Kidney360最新文献

Background: Hemodialysis therapy for end-stage kidney disease (ESKD) requires suitable vascular access, most commonly the arteriovenous fistula (AVF). Forty percent of AVFs fail within one year, leading to morbidity and care costs. Failure mechanisms remain unclear and current therapies are inadequate. Cellular senescence may be critical in AVF failure, and ESKD itself may accelerate senescence and subsequent vascular dysfunction. Senescence follows AVF placement in rodents with normal kidney function, but the temporal and spatial features in uremic conditions are unknown. This study aimed to characterize AVF changes in uremic mice over time and versus control vessels.

Methods: Six- to eight-week-old male C57BL6/J mice underwent 5/6 nephrectomy. Twenty-eight days later an AVF was created by cuff anastomosis (right carotid artery to the right jugular vein). Transcriptomic analysis was performed seven days post-AVF, and further samples were collected at fourteen and twenty-eight days post-AVF creation for histological assessment.

Results: AVF outflow vein morphometry showed reduced neointimal cell density. Whole transcriptomic analysis of outflow vs control veins at seven days post-AVF placement revealed 1187 upregulated and 3256 downregulated genes. Differentially expressed genes were significantly enriched in two established senescence related gene sets, SenMayo (a curated panel of ∼125 genes validated across species to capture senescence and associated proteins) and SenSig (a broader panel assessed to represent fibrotic and stress induced cell response). Histologically, senescence markers p16, p21, and phospho53 increased between day 14 and 28. Genes common to our dataset, SenMayo, and SenSig were validated with qPCR.

Conclusions: These data support established markers of AVF failure like matrix-metalloproteinases and monocyte chemokines and identify potential novel modulators of AVF survival that may inform senolytic strategies to improve patency. In summary, this study reveals for the first time the chronological progression of vascular senescence in the AVF of uremic mice.

Background: Chronic kidney disease - mineral bone disorder (CKD-MBD) is a syndrome that contributes to cardiovascular mortality. We have shown that CKD decreases cardiac mitochondrial function independent of vascular disease and prior to cardiac hypertrophy. Hyperphosphatemia, a component of the CKD-MBD occurring in later stages of CKD, has been shown to stimulate vascular calcification. In a mouse model of Alport syndrome CKD resistant to vascular calcification, we examine the effects of a high-phosphate Western-type diet (HP) on the components of the CKD-MBD, including cardiac respiration.

Methods: Col4a5-deficient mice and wild type (WT) littermates were fed an animal protein 1.2% high phosphate diet or a standard vegetable protein 0.6% phosphate diet. At CKD progression equivalent to human CKD stage 4-5, we examined cardiac tissue for mitochondrial respiration; kidney histology for fibrosis; blood for BUN and CKD-MBD components; kidney tissue for klotho production; and aorta for vascular calcification.

Results: The HP diet produced hyperphosphatemia in the CKD animals compared to WT. The diet increased plasma PTH (17 fold), FGF23 intact (14 fold), and reduced kidney klotho mRNA and protein more than 50%. Alport CKD mice fed the HP diet showed a reduction in cardiac mitochondrial complex II-mediated oxidative phosphorylation, and higher levels of plasma PTH and FGF23 than CKD mice fed the vegetable protein diet. Comparing WT groups, the HP diet increased PTH and intact FGF23, reduced renal klotho, and decreased cardiac mitochondrial oxidative phosphorylation capacity. Vascular calcification was not induced by the HP diet.

Conclusions: The Western-style high-phosphate diet primed the development of the CKD-MBD in non-diseased animals and worsened the CKD-MBD during CKD progression. Cardiac respiration, renal klotho, FGF23, and PTH are affected by a high Pi diet even with normal kidney function, suggesting a need for early intervention in the management of phosphate homeostasis as a component of CKD therapy.

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 miRNAs and their target genes in Pkd1RC/RC mice and further compared them with other murine models of PKD and a model of CKD, and individuals with ADPKD.

Methods: Pkd1RC/RC and WT mice (n=10 each, 5 males and 5 females) were studied at 1, 6, and 12 months. At each time point, kidney volume was determined in vivo (MRI), followed by ex vivo histomorphometric analyses. In randomly selected Pkd1RC/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 Pkd1RC/RC and other commonly used murine models of PKD, diabetic kidney disease (DKD) and individuals with ADPKD.

Results: miRNA-seq analysis identified 41 and 181 miRNAs DE in Pkd1RC/RC versus WT kidneys at 1 and 12 months, respectively, which were confirmed by qPCR. Target genes of miRNAs DE in Pkd1RC/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 pro-inflammatory and metabolic processes. Urine α-KG concentration (1H NMR spectroscopy), its fractional excretion, and tissue levels were higher in Pkd1RC/RC during the entire course of the disease and associated with decreased protein expression of α-KG transporters NaDC3 and Oat1. We further identified common DE miRNAs among murine models of PKD, DKD and previous reports in individuals with ADPKD, as well as several novel miRNAs DE in early and late Pkd1RC/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.

Background: Arterial blood gas (ABG) analysis remains the gold standard for diagnosis and management of acid-base disorders. Obtaining arterial blood through arterial puncture, however, is cumbersome, at times difficult and carries potential risks. For these reasons, the venous blood gas (VBG), despite of its inaccuracy, is increasingly used instead of the ABG. Currently, there is no standardized accepted calculation to estimate arterial values of pCO2, pH, and HCO3- from the venous gas panel. Here, we report the relationship between arterial and venous blood gas parameters (pH, pCO2, and HCO3-) based on 5419 samples collected concurrently.

Methods: For pCO2, linear regression analysis of venous and arterial values showed a strong correlation (r = 0.93, p < 0.0001) and a formula derived from this relationship calculated the estimated arterial pCO2, compared to the actual measured arterial pCO2, with a median difference of 0.02 mmHg and 95% limits of agreement ranging from -5.6 to +5.5 mmHg. For pH, linear regression analysis of venous and arterial values also showed a strong correlation (r = 0.94, p < 0.0001) and a formula derived from this relationship calculated the estimated arterial pH, compared to the actual measured arterial pH, with a median difference of -0.002 pH units and 95% limits of agreement ranging from -0.05 to +0.04 pH units. To calculate an estimated arterial HCO3-, the arterial pCO2 and pH estimated from the respective formulas, were entered into the Henderson-Hasselbalch equation.

Results: This resulted in an estimated arterial HCO3- with a median difference of -0.08 mEq/L and 95% limits of agreement ranging from -2.29 to +1.96 mEq/L as compared to the reported arterial HCO3-. The data show that the VBG can be transformed with reasonable confidence intervals to arrive at a corresponding ABG.

Conclusions: The results of this transformation meet acceptable clinical expectations and are supported by the large database used to generate the formulas that estimate independently the three ABG components (pCO2, pH and HCO3-).

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.