals met both criteria in all samples, but exon 1 remained undercovered, and nominal depth in duplicated sequence did not establish authentic-locus callability. Signals were observed at all four positive-comparator loci, although two lacked sufficient support for independent reporting. Seven of nine panel-first cases yielded observations: one HNF1B and one unique-locus PKD1 finding were supported, whereas four duplicated-sequence PKD1 findings remained confirmation-dependent. Conclusions: Responsible implementation requires explicit analytical boundaries and staged complementary testing.