Hyperuricemia Subtypes Classified According to Renal Uric Acid Handling Manifesting Distinct Phenotypic and Genetic Profiles in People With Gout.

OBJECTIVE: Hyperuricemia can be stratified into four subtypes according to renal uric acid handling. The aim of this study was to comprehensively describe the biologic characteristics (including genetic background) of clinically defined hyperuricemia subtypes in two large geographically independent gout cohorts. METHODS: Hyperuricemia subtype was defined as renal uric acid overload (ROL), renal uric acid underexcretion (RUE), combined, or renal normal. Twenty single nucleotide polymorphisms (SNPs) previously identified as gout risk loci or associated with serum urate (SU) concentration in the East Asian population were genotyped. Weighted polygenic risk scores were calculated to assess the cumulative effect of genetic risks on the subtypes. RESULTS: Of the 4,873 participants, 8.8% had an ROL subtype, 60.9% RUE subtype, 23.1% combined subtype, and 7.2% normal subtype. The ROL subtype was independently associated with older age at onset, lower SU, tophi, and diabetes mellitus; RUE was associated with lower body mass index (BMI) and non-diabetes mellitus; the combined subtype was associated with younger age at onset, higher BMI, SU, estimated glomerular filtration rate (eGFR), and smoking; and the normal subtype was independently associated with older age at onset, lower SU, and eGFR. Thirteen SNPs were associated with gout with 6 shared loci and subtype-dependent risk loci patterns. High polygenic risk scores were associated with ROL subtype (odds ratio [OR] = 9.63, 95% confidence interval [95% CI] 4.53-15.12), RUE subtype (OR = 2.18, 95% CI 1.57-3.03), and combined subtype (OR = 6.32, 95% CI 4.22-9.48) compared with low polygenic risk scores. CONCLUSION: Hyperuricemia subtypes classified according to renal uric acid handling have subtype-specific clinical and genetic features, suggesting subtype-unique pathophysiologic mechanisms.

Cadmium exposure dysregulates purine metabolism and homeostasis across the gut-liver axis in a mouse model.

Cadmium (Cd) exposure has been associated with the development of enterohepatic circulation disorders and hyperuricemia, but the possible contribution of chronic low-dose Cd exposure to disease progression is still need to be explored. A mouse model of wild-type mice (WT) and Uox-knockout mice (Uox-KO) to find out the toxic effects of chronic low-dose Cd exposure on liver purine metabolism by liquid chromatography-mass spectrometry (LC-MS) platform and associated intestinal flora. High throughput omics analysis including metabolomics and transcriptomics showed that Cd exposure can cause disruption of purine metabolism and energy metabolism. Cd changes several metabolites associated with purine metabolism (xanthine, hypoxanthine, adenosine, uridine, inosine) and related genes, which are associated with elevated urate levels. Microbiome analysis showed that Cd exposure altered the disturbance of homeostasis in the gut. Uox-KO mice were more susceptible to Cd than WT mice. Our findings extend the understanding of potential toxicological interactions between liver and gut microbiota and shed light on the progression of metabolic diseases caused by Cd exposure.

Superiority of Low-Dose Benzbromarone to Low-Dose Febuxostat in a Prospective, Randomized Comparative Effectiveness Trial in Gout Patients With Renal Uric Acid Underexcretion.

OBJECTIVE: The predominant mechanism driving hyperuricemia in gout is renal uric acid underexcretion; however, the standard urate-lowering therapy (ULT) recommendation is first-line xanthine oxidase inhibitor (XOI), irrespective of the cause of hyperuricemia. This comparative effectiveness clinical trial was undertaken to compare first-line nontitrated low-dose benzbromarone (LDBen) uricosuric therapy to XOI ULT with low-dose febuxostat (LDFeb) in gout patients with renal uric acid underexcretion. METHODS: We conducted a prospective, randomized, single-center, open-label trial in men with gout and renal uric acid underexcretion (defined as fractional excretion of urate <5.5% and uric acid excretion ≤600 mg/day/1.73 m2 ). A total of 196 participants were randomly assigned to receive LDBen 25 mg daily or LDFeb 20 mg daily for 12 weeks. All participants received daily urine alkalization with oral sodium bicarbonate. The primary end point was the rate of achieving the serum urate target of <6 mg/dl. RESULTS: More participants in the LDBen group achieved the serum urate target than those in the LDFeb group (61% compared to 32%, P < 0.001). Rates of adverse events, including gout flares and urolithiasis, did not differ between groups, with the exception of greater transaminase elevation in the LDFeb group (4% for LDBen compared to 15% for LDFeb, P = 0.008). CONCLUSION: Compared to LDFeb, LDBen has superior urate-lowering efficacy and similar safety in treating relatively young and healthy patients with renal uric acid underexcretion-type gout.

Association of acidic urine pH with impaired renal function in primary gout patients: a Chinese population-based cross-sectional study.

BACKGROUND: Patients with gout frequently have low urinary pH, which is associated with the nephrolithiasis. However, the specific distribution of urinary pH and potential relationship of acidic urine pH to broader manifestations of kidney disease in gout are still poorly understood. METHODS: A 2016-2020 population-based cross-sectional study was conducted among 3565 gout patients in the dedicated gout clinic of the Affiliated Hospital of Qingdao University to investigate the association between low urinary pH and kidney disease. We studied patients that we defined to have "primary gout", based on the absence of > stage 2 CKD. All subjects underwent 14 days of medication washout and 3-day standardized metabolic diet. We obtained general medical information, blood and urine biochemistries, and renal ultrasound examination on the day of the visit. The primary readouts were urine pH, eGFR, nephrolithiasis, renal cysts, microhematuria, and proteinuria. Patients were assigned into 5 subgroups (urine pH ≤5.0, 5.0 6.9), aligning with the clinical significance of urine pH. RESULTS: Overall, the median urine pH and eGFR of all patients was 5.63 (IQR 5.37~6.09), and 98.32 (IQR 86.03~110.6), with acidic urine in 46.5% of patients. The prevalence of nephrolithiasis, microhematuria, and proteinuria were 16.9%, 49.5%, and 6.9%, respectively. By univariate analysis, eGFR was significantly associated with age, sex, duration of gout, tophus, body mass index, systolic blood pressure, diastolic blood pressure, fasting blood glucose, total cholesterol, serum utare, hypertension, diabetes, and urine pH. On multivariable analysis, eGFR was associated with age, sex, diastolic blood pressure, serum uric acid, hypertension, diabetes, and urine pH. Acidic urine pH, especially urine pH < 5.0, was significantly associated with the prevalence of kidney disease, including > stage 1 CKD, nephrolithiasis, kidney cyst, and microhematuria. Patients with 6.2 ≤ urine pH ≤ 6.9 and SU ≤ 480 µmol/L had the highest eGFR with the lowest prevalence of nephrolithiasis, microhematuria, and proteinuria. CONCLUSIONS: Approximately half of gout subjects had acidic urine pH. Urine pH < 5.0 was associated with significantly increased nephrolithiasis, renal cyst, microhematuria, and proteinuria. The results support prospective clinical investigation of urinary alkalinization in selected gout patients with acidic urine pH.

Self-Albumin Camouflage of Carrier Protein Prevents Nontarget Antibody Production for Enhanced LDL-C Immunotherapy.

Elevated low-density lipoprotein cholesterol (LDL-C) increases the risk of atherosclerotic cardiovascular disease. Peptide-based PCSK9 vaccines have shown a promising prospect of reducing LDL-C. In peptide vaccine (pVax) design, the peptide antigens need to conjugate with carrier protein (CP). However, CP incorporation can induce undesirable anti-CP antibodies, which sterically mask peptide epitopes from being recognized by specific B cells and impair subsequent therapeutically antibody production. This epitopic suppression has posed a barrier in clinical translation of conjugate vaccines all along. A model CP (keyhole limpet hemocyanin, KLH) is herein camouflaged with serum albumin (SA) into hybrid nanocarriers (SA@N), with PCSK9 peptide being anchored onto the surface to form nanovaccine (SA@NVax). Such camouflage of KLH via high "self" SA coverage is able to inhibit KLH from extracellular immune recognition and prevent detectable anti-KLH antibody production. Furthermore, the nanovaccine around 70 nm stabilized by intermolecular disulfide network is ideal for internalization and biodegradation by antigen presenting cells as well as better retention in draining lymph nodes and spleen. As expected, the SA@NVax efficiently primes higher anti-PCSK9 IgG antibody titer than PCSK9 pVax.