Arlene B. Chapman

Hydralazine is a vasodilator typically used in the treatment of resistant hypertension and heart failure. N‐acetyltransferase 2 (NAT2) catalyzes the metabolism of hydralazine into inactive metabolites. NAT2 poor metabolizers (historically referred to as “slow acetylators”) are predicted to have increased plasma hydralazine concentrations compared with NAT2 rapid and intermediate metabolizers (historically referred to as “rapid acetylators” and “intermediate acetylators,” respectively), which may lead to both increased clinical efficacy and adverse effects, including drug‐induced systemic lupus erythematosus. This guideline summarizes the evidence from the literature relevant to NAT2 /hydralazine and provides recommendations for hydralazine prescribing based on NAT2 genotype‐predicted acetylator phenotype (updates at www.cpicpgx.org ).

Key Points: Cardiac localized polycystin facilitates natriuretic peptide signaling pathways. Hypertension associated with autosomal dominant polycystic kidney disease may arise from impaired cardiac natriuretic peptide signaling. Background: Hypertension is seen in 70% of patients with autosomal dominant polycystic kidney disease by age of 30 years before decline in kidney function. However, cardiac origins of hypertension, such as the natriuretic peptide signaling pathway, have not been fully investigated. We hypothesized that cardiomyocyte localized polycystin proteins contribute to production of natriuretic peptides, and loss of this pathway would contribute to hypertension. Methods: Telemetry, echocardiography, and a molecular analysis of the natriuretic peptide pathway from left ventricular tissue of cardiomyocyte specific knockout models of polycystin-2 (cPC2-KO) mice and Cre control littermates were conducted. Complementary studies were conducted in ex vivo murine hearts, engineered heart tissue with human iPSCs driven into cardiomyocytes with CRISPR/Cas9 knockout of PKD2 and in in vitro cell lines. Results: cPC2-KO mice demonstrated diurnal hypertension. Circulating atrial natriuretic peptide (ANP) and brain natriuretic peptide were unchanged between cPC2-KO and Cre mice. Analysis of the pathways involved in production, maturation, and activity of natriuretic peptides identified decreased transcription of chromogranin B, PCSK6, NPR1, and NFAT genes in cPC2-KOs. Human iPSC-derived cardiomyocytes with PC2-KO failed to produce ANP. Re-expression of polycystin-2 in a myoblast cell line, but not pathogenic forms of polycystin-2, restored ANP production. Conclusions: Natriuretic peptide production required cardiac localized polycystin-2, and loss of this pathway may contribute to the development of hypertension in autosomal dominant polycystic kidney disease. Podcast: This article contains a podcast at https://dts.podtrac.com/redirect.mp3/www.asn-online.org/media/podcast/JASN/2024_10_08_ASN0000000000000490.mp3

Hypertensive patients with a higher proportion of genetic West African ancestry (%GWAA) have better blood pressure (BP) response to thiazide diuretics (TDs) and worse response to β‐blockers (BBs) than those with lower %GWAA, associated with their lower plasma renin activity (PRA). TDs and BBs are suggested to reduce BP in the long term through vasodilation via incompletely understood mechanisms. This study aimed at identifying pathways underlying ancestral differences in PRA, which might reflect pathways underlying BP‐lowering mechanisms of TDs and BBs. Among hypertensive participants enrolled in the Pharmacogenomics Evaluation of Antihypertensive Responses (PEAR) and PEAR‐2 trials, we previously identified 8 metabolites associated with baseline PRA and 4 metabolic clusters (including 39 metabolites) that are different between those with GWAA <45% versus ≥45%. In the current study, using Ingenuity Pathway Analysis (IPA), we integrated these signals. Three overlapping metabolic signals within three significantly enriched pathways were identified as associated with both PRA and %GWAA: ceramide signaling, sphingosine 1‐ phosphate signaling, and endothelial nitric oxide synthase signaling. Literature indicates that the identified pathways are involved in the regulation of the Rho kinase cascade, production of the vasoactive agents nitric oxide, prostacyclin, thromboxane A2, and endothelin 1; the pathways proposed to underlie TD‐ and BB‐induced vasodilatation. These findings may improve our understanding of the BP‐lowering mechanisms of TDs and BBs. This might provide a possible step forward in personalizing antihypertensive therapy by identifying patients expected to have robust BP‐lowering effects from these drugs.

PurposeOur study aims to investigate the impact of preprocessing on magnetic resonance imaging (MRI) radiomic features extracted from the noncystic kidney parenchyma of patients with autosomal dominant polycystic kidney disease (ADPKD) in the task of classifying PKD1 versus PKD2 genotypes, which differ with regard to cyst burden and disease outcome.ApproachThe effect of preprocessing on radiomic features was investigated using a single T2-weighted fat saturated (T2W-FS) MRI scan from PKD1 and PKD2 subjects (29 kidneys in total) from the Consortium for Radiologic Imaging Studies of Polycystic Kidney Disease study. Radiomic feature reproducibility using the intraclass correlation coefficient (ICC) was computed across MRI normalizations (z-score, reference-tissue, and original image), gray-level discretization, and upsampling and downsampling pixel schemes. A second dataset for genotype classification from 136 subjects T2W-FS MRI images previously enrolled in the HALT Progression of Polycystic Kidney Disease study was matched for age, gender, and Mayo imaging classification class. Genotype classification was performed using a logistic regression classifier and radiomic features extracted from (1) the noncystic kidney parenchyma and (2) the entire kidney. The area under the receiver operating characteristic curve (AUC) was used to evaluate the classification performance across preprocessing methods.ResultsRadiomic features extracted from the noncystic kidney parenchyma were sensitive to preprocessing parameters, with varying reproducibility depending on the parameter. The percentage of features with good-to-excellent ICC scores ranged from 14% to 58%. AUC values ranged between 0.47 to 0.68 and 0.56 to 0.73 for the noncystic kidney parenchyma and entire kidney, respectively.ConclusionsReproducibility of radiomic features extracted from the noncystic kidney parenchyma was dependent on the preprocessing parameters used, and the effect on genotype classification was sensitive to preprocessing parameters. The results suggest that texture features may be indicative of genotype expression in ADPKD.

The underlying pathology of immunoglobulin A (IgA) nephropathy (IgAN), the most common glomerulonephritis worldwide, is driven by the deposition of immune complexes containing galactose-deficient IgA1 [Tn(+)IgA1] in the glomerular mesangium. Here, we report that novel anti-Tn circulating immune complexes (anti-Tn CICs) contain predominantly IgM, representing large macromolecular complexes of ~1.2 megadaltons to several megadalton sizes together with Tn(+)IgA1 and some IgG. These complexes are significantly elevated in sera of patients with IgAN, which contains higher levels of complement C3, compared to healthy individuals. Anti-Tn CICs are bioactive and induce specific proliferation of human renal mesangial cells. We found that these anti-Tn CICs can be dissociated with small glycomimetic compounds, which mimic the Tn antigen of Tn(+)IgA1, releasing IgA1 from anti-Tn CICs. This glycomimetic compound can also significantly inhibit the proliferative activity of anti-Tn CICs of patients with IgAN. These findings could enhance both the diagnosis of IgAN and its treatment, as specific drug treatments are now unavailable.

SPIE Digital Library Proceedings

Autosomal dominant polycystic kidney disease (ADPKD) is the most common hereditary kidney disease and is characterized by gradual cyst growth and expansion, increase in kidney volume with an ultimate decline in kidney function leading to end stage renal disease (ESRD). Given the decades long period of stable kidney function while cyst growth occurs, it is important to identify those patients who will progress to ESRD. Recent data from our and other laboratories have demonstrated that metabolic reprogramming may play a key role in cystic epithelial proliferation resulting in cyst growth in ADPKD. Height corrected total kidney volume (ht-TKV) accurately reflects cyst burden and predicts future loss of kidney function. We hypothesize that specific plasma metabolites will correlate with eGFR and ht-TKV early in ADPKD, both predictors of disease progression, potentially indicative of early physiologic derangements of renal disease severity. To investigate the predictive role of plasma metabolites on eGFR and/or ht-TKV, we used a non-targeted GC-TOF/MS-based metabolomics approach on hypertensive ADPKD patients in the early course of their disease. Patient data was obtained from the HALT-A randomized clinical trial at baseline including estimated glomerular filtration rate (eGFR) and measured ht-TKV. To identify individual metabolites whose intensities are significantly correlated with eGFR and ht-TKV, association analyses were performed using linear regression with each metabolite signal level as the primary predictor variable and baseline eGFR and ht-TKV as the continuous outcomes of interest, while adjusting for covariates. Significance was determined by Storey’s false discovery rate (FDR) q-values to correct for multiple testing. Twelve metabolites significantly correlated with eGFR and two triglycerides significantly correlated with baseline ht-TKV at FDR q-value < 0.05. Specific significant metabolites, including pseudo-uridine, indole-3-lactate, uric acid, isothreonic acid, and creatinine, have been previously shown to accumulate in plasma and/or urine in both diabetic and cystic renal diseases with advanced renal insufficiency. This study identifies metabolic derangements in early ADPKD which may be prognostic for ADPKD disease progression. HALT Progression of Polycystic Kidney Disease (HALT PKD) Study A; Clinical www.clinicaltrials.gov identifier: NCT00283686; first posted January 30, 2006, last update posted March 19, 2015.