Renal Excretion Research Articles

Impact of renal impairment (RI) on pharmacokinetics (PK) and clinical outcomes with mezigdomide plus dexamethasone (DEX) in relapsed/refractory multiple myeloma (RRMM).

7539 Background: RI is a common complication in MM and may alter drug elimination, leading to increased systemic exposures, risk of adverse events (AEs), and dosing adjustments. The novel CELMoD agent mezigdomide (MEZI) is being investigated alone or with DEX in the CC-92480-MM-001 (NCT03374085) phase 1/2 trial. MEZI has shown dose-dependent linear PK with rapid absorption and is mainly eliminated through hepatic metabolism, with renal elimination playing a smaller role. Here we investigate the impact of RI on the efficacy, safety, and PK of MEZI + DEX in RRMM. Methods: Eligible patients (pts) had RRMM, ≥ 3 prior lines of therapy, triple-class refractoriness, and disease progression ≤ 60 days of last therapy. Pts were stratified by creatinine clearance (CrCl), excluding those with CrCl < 45 mL/min or needing dialysis. Oral MEZI (1 mg) was given on days 1–21 per 28-day cycle + weekly DEX. MEZI doses were not adjusted based on RI. Responses, AEs, and PK were assessed descriptively over the full population and in pts with no RI (CrCl ≥ 90 mL/min), mild RI (CrCl 60–< 90 mL/min), and moderate RI (CrCl 30–< 60 mL/min) at baseline. MEZI clearance and PK exposure were estimated from an integrated population PK model. PK exposure parameters were stratified by chronic kidney disease (CKD) staging. Results: 101 pts received MEZI + DEX in the dose-expansion cohort; 37 had no RI, 41 had mild RI, and 23 had moderate RI. Grade (Gr) 3/4 treatment-emergent AEs (TEAEs) were similar, occurring in 91.1% (overall), 89.2% (no RI), 90.2% (mild RI), and 95.7% (moderate RI) of pts. TEAEs were mostly hematologic, with neutropenia the most common Gr 3/4 TEAE; its occurrence did not differ in no RI (75.7%), mild RI (75.6%), and moderate RI (73.9%) cohorts. Non-hematologic Gr 3/4 TEAEs were low. Eighty-nine (88.1%) and 32 (31.7%) pts had MEZI dose interruptions and reductions, respectively. Overall response rate (ORR) was 40.6% in all pts, 56.8% in no-RI pts, 29.3% in mild-RI pts, and 34.8% in moderate-RI pts (Table). Evaluated as a continuous variable, CrCl showed no apparent relationship with MEZI oral clearance or systemic exposures. This was supported by subgroup evaluation of MEZI exposures by CKD stage. Results showed MEZI exposures in mild or moderate RI are consistent with no RI. Conclusions: Based on renal function, there was no adverse trend between efficacy, safety, and PK of MEZI + DEX. MEZI dose modifications are likely not required for pts with mild to moderate RI. Clinical trial information: NCT03374085 . [Table: see text]

Study of ELU001, a C’Dot drug conjugate (CDC) targeting folate receptor α (FRα) overexpressing solid tumors.

TPS3173 Background: ELU001, pasifolate exatecan, is an ultra-small nanoparticle drug conjugate, known as a CDC (~6 nm), designed to target and penetrate into solid tumors. Due to its size, ELU001 exhibits rapid renal elimination which is expected to reduce or eliminate the toxicities associated with many antibody drug conjugates. ELU001 has ~13 folic acid targeting moieties and ~21 cathepsin-B cleavable exatecan topoisomerase-1 inhibitor payloads covalently bound to short polyethylene glycol chains surrounding a silica core, the C’Dot. ELU001 binds to cancer cells expressing FRα and is internalized into the lysosome where it releases the exatecan payload. ELU001’s dose escalation study reported at ESMO Congress 2023 (1), examined weekly, bi-weekly (Q2W), and tri-weekly schedules over a range of doses in 42 patients. The study revealed that ELU001 could be administered safely and identified a dose level and schedule for the Expansion Studies described below. 22 of the patients with ovarian or endometrial cancers had >1 post-baseline scan(s), of these 2 had a PR and 19 had SD by RECIST v1.1 criteria. ELU001 demonstrated activity against tumors across a range of FRα expression levels, from low to high, retrospectively assessed using the VENTANA FOLR1 RxDx assay and the PS2+ scoring system. Methods: The current multicenter, Tumor Group Expansion open-label phase 1/2 clinical trial investigates ELU001 in patients with ovarian and endometrial cancers and is enrolling three cohorts; 1) ovarian cancer with high FRα expression, 2) ovarian cancer with moderate and low expression and 3) endometrial cancer with low to high expression with assessments based upon the PS2+ scoring system (high = ≥ 75%, moderate = ≥ 50% to < 75%, low = 25% to < 50%, negative = <25% of tumor cells with 2+ or 3+ staining intensity). An initial exploratory dose of 2.0 mg/m2 Q2W was employed in all three cohorts and a second dose of 1.7 mg/m2 Q2W will be studied in the ovarian cancer cohorts. Patients will ultimately be randomized to one of two or more doses to optimize dosing for registration. Primary endpoint: Objective Response Rate (ORR); secondary endpoints include DOR, PFS, TFST, PFS2, OS, adverse events, PK, and ADA assessments. Approximately 20 patients per tumor group will be recruited in the U.S. 1. Ann. Oncol. (2023) 34 (suppl_2): S458-S497. Clinical trial information: NCT05001282 .

Controversias en la fisiopatología de la hipertensión arterial.

Introduction: Purinergic receptors actively participate in the renal alterations in high blood pressure. The elevation of ATP in the renal interstitium activates purinergic receptors, constituting a fundamental pathway in the generation and persistence of arterial hypertension. Objective of the review: This article is a narrative review that aims to show the importance of new concepts in the pathophysiology of arterial hypertension. Essential points of the review: Purinergic receptors are ATP receptors; the more significant the ATP, the greater the purinergic receptors. Elevated ATP concentrations alter fundamental mechanisms related to blood pressure control, such as the pressure natriuresis mechanism and renal sodium excretion, the regulation of glomerular filtration, and the tubuloglomerular feedback mechanism. The alteration of these mechanisms decreases urinary sodium excretion. Whether influenced by genetic alterations or induced by vasoconstrictor peptides, a decrease in renal function and tubulointerstitial injury occur before the glomerulus is injured. The interaction between angiotensin II and purinergic receptors favors the progression of kidney damage. Conclusion: Kidney damage in high blood pressure is critical, so efforts should be made to control hypertension to prevent the progression of kidney damage that leads to kidney failure. To obtain better blood pressure control, developing purinergic receptor antagonists for clinical use is possible.

Charge barriers in the kidney elimination of engineered nanoparticles

The renal elimination pathway is increasingly harnessed to reduce nonspecific accumulation of engineered nanoparticles within the body and expedite their clinical applications. While the size of nanoparticles is recognized as crucial for their passive filtration through the glomerulus due to its limited pore size, the influence of nanoparticle charge on their transport and interactions within the kidneys remains largely elusive. Herein, we report that the proximal tubule and peritubular capillary, rather than the glomerulus, serve as primary charge barriers to the transport of charged nanoparticles within the kidney. Employing a series of ultrasmall, renal-clearable gold nanoparticles (AuNPs) with precisely engineered surface charge characteristics as multimodal imaging agents, we have tracked their distribution and retention across various kidney components following intravenous administration. Our results reveal that retention in the proximal tubules is governed not by the nanoparticle's zeta-potential, but by direct Coulombic interactions between the positively charged surface ligands of the AuNPs and the negatively charged microvilli of proximal tubules. However, further enhancing these interactions leads to increased binding of the positively charged AuNPs to the peritubular capillaries during the initial phase of elimination, subsequently facilitating their slow passage through the glomeruli and interaction with tubular components in a charge-selective manner. By identifying these two critical charge-dependent barriers in the renal transport of nanoparticles, our findings offer a fundamental insight for the design of renal nanomedicines tailored for selective targeting within the kidney, laying down a foundation for developing targeting renal nanomedicines for future kidney disease management in the clinics.

Multimodal Imaging-Guided Stem Cell Ocular Treatment.

Stem cell therapies are gaining traction as promising treatments for a variety of degenerative conditions. Both clinical and preclinical studies of regenerative medicine are hampered by the lack of technologies that can evaluate the migration and behavior of stem cells post-transplantation. This study proposes an innovative method to longitudinally image in vivo human-induced pluripotent stem cells differentiated to retinal pigment epithelium (hiPSC-RPE) cells by multimodal photoacoustic microscopy, optical coherence tomography, and fluorescence imaging powered by ultraminiature chain-like gold nanoparticle cluster (GNC) nanosensors. The GNC exhibits an optical absorption peak in the near-infrared regime, and the 7-8 nm size in diameter after disassembly enables renal excretion and improved safety as well as biocompatibility. In a clinically relevant rabbit model, GNC-labeled hiPSC-RPE cells migrated to RPE degeneration areas and regenerated damaged tissues. The hiPSC-RPE cells' distribution and migration were noninvasively, longitudinally monitored for 6 months with exceptional sensitivity and spatial resolution. This advanced platform for cellular imaging has the potential to enhance regenerative cell-based therapies.

Formulae for estimation of kidney function as an approach to calculating drug doses: A scoping review

Background: The kidneys are the main organ for drug excretion, and it is critical to assess kidney function when designing dosage regimens for drugs that undergo renal elimination. Various formulae have been used to estimate kidney function and safely adjust doses. Objective: This research reviewed studies that assessed patients' kidney function with various approaches to provide appropriate choices of kidney function estimation formulas based on patients' age and clinical conditions. Method: The search involved browsing scientific articles in PubMed and ScienceDirect with the keywords (("assessment") AND ("GFR") AND ("formula")) OR ("renal function") AND ("human")) AND (“Creatinine”). The articles included were those available in full text and English. Thirty articles addressing the formulae for kidney function assessment were reviewed. Result: The Schwartz formula is more appropriate for pediatric and adult patients, whereas the creatinine-based chronic kidney disease epidemiology (CKD-EPI) formula can be used in geriatrics, obese patients, and patients already known to have decreased kidney function. The cystatin C-based CKD-EPI formula is for patients with HIV and post-transplant patients. Conclusion: This study identified that physiological conditions, especially patients’ age and pathology, should be considered in devising formulae to estimate kidney function to accurately calculate safe drug doses.

A phase 1 study to assess the absolute bioavailability, mass balance, pharmacokinetics, metabolism, and excretion of [14C]-mobocertinib, an oral inhibitor of EGFR exon 20 insertion mutations, in healthy participants

Mobocertinib (TAK-788) is a first-in-class oral epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor that received accelerated approval for the treatment of patients with non-small cell lung cancer with EGFR exon 20 insertion mutations previously treated with platinum-based chemotherapy. This phase 1, 2-period, study was conducted to assess the absolute bioavailability of mobocertinib (Period 1), as well as mass balance, pharmacokinetics, metabolism, and excretion of [14C]-mobocertinib (Period 2) in healthy adult males. In Period 1, participants received a single oral capsule dose of 160 mg mobocertinib, followed by a 15-minute intravenous infusion of 50 µg (~ 2 µCi) [14C]-mobocertinib administered from 3.75 to 4 h after the capsule dose. In Period 2, a single oral dose of 160 mg (~ 100 µCi) [14C]-mobocertinib was administered as an oral solution. The geometric mean absolute bioavailability of mobocertinib was determined to be 36.7%. After oral administration of [14C]-mobocertinib, mobocertinib and its active metabolites, AP32960 and AP32914, were minor components in plasma, accounting for only 0.275% of total plasma radioactivity as the majority of mobocertinib-related material was covalently bound to plasma proteins. The geometric mean percentage of the administered radioactive dose recovered in the urine and feces was 3.57% and 76.0%, respectively. Only 0.39% of the oral dose of [14C]-mobocertinib was recovered in the urine as mobocertinib; thus, indicating that renal excretion of unchanged drug was a very minor pathway of elimination. In both treatment periods, mobocertinib was generally safe and well-tolerated as all adverse events were Grade 1 in severity. (Trial registration number ClinicalTrials.gov NCT03811834. Registration date January 22, 2019).

#1429 Daily urinary potassium excretion is not a fixed percentage of daily potassium intake

Abstract Background and Aims High potassium intake is associated with a lower blood pressure and lower incidence of chronic kidney disease. Since a significant amount of potassium is lost via stool, the World Health Organization advices to multiply 24-hour renal potassium excretion by 1.3 for estimation of dietary intake. We analyzed whether this 1.3 factor for potassium intake varies in healthy volunteers and evaluated whether factors associated with tissue cation storage, namely sodium intake, aldosterone, cortisol and urine volume, affect the renal potassium excretion. Method We performed a post-hoc analysis of the long-term sodium balance studies Mars105 and Mars520. Ten healthy male participants consumed a fixed amount of salt (6, 9 and 12 grams/day for >29 days) and potassium (4 grams/day) for 105 (n = 4) and 205 days (n = 6). During the entire study period all urine was collected in 24-hour aliquots. We calculated the percentage of potassium intake that was excreted in the corresponding 24-hour urine collection during steady-state. We assessed whether this percentage was associated with sodium intake, potassium intake, urinary aldosterone, urinary cortisol and urine volume using a multivariable mixed-effects model. Results Overall, the median renal potassium excretion was 80% of potassium intake (IQR 65-97%; range 24-304%). This corresponds to a conversion factor of 1.25 (IQR 1.03-1.54). Within individual subjects we also observed a marked day-to-day variation in the percentage of renal potassium excretion: the average intraperson width of the IQR was 25%. A higher sodium intake was associated with an increased percentage of renal potassium excretion, whereas a higher potassium intake was associated with a decreased percentage of renal potassium excretion. A significant positive interaction between the effects of sodium and potassium intake was present (P < .001; Fig. A). Furthermore, urinary aldosterone (Fig. B), urinary cortisol (Fig. C) and urine volume (Fig. D) were positively associated with the percentage of renal potassium excretion. Conclusion The percentage of consumed potassium that is excreted via urine shows considerable intra- and inter-subject variability. During steady-state this percentage is independently affected by sodium intake, potassium intake, urinary aldosterone, urinary cortisol, and urine volume. Our results suggest that the WHO's fixed 1.3 conversion factor may lead to inaccurate estimations of potassium intake.

#1448 Regulation of renal phosphate excretion independent of FGF23 and PTH

Abstract Background and Aims The phosphaturic hormones fibroblast growth factor 23 (FGF23) and parathyroid hormone (PTH) promote renal phosphate excretion through FGFR1/Klotho and PTH1R-mediated ERK1/2 activation, respectively, leading to inhibition of the sodium-phosphate cotransporters NPT2a (SLC34A1) and NPT2c (SLC34A3) in proximal tubule (PT) cells. In bone cells, high extracellular phosphate can directly activate ERK1/2 via the sodium-phosphate cotransporters PiT-1 (SLC20A1) and PiT-2 (SLC20A2). To date, it is unclear to what extent phosphate can also regulate its own excretion in the kidney independently of FGF23 and PTH. Method To further investigate the role of phosphate in the regulation of renal phosphate homeostasis, male C57BL/6 mice were placed on a 0.8% control phosphate diet (CPD) or a 2% high phosphate diet (HPD) for 6 months. After four months, one HPD group was additionally treated with a calcimimetic (etelcalcetide) to lower FGF23 and PTH. In vitro, PT cells were stimulated with phosphate, FGF23 or PTH ± the phosphate transporter inhibitor foscarnet. Results HPD resulted in increased plasma concentrations of FGF23 and PTH, which were associated with reduced tubular phosphate reabsorption and increased fractional phosphate excretion. RNAseq analyses from isolated PT cells showed a reduction of Fgfr1, Kl, Slc34a1 and Slc34a3 and an induction of Slc20a2 in the HPD group compared to CPD. qPCR and immunoblot analyses of whole kidney tissue confirmed the reduction of the FGF23 co-receptor Klotho in the HPD group, while Fgfr1 was not significantly altered. Protein expression of NPT2a was decreased in isolated brush border membrane vesicles from HPD-fed mice, and immunofluorescence staining showed internalization of NPT2a from the apical brush border membrane. Treatment with etelcalcetide resulted in a reduction of circulating FGF23 and PTH, whereas urinary phosphate excretion in HPD mice remained elevated. In cultured PT cells, high phosphate induced phosphorylation of ERK1/2 and mRNA expression of Slc20a2, while Slc34a1 was suppressed. Phosphate-mediated PiT-2/ERK1/2 activation could be blocked by simultaneous treatment with foscarnet. Conclusion Our data suggest that high phosphate leads to internalization of NPT2a via direct activation of the PiT-2/ERK1/2 signaling cascade, independent of FGF23 and PTH, resulting in increased renal phosphate excretion.

#1926 Persistence to first- and second- generation potassium binder treatment—an observational study based on the DEMONSTRATE database

Abstract Background and Aims Hyperkalemia (HK) is a common electrolyte abnormality mainly caused by reduced renal potassium excretion in patients with chronic kidney disease (CKD). Potassium binders, such as sodium polystyrene sulfonates (SPS) are widely used but may lead to adverse gastrointestinal (GI) symptoms, reducing their tolerability. Patiromer and sodium zirconium cyclosilicate (SZC) are newer ion exchange resins for treatment of HK which may cause fewer GI side-effects. This study aims to evaluate the persistence to first- (SPS) and second-generation potassium binder (patiromer and SZC) treatment and the related clinical characteristics. Method In this observational study based on the DEMONSTRATE database, a novel national and regional database comprising laboratory data from six regions in central Sweden (18% of the Swedish population), linked to the national health registry data, we selected all patients in Sweden having at least one pharmacy dispensation of either first (SPS) or second (patiromer or SZC) generation potassium binder between July 2005 and December 2022. By semi-automatically interpreting the prescribed dosages in combination with the amount of medical supply, duration for each dispensation was estimated and episodes of potassium binder treatments were established. For all potassium binder episodes, we described patient characteristics and persistence to treatment. Results are mainly presented by treatment episodes and by strata of (a) all, (b) first and (c) second generation potassium binders. Results Between July 2005 and December 2022, we identified 68 133 treatment episodes of potassium binders for 32 424 patients (Table 1). Of these, 31 730 individuals and 66 309 treatment episodes were attributed to first generation (throughout the study period), and 1,276 individuals and 1,824 treatment episodes to second-generation potassium binders (between 2018-2022) Mean (SD) age was slightly lower in patients initiating second compared to first generation potassium binders; 68.5 (15.6) vs 65.2 (16.6) years. Potassium binder treatment was more common in men compared to women (66.9% vs. 33.1%) with similar gender distribution between first- and second-generation potassium binders. Comorbidities were more common in patients initiating treatment with second than first generation potassium binders, notably for heart failure (40.0% vs. 29.7%) and dialysis (38.8% vs 29.2%). RAASi and MRA were more often prescribed to the second generation potassium binders vs first; 70.8% vs 62.9% for RAASi and 18.8% vs. 8.5% for MRA. Second generation potassium binders were more commonly initiated in cardiology/internal medicine units (41.7% vs. 34.8%) and dialysis (38.8% vs. 29.2%). Persistence was higher among patients treated with second generation potassium binders (Fig. 1). Conclusion Second generation potassium binders were more often prescribed to younger patients that had more co-morbidities being slightly more persistent to treatment when compared to patients on first generation potassium binders.

#2050 APRT deficiency: insights from in vitro modelling of DHA-induced kidney injury and identification of therapeutic target

Abstract Background and Aims Adenine phosphoribosyltransferase (APRT) deficiency is a rare autosomal recessive disorder of adenine metabolism that results in renal excretion of 2,8-dihydroxyadenine (DHA) in excessive amounts, leading to kidney stones and crystal nephropathy with associated inflammation and fibrosis. The effects of other kidney stone constituents, such as calcium oxalate and uric acid, have been thoroughly studied in cell culture models, both in monolayer and three-dimensional (3D) assays. However, the effect of DHA in cell culture models has not yet been investigated. This study aimed to establish a comprehensive cell culture model to investigate DHA crystal-induced kidney injury and to identify therapeutic targets for clinical intervention. Method Three lines of kidney cells (MDCK, HK-2, and HEK293) were utilized in monolayer and 3D assays, employing both liquid-liquid interface (LLI) and “on-top” of Matrigel culture models. DHA exposure, matching the quantities found in the urine of untreated patients with APRT deficiency, was used in conjunction with siRNA-mediated APRT gene knockdown to assess the changes in cellular phenotypes. Assessments included cell viability and migration assays, RT-PCR, western blotting, phase-contrast microscopy, and immunostaining. Paraffin-embedded kidney tissue samples from patients with APRT deficiency and healthy controls were obtained from the Landspitali National University Hospital Biobank (Icelandic IRB permit: VSN 21-117-V1) and phenotypically analyzed using immunohistochemistry (IHC) staining for collagen I (Col I), collagen III (Col III), and APRT. Results After 72 h of incubation with DHA at concentrations of 60, 120, 240, and 480 μg/mL, the viability of all cell lines decreased. Proliferation was evaluated using a scratch assay after treatment with DHA at two different concentrations (120 and 480 μg/mL) for 24 h, and all cell lines showed decreased migration at the highest concentration. Enhanced CD44 expression was observed in both HEK293 and MDCK cells with increasing DHA concentration. In a 3D environment “on-top” of Matrigel, MDCK cells maintained polarized structures despite accumulation of DHA and did not show an increased EMT phenotype compared with TGFβ-treated cells. HEK293 and HK-2 cells formed solid colonies with DHA accumulation within the colony. MDCK cells formed a polarized cell layer grown on Transwell polyester membranes and demonstrated trans-epithelial electrical resistance (TEER) in LLI, which decreased when the cells were treated with DHA at 120 and 480 μg/mL. APRT expression was significantly reduced in all cell lines after successful knockdown. Analysis of kidney tissue specimens using IHC showed increased expression of Col III in patients with APRT deficiency compared to healthy controls. Enhanced Col I expression was also observed in these patients, which, together with Col III, was consistent with increased fibrosis. Conclusion This study revealed that incubation with varying concentrations of DHA led to decreased viability and impaired migration in all cell lines tested. Increased CD44 expression suggests potential crystal binding to renal tubular epithelial cells when exposed to increasing DHA concentrations. In a 3D environment, MDCK cells maintained polarized structures with DHA accumulation without enhancement of the EMT phenotype. Treatment with DHA resulted in a decrease in TEER, indicating a defective barrier function. Increased expression of Col III and Col I was observed in kidney tissue samples from APRT-deficient patients, suggesting increased fibrosis. Overall, these findings highlight the impact of DHA on cell viability, proliferation, EMT, and barrier function, highlighting the role of DHA in kidney fibrosis in patients with APRT-deficiency.

Population pharmacokinetics and dose rationale for aciclovir in term and pre-term neonates with herpes.

Aciclovir is considered the first-line treatment against Herpes simplex virus (HSV) infections in new-borns and infants. As renal excretion is the major route of elimination, in renally-impaired patients, aciclovir doses are adjusted according to the degree of impairment. However, limited attention has been given to the implications of immature renal function or dysfunction due to the viral disease itself. The aim of this investigation was to characterize the pharmacokinetics of aciclovir taking into account maturation and disease processes in the neonatal population. Pharmacokinetic data obtained from 2 previously published clinical trials (n = 28) were analyzed using a nonlinear mixed effects modeling approach. Post-menstrual age (PMA) and creatinine clearance (CLCR) were assessed as descriptors of maturation and renal function. Simulation scenarios were also implemented to illustrate the use of pharmacokinetic data to extrapolate efficacy from adults. Aciclovir pharmacokinetics was described by a one-compartment model with first-order elimination. Body weight and diagnosis (systemic infection) were statistically significant covariates on the volume of distribution, whereas body weight, CLCR and PMA had a significant effect on clearance. Median clearance varied from 0.2 to 1.0 L/h in subjects with PMA <34 or ≥34 weeks, respectively. Population estimate for volume of distribution was 1.93 L with systemic infection increasing this value by almost 3-fold (2.67 times higher). A suitable model parameterization was identified, which discriminates the effects of developmental growth, maturation, and organ function. Exposure to aciclovir was found to increase with decreasing PMA and renal function (CLCR), suggesting different dosing requirement for pre-term neonates.

ADVANCEMENTS IN UNDERSTANDING THE MOLECULAR MECHANISMS REGULATING URIC ACID METABOLISM IN THE INTESTINE

This review provides contemporary insights into the direct and indirect pathogenetic connections between purine compound metabolism and biochemical processes within the cells of the gastrointestinal system. A thorough analysis of recent publications from 2000 to 2024, sourced from databases including Scopus, PubMed, eLIIBRARY, and Google Scholar, was conducted. Uric acid serves as the end product of purine-containing compound catabolism. Its concentration is intricately regulated through the collaboration of the kidneys and gastrointestinal organs, namely the small intestine and liver. Gout, a chronic condition, emerges from the interplay between molecular genetic factors and external influences. Elevated levels of urates in the blood serum (hyperuricemia) and the deposition of sodium urate crystals in organs and tissues set off a cascade of inflammatory and fibrotic processes within mucosal, smooth muscle, parenchymal, and endothelial cells, including those within the gastrointestinal tract. Normally, a person excretes about 1.5 g of uric acid per day. Under physiological conditions, two-thirds of uric acid is excreted from the body by the kidneys, one-third through the intestines, and a small part is excreted with bile. The hypothesis that links the pathogenesis of hyperuricemia with “renal overload” suggests that the disease may develop as a result of impaired renal excretion with insufficient elimination of uric acid through the intestines. Part of uric acid transport systems actively works in hepatocytes and enterocytes, which determines its formation and clearance. Uric acid transporter proteins are divided into two categories: urate reabsorption transporters and urate excretion transporters, their expression is regulated by transcription factors, hormones and metabolites of intestinal microflora. The influence of intestinal microbiota on uric acid metabolism is related to its participation in purine metabolism, decomposition and elimination of uric acid with metabolites of intestinal flora and inhibition of gouty inflammation and is evaluated as a new therapeutic potential in gout and hyperuricemia, which allows to avoid kidney damage and urolithiasis.

Association between polypharmacy and chronic kidney disease among community-dwelling older people: a longitudinal study in southern China

BackgroundPolypharmacy would increase the risk of adverse drug events and the burden of renal drug excretion among older people. Nevertheless, the association between the number of medication and the risk of chronic kidney disease (CKD) remains controversial. Therefore, this study aims to investigate the association between the number of medication and the incidence of CKD in older people.MethodsThis study investigates the association between the number of medications and CKD in 2672 elderly people (≥ 65 years older) of the community health service center in southern China between 2019 and 2022. Logistic regression analysis was used to evaluate the relationship between polypharmacy and CKD.ResultsAt baseline, the average age of the study subjects was 71.86 ± 4.60, 61.2% were females, and 53 (2.0%) suffer from polypharmacy. During an average follow-up of 3 years, new-onset CKD developed in 413 (15.5%) participants. Logistic regression analysis revealed that taking a higher number of medications was associated with increase of CKD. Compared with people who didn’t take medication, a higher risk of CKD was observed in the older people who taken more than five medications (OR 3.731, 95% CI 1.988, 7.003), followed by those who take four (OR 1.621, 95% CI 1.041, 2.525), three (OR 1.696, 95% CI 1.178, 2.441), two drugs (OR 1.585, 95% CI 1.167, 2.153), or one drug (OR 1.503, 95% CI 1.097, 2.053). Furthermore, age, systolic blood pressure (SBP), white blood cell (WBC), blood urea nitrogen (BUN) and triglyceride (TG) were also independent risk factors CKD (P < 0.05).ConclusionThe number of medications was associated with CKD in older people. As the number of medications taken increased, the risk of CKD was increased.

Exploring the therapeutic benefits of paliperidone in the management of schizophrenia: A promising approach for the mental well-being of this population

Paliperidone is a safe and effective option for the treatment of schizophrenia, with long-acting oral or intramuscular administration. Its low hepatic metabolization and renal excretion minimize complications in patients with pre-existing liver disease, providing greater adherence and therapeutic efficacy. The current study is a literature review, with an active search for “Paliperidone” and “Schizophrenia” on national and international platforms. Twenty-one articles were analyzed in the PubMed and Scielo databases. Twenty-one articles were selected based on an evaluation of the title, abstract and relevance to the study. The period of publication ranged from 2007 to 2024, and all were organized in terms of title, authorship, year of publication and methodology used. The data shows the consistent efficacy of paliperidone in relieving schizophrenic symptoms, its safety and tolerability, highlighting its ability to improve patients' quality of life. Although adverse events were observed, these were generally mild and did not compromise the continuity of treatment. In summary, the data support paliperidone as an effective and safe therapeutic option for schizophrenia, with the potential to improve patients' clinical and psychosocial outcomes. Paliperidone is an effective and well-tolerated option for treating schizophrenia, with studies indicating improved patient compliance and clinical stability. Its low incidence of serious side effects increases long-term safety. This reduces relapse and hospitalization rates, improving quality of life.

Hypoparathyroidism update.

Since the release of the 2022 Second International Workshop Evaluation and Management of Hypoparathyroidism Summary Statement and Guidelines, updates and advances are now available in the cause, complications, and treatment of adult chronic hypoparathyroidism (hypoPTH). This review aims to highlight these new findings and implications to patient care. Postsurgical hypoparathyroidism remains the most common cause, immune-related hypoparathyroidism from checkpoint inhibitors is an emerging autoimmune cause. In a large retrospective cohort study of thyroidectomies, incident fracture was lower, particularly in the vertebra, in the hypoPTH cohort, compared with postthyroidectomy control group. Hypercalciuria increases risk for renal calculi in hypoPTH independent of disease duration and treatment dose. Quality of life is impaired in hypoPTH patients on conventional therapy, improvement was noted post-PTH replacement. TranCon PTH phase 3 RCT reported eucalcemia with reduced renal calcium excretion, normalization of bone turn-over markers, stable BMD and improved quality of life. HypoPTH is a chronic disease associated with significant morbidity and poor Quality of Life. Awareness of treatment targets and follow-up investigations can alleviate patient anxiety regarding over-treatment and under-treatment. Progress in long-acting PTH replacement strategies might provide accessible, feasible alternatives to conventional therapy in brittle hypoPTH patients.

A multiomics approach reveals evidence for phenylbutyrate as a potential treatment for combined D,L-2- hydroxyglutaric aciduria

PurposeTo identify therapies for combined D, L-2-hydroxyglutaric aciduria (C-2HGA), a rare genetic disorder caused by recessive variants in the SLC25A1 gene. MethodsPatients C-2HGA were identified and diagnosed by whole exome sequencing and biochemical genetic testing. Patient derived fibroblasts were then treated with phenylbutyrate and the functional effects assessed by metabolomics and RNA-sequencing. ResultsIn this study, we demonstrated that C-2HGA patient derived fibroblasts exhibited impaired cellular bioenergetics. Moreover, Fibroblasts form one patient exhibited worsened cellular bioenergetics when supplemented with citrate. We hypothesized that treating patient cells with phenylbutyrate (PB), an FDA approved pharmaceutical drug that conjugates glutamine for renal excretion, would reduce mitochondrial 2-ketoglutarate, thereby leading to improved cellular bioenergetics. Metabolomic and RNA-seq analyses of PB-treated fibroblasts demonstrated a significant decrease in intracellular 2-ketoglutarate, 2-hydroxyglutarate, and in levels of mRNA coding for citrate synthase and isocitrate dehydrogenase. Consistent with the known action of PB, an increased level of phenylacetylglutamine in patient cells was consistent with the drug acting as 2-ketoglutarate sink. ConclusionOur pre-clinical studies suggest that citrate supplementation has the possibility exacerbating energy metabolism in this condition. However, improvement in cellular bioenergetics suggests phenylbutyrate might have interventional utility for this rare disease.

Correlation of Serum Magnesium Level in Type 2 Diabetes Mellitus Patient with Microalbuminuria

Diabetic nephropathy is the leading cause of end stage renal disease world wide. Approximately one third of patients with type 2 diabetes have hypomagnesemia, mainly caused by enhanced renal excretion. Magnesium deficit in the diet would induce insulin resistance in humans. If it is chronic, this may lead to macro-vascular and micro-vascular complications of diabetes. This study was designed to know the relationship of serum magnesium level in type 2 diabetic patients with microalbuminuria. This study was conducted at the Department of Laboratory Medicine in Bangabandhu Sheikh Mujib Medical University, Dhaka, Bangladesh. In this study, serum magnesium level and urine microalbumin level of 60 type 2 diabetic patients were measured. Both serum magnesium and urine microalbumin levels were measured by biochemical auto analyzer (Siemens Dimension RL Max). The mean serum magnesium level is lower in type 2 diabetes mellitus patient. There was a negative correlation between serum magnesium level and urinary microalbumin in hypomagnesemia diabetic patients. Identifying and treating hypomagnesemia can delay end stage renal disease in diabetic patient and reduce the clinical and economic burden of diabetic complications in future. The potential benefits of supplementing magnesium in type 2 diabetic patients with hypomagnesemia need to be evaluated further.

Facile Synthesis of Rigid Binuclear Manganese Complexes for Magnetic Resonance Angiography and SLC39A14-Mediated Hepatic Imaging.

Manganese(II)-based contrast agents (MBCAs) are potential candidates for gadolinium-free enhanced magnetic resonance imaging (MRI). In this work, a rigid binuclear MBCA (Mn2-PhDTA2) with a zero-length linker was developed via facile synthetic routes, while the other dimer (Mn2-TPA-PhDTA2) with a longer rigid linker was also synthesized via more complex steps. Although the molecular weight of Mn2-PhDTA2 is lower than that of Mn2-TPA-PhDTA2, their T1 relaxivities are similar, being increased by over 71% compared to the mononuclear Mn-PhDTA. In the presence of serum albumin, the relaxivity of Mn2-PhDTA2 was slightly lower than that of Mn2-TPA-PhDTA2, possibly due to the lower affinity constant. The transmetalation reaction with copper(II) ions confirmed that Mn2-PhDTA2 has an ideal kinetic inertness with a dissociation half-life of approximately 10.4 h under physiological conditions. In the variable-temperature 17O NMR study, both Mn-PhDTA and Mn2-PhDTA2 demonstrated a similar estimated q close to 1, indicating the formation of monohydrated complexes with each manganese(II) ion. In addition, Mn2-PhDTA2 demonstrated a superior contrast enhancement to Mn-PhDTA in in vivo vascular and hepatic MRI and can be rapidly cleared through a dual hepatic and renal excretion pattern. The hepatic uptake mechanism of Mn2-PhDTA2 mediated by SLC39A14 was validated in cellular uptake studies.

255 Anchor Talk: Consider intrinsic factors that regulate homeostasis to optimize sustainability of mineral supplements for swine

Abstract Decades of research has focused on methodologies to improve the efficiency of mineral use while assuring sufficient intake to meet animal well-being and production needs. A primary focus of these efforts is P, as P is the third most expensive category of nutrients supplemented in swine diets. Bioavailability of P is more variable than other nutrients in feed ingredients commonly fed to swine. Due to complexities involved in assessments of P bioavailability efforts shifted to defining P digestibilities for each ingredient. Efforts to refine P digestibilities, based on intake and fecal excretion, even with corrections for endogenous losses, have failed to provide a constant coefficient for feed ingredients that can be included in diet formulations, as the digestibility estimates vary with animal age, production phases and inclusion of enzymes such as phytase. An under-appreciated contribution to inaccuracies of digestible P relates to intrinsic regulation of Ca and P homeostasis by the animal. Regulation of Ca and P homeostasis by PTH and 1,25(OH)2D3, must now include a third mineralotropic hormone, FGF23. Applying insights for intrinsic roles of FGF23 will allow more efficient use of nutrients, especially P and vitamin D. FGF23 regulates activation of vitamin D and controls renal P excretion. Over-supplementation of P signals osteocytes (bone cells embedded in a mineralized matrix) to release intact FGF23 which targets the kidney to block reabsorption of P for maintenance of soft tissue homeostasis, resulting in an inefficient use of dietary P. Intact FGF23 also inhibits hydroxylation of 25-OH D3 to form 1,25(OH)2D3. These endocrine pathways illustrate major roles provided by kidneys and bone to allow adaptation to variable Ca and P inputs, thus maintaining homeostasis. Recent efforts to assess P requirements of sows during gestation and lactation illustrate the sensitivity of using renal excretion of Ca and P to assess requirements. Based on 24-h collections, urine Ca:P ratios &amp;gt; 1.5 were consistent with deficient P intake, ratios from 0.5 to 1.5 reflected P adequacy, and ratios &amp;lt; 0.5 indicated excessive P intake. As a practical method, spot urine samples collected at variable times throughout the day reliably predicted Ca:P ratios in 24-h urine collections. Thus, a simplified approach using Ca to P ratio in spot urine samples can be used to assess P intake adequacy. This practical approach can be applied in commercial sow herd to allow herd-based assessment of P status. In conclusion, within herd assessments, based on urine Ca:P ratios, can be used to determine if P supplements are deficient, adequate, and excessive. As such, significant progress can be made to provide a balance between the need to adequately meet animal need with efforts to minimize negative environmental impacts from over-supplementation of P.