Background Polycystic kidney disease (PKD) is the leading genetic cause of kidney failure, resulting in the accumulation of fluid-filled cysts and gross enlargement of the kidney. Mutations in PKD1 or PKD2, which encode ciliary polycystin proteins, are the most common cause of PKD. These proteins function in a cilia-dependent cyst activation (CDCA) pathway-one that requires cilia for its procystic function-yet the molecular driver(s) of this pathway are unknown. ARL13B is a regulatory GTPase enriched in cilia and links to cystogenesis in the kidneys. ARL13B possesses guanine nucleotide exchange factor (GEF) activity for ARL3, another ADP-ribosylation factor-like family GTPase with links to cilia.Methods We used 2 distinct Arl13b mouse alleles to investigate whether ARL13B is a component of the CDCA pathway: Arl13b V358A encodes for enzymatically normal ARL13B that is undetectable in cilia, and Arl13b R79Q encodes for cilia-localized ARL13B lacking a residue critical for its ARL3 GEF activity. We used these alleles in a Pkd1-deficient adult mouse model and investigated kidney morphology (hematoxylin and eosin and cystic index analysis), physiology (BUN measurements), kidney fibrosis (picrosirius staining and alpha-smooth muscle actin levels), kidney injury (SRY box transcription factor 9 immuno-fluorescent staining and quantification), and Wnt signaling (beta-catenin and cyclin D1 protein levels).Results We found that loss of ciliary ARL13B or mutation of a single residue critical for its ARL3 GEF activity suppressed Pkd1-dependent cysts. We observed reductions in kidney size, cystic index, and BUN. We also observed suppression of kidney fibrosis, kidney injury, and beta-catenin and cyclin D1 protein levels.Conclusions Our results identified a subcellular location and mechanism driving Pkd1-dependent cystogenesis in the kidneys. We demonstrated that expression of a critical residue for ARL13B's GEF activity specifically in cilia is a key mechanism of the CDCA pathway driving cystogenesis in the kidneys.
Introduction The novel nonsteroidal mineralocorticoid receptor antagonist balcinrenone in combination with dapagliflozin reduced urinary albumin-to-creatinine ratio (UACR) over 12 weeks in the MIRO-CKD phase 2 trial in CKD and induced a modest acute eGFR reduction upon treatment initiation. This prespecified analysis explored the acute eGFR changes in response to balcinrenone/dapagliflozin and the association of these acute eGFR changes on safety and efficacy parameters. Methods Adults with CKD (N=324, eGFR >= 25-<60 ml/min per 1.73 m(2); UACR >= 100-<5000 mg/g) were randomized to balcinrenone/dapagliflozin 15/10 mg, balcinrenone/dapagliflozin 40/10 mg, or dapagliflozin 10 mg/placebo as adjunct to renin-angiotensin system therapy. The primary outcome was the relative change in UACR from baseline over 12 weeks. Acute eGFR changes 4 weeks post randomization and 4 weeks post treatment were assessed using mixed model repeated measures. We categorized participants according to relative eGFR changes: >= 10% reduction (eGFR dip); >0-<10% reduction; or an eGFR increase. We examined safety and concomitant changes in systolic BP (SBP) and UACR across categories of eGFR changes. Results Relative to dapagliflozin/placebo, the acute eGFR dip at week 4 with balcinrenone/dapagliflozin 15/10 mg was -0.6 ml/min per 1.73 m(2 )(95% confidence interval, -2.4 to 1.1) and with balcinrenone/dapagliflozin 40/10 mg -1.7 ml/min per 1.73 m2 (95% confidence interval, -3.5 to -0.01). The acute reduction in eGFR with balcinrenone/dapagliflozin was reversible 4 weeks after treatment discontinuation. This finding was consistent across subgroups. In the overall cohort, larger acute eGFR reductions were associated with larger reductions in UACR and SBP across treatment arms. Rates of serious adverse events and adverse events of special interest were low, similar in the balcinrenone/dapagliflozin versus placebo/dapagliflozin group, and unrelated to the acute eGFR change. Conclusion In adults with CKD, balcinrenone/dapagliflozin induced a modest acute eGFR reduction that was reversible after treatment discontinuation, did not lead to increased rates of adverse events, and was associated with greater SBP and UACR lowering.Clinical Trial registry name and registration number: .
Background Diabetes is the leading cause of kidney failure globally affecting 40% of people receiving peritoneal dialysis (PD). High-quality data on the potential impact of improving glycemic control is needed to inform the current recommendations to individualize HbA(1C) targets. Methods Data from 8 countries in the prospective cohort Peritoneal Dialysis Outcomes and Practice Patterns Study (2014-2022) were used to assess the association between baseline HbA(1C) and all-cause mortality in people with type 2 diabetes on PD for at least 90 days. Cox proportional hazards model adjusted for potential confounders was used to assess the relationship in the whole cohort and subgroups. Using inverse probability weighting, an average treatment effect in the treated analysis further investigated potential implications of improved glycemic control. Results HbA(1C) was measured at least once in 8436 patients during a mean follow-up of 16 months. Compared with HbA(1C) <= 8% (Diabetes Control and Complications Trial units), HbA(1C) >8% was associated with higher risk of all-cause mortality in the cohort as a whole (hazard ratio [HR] 1.18 P = 0.02 95% confidence interval [CI], 1.03 to 1.35) and within subgroups: age younger than 65 years (HR, 1.28; P = 0.01; 95% CI, 1.05 to 1.56), average albumin >3.0 g/dl (HR, 1.25; P = 0.004; 95% CI, 1.07 to 1.46), no preexisting coronary artery disease (CAD; HR, 1.24; P = 0.008; 95% CI, 1.06 to 1.46), hemoglobin <10 g/L (HR, 1.50; P = 0.01; 95% CI, 1.09 to 2.07), and PD vintage <1 year (HR, 1.22; P = 0.02; 95% CI, 1.03 to 1.45). The projected survival advantage at 3 years for those with HbA(1C) <= 8% compared with >8% was 7% overall, increasing to 12% in younger cohorts (age younger than 65 years). The largest predicted absolute survival advantage of 16% (78% versus 61%) was seen in those aged younger than 65 years, with a normal serum albumin level and no history of CAD. Conclusions Associations between HbA1C and mortality argue for tighter individualized targets for patient subgroups (younger, noninflamed, and without established CAD). Our weighted analysis suggests improved glycemic control (reducing HbA(1C) to <8%) may result in an absolute reduction in mortality at 3 years of up to 12% in younger cohorts.
Background Diabetic kidney disease (DKD) is driven by complex pathologic mechanisms including lipid accumulation, chronic inflammation, and fibrosis, contributing to progressive kidney dysfunction. Macrophages are key contributors to DKD pathogenesis, yet their functional heterogeneity in the diabetic kidney remains poorly defined. Although triggering receptor expressed on myeloid cells 2 (TREM2+) macrophages have been identified within the diabetic microenvironment, the relationship between their developmental origin, anatomic localization, and functional specialization remains unclear.Methods In this study, we integrated single-cell RNA sequencing, spatial transcriptomic analysis of diabetic OVE26 kidneys, and reciprocal bone marrow transplantation in a high-fat diet plus streptozotocin-induced diabetic model to examine how TREM2+ macrophages are distributed across renal compartments and how TREM2 deficiency affects DKD injury.Results Global TREM2 deficiency markedly exacerbated tubulointerstitial injury and glomerular hypertrophy in DKD, establishing TREM2 as a protective factor. Single-cell RNA sequencing and spatial mapping revealed that TREM2 induction in diabetic kidneys occurs in 2 spatially distinct macrophage populations: Mrc1+ kidney-resident macrophages localized to the periglomerular niche and Ccr2+ monocyte-derived macrophages infiltrating the tubulointerstitium. Transcriptomic and functional analyses were consistent with a role of TREM2 in macrophage phagocytic and lipid-handling programs. Its loss led to the downregulation of phagosome and endocytic pathways, resulting in failed clearance of apoptotic debris and lipid aggregates, which was particularly pronounced in the tubulointerstitium. Reciprocal bone marrow transplant experiments suggest that recipient-resident TREM2 was more associated with preservation of glomerular structure, whereas donor-derived hematopoietic TREM2 was more strongly associated with limiting tubular lipid accumulation, apoptotic tubular epithelial cells, and tubulointerstitial injury.Conclusions These findings suggested that TREM2-expressing macrophages contributed to compartment-specific protective responses in DKD. TREM2 deficiency was associated with greater diabetic glomerular and tubular injury, with distinct phenotypes observed in donor hematopoietic and recipient compartments.
