The influence of exposure to inorganic arsenic and other arsenic species on early renal impairment among young adults in Taiwan.

Chronic kidney disease (CKD) poses a significant global public health challenge, with environmental toxins potentially contributing to its prevalence. In Taiwan, where arsenic (As) contamination is endemic in certain areas, assessing its impact on renal health is crucial due to the country's high rates of unexplained CKD. This cross-sectional study assessed associations between urinary As species and early renal impairment biomarkers-the microalbumin-to-creatinine ratio (ACR) and ß2-microglobulin (B2MG)-in 248 young Taiwanese adults (aged 20-29 years). We measured urinary As species (including arsenite [As3+], arsenate [As5+], monomethylarsonic acid [MMA], and dimethylarsinic acid [DMA]) and early renal impairment biomarkers (urinary microalbumin and B2MG levels). Median concentrations of urinary As3+, As5+, MMA, DMA, inorganic As (iAs), and the sum of inorganic and methylated As species (iSumAs) were 1.43, 1.02, 3.79, 31.53, 2.82, and 39.22 µg/g creatinine (Cre.), respectively. We also evaluated the first methylation ratio (FMR) and the second methylation ratio (SMR). After adjusting for potential confounding factors, a multivariate linear regression showed significant associations between B2MG and urinary As5+ (ß = 0.299, 95% confidence interval [CI]: 0.113-0.485) and iAs (ß = 0.281, 95% CI: 0.061-0.502) concentrations. A generalized additive model revealed non-linear relationships among As5+, iAs, and B2MG concentrations. Moreover, there were elevated risks associated with the highest tertile of B2MG concentrations compared to the highest tertile of urinary As5+ (odds ratio [OR] = 2.366, 95% CI: 1.196-4.682), MMA (OR = 1.917, 95% CI: 1.002-3.666), DMA (OR = 1.952, 95% CI: 1.015-3.753), and iSumAs (OR = 2.302, 95% CI: 1.182-4.483). These results indicated that exposure to As was associated with early renal impairment, particularly evidenced by increased urinary B2MG concentrations.

Carfilzomib­Induced Thrombotic Microangiopathy­Two Case Reports.

BACKGROUND: Thrombotic microangiopathy (TMA) is a pathological syndrome characterized by a combination of three key features: microangiopathic hemolytic anemia (MAHA), thrombocytopenia, and organ damage, primarily affecting the kidneys. There are several drugs known to have a definite or probable causal association with TMA, and carfilzomib, a second-generation irreversible proteasome inhibitor (PI), approved for the treatment of multiple myeloma (MM), is one of them. In the medical literature, there have been a growing number of reports describing this serious adverse event occurring in MM patients. The precise mechanisms underlying the development of PI-induced TMA are not yet fully understood. Significant improvements in both renal and hematological aspects have been documented following the administration of eculizumab. RECENT FINDINGS: In this report, we present two cases of MM patients who developed TMA while undergoing carfilzomib therapy. These cases were successfully treated at the Haematology Unit, Careggi Hospital in Florence. In our cases as well, the introduction of eculizumab resulted in rapid enhancements in renal function and platelet count, ultimately leading to the discontinuation of hemodialysis after 4 and 2 weeks, respectively. DISCUSSION AND CONCLUSION: We assessed 91 patients who received carfilzomib-based therapies at our Haematology Department, during which we identified two cases of DITMA (2.2% incidence). Additionally, we conducted a literature review and discovered a total of 75 documented cases of carfilzomib-induced TMA. Our experience aligns with the cases reported in literature: this adverse event can manifest at any point during treatment, regardless of the specific drug combinations used alongside carfilzomib. The initial and most crucial step in its management involves discontinuing carfilzomib therapy; therefore, recognizing TMA in a timely manner is of utmost importance. Eculizumab could play a role in improving and expediting the resolution of this potentially fatal adverse event, but further studies are needed. In a MM patient receiving carfilzomib, presenting with anemia, thrombocytopenia, and impaired renal function, a carfilzomib-induced TMA should be suspected in order to discontinue the causative agent.

Population Pharmacokinetic Simulations for Dose Optimization of Tenofovir Disoproxil Fumarate in HIV-Infected Patients with Moderate-to-Severe Renal Impairment.

Tenofovir disoproxil fumarate (TDF) requires dosage adjustments from the standard 300 mg once daily to every 48-96 h for moderate-to-severe renal impairment to avoid excessive exposure. However, this extended interval can lead to variable drug exposure and inconvenience. This study aimed to utilize the population pharmacokinetic (PPK) models to optimize TDF dosing regimens for HIV-infected patients with renal impairment. A systematic literature search was conducted across PubMed, Cochrane Library, and Scopus databases to identify relevant PPK studies of TDF in HIV-infected patients. From the included studies, the PPK models and associated parameters were extracted. Monte Carlo simulations (n = 2000) were performed to generate concentration-time profiles and derive PK parameters compared against reference ranges. For moderate renal impairment, the TDF 150 mg once-daily regimen achieved cumulative exposure comparable to the approved 300 mg every-other-day regimen. In severe renal impairment, TDF 75-100 mg administered once daily provided similar cumulative exposure as 300 mg every 72-96 h regimen while maintaining daily exposure comparable to the standard dose in patients with normal renal function. The approved extended dosing intervals of 72-96 h exhibited high drug exposure variability, initially resulting in supratherapeutic levels followed by suboptimal levels preceding the subsequent dose administration. In conclusion, administering smaller once-daily doses of TDF maintains consistent daily drug exposure comparable to the standard dose in patients with normal renal function while reducing variability in drug exposure, potentially mitigating the risk of nephrotoxicity. However, additional clinical studies are required to confirm these findings.

A comparative study of postadrenalectomy hyperuricemia and renal impairment in patients with unilateral primary aldosteronism: does histopathology subtype matter?

BACKGROUND: Primary aldosteronism (PA), which is present in 5-18% of hypertensive patients, is a leading cause of secondary hypertension. Adrenalectomy is often recommended for patients with unilateral primary aldosteronism (uPA), yielding good long-term outcomes. PA patients without hyperuricemia and chronic renal failure before adrenalectomy were enrolled in this cohort study. Serum uric acid (SUA) and renal filtration were measured one year post-adrenalectomy. Their relationships with pathologic features, histopathological subtype (classical or nonclassical (HISTALDO consensus)), and vessel stiffness were explored. The aim of this cohort study is to evaluate the correlation between post-adrenalectomy serum uric acid (SUA) levels and estimated glomerular filtration rate (eGFR) with the pathologic features delineated by the HISTALDO consensus. Additionally, the study seeks to assess the impact of these biochemical markers on peripheral vessel stiffness and brachial-ankle pulse wave velocity (baPWV) at a one-year follow-up visit. METHODS: This prospective cohort study included patients (N = 100) diagnosed with uPA who underwent adrenalectomy from Jan 1, 2007 to Dec 31, 2022. RESULTS: At follow-up, elevated SUA, hyperuricemia, and a > 25% eGFR decrease were significantly more common in the classical than the nonclassical group. The incidence of postoperative hyperuricemia, herein referred to as post-adrenalectomy hyperuricemia (PAHU), was 29% (29/100) overall, 34.8% (23/66) in the classical group and 17.6% (6/34) in the nonclassical group. The incidence of eGFR reduction > 25% was 33% (33/100), 43.9% (29/66), and 11.8% (4/34), respectively. baPWV decreased more in the classical group than the nonclassical group. CONCLUSION: For PA patients with PAHU and/or renal impairment, we suggest monitoring SUA, pH, urine uric acid, and urine crystals and performing a KUB study and peripheral vascular and renal sonography (on which pure uric acid stones in the KUB are radiolucent) to determine whether drug intervention is required for cases of asymptomatic PAHU, especially patients in male gender, classical histopathology, or renal impairment.

The role of interleukin-20 and vascular endothelial growth factor-A biomarkers in the detection of renal impairment in patients with multiple myeloma.

BACKGROUND: Multiple myeloma (MM) is a malignant incurable disease characterized by monoclonal plasma cell increase associated with renal impairment. Evaluation of neutrophil-to-lymphocyte ratio (NLR), monocyte-to-lymphocyte ratio (MLR), platelet-to-lymphocyte ratio (PLR), hemoglobin/red cell distribution width (HB/RDW), interleukin-20 (IL-20), and vascular endothelial growth factor-A (VEGFA) in patients with MM (with or without renal impairment) as prognostic and severity indicators. RESEARCH DESIGN AND METHODS: A cross-sectional study was conducted on sixty MM patients with renal impairment, sixty MM patients without renal impairment, and sixty subjects (control group). Complete blood count, IL-20 immunoassay, and gene expression of IL-20, and VEGFA were evaluated. RESULTS: Higher levels of NLR, MLR, and IL-20, and moreover lower levels of PLR, HB/RDW, as well as upregulation of IL-20, and VEGFA gene expression were detected in MM patients, especially those with renal impairment. Receiver operating characteristic curves analysis of NLR, MLR, PLR, and IL-20 showed high sensitivity and specificity in the diagnosis of MM and disease stages. CONCLUSIONS: NLR, MLR, PLR, HB/RDW, IL-20, and VEGFA may be implicated in the inflammatory process of MM and renal impairment pathogenesis. NLR, MLR, and IL-20 can be used as prognostic markers in MM stages.

Prevalence and Risk Factors of Inappropriate Drug Dosing among Older Adults with Dementia or Cognitive Impairment and Renal Impairment: A Systematic Review.

Background: Potentially inappropriate medication prescribing is prevalent and well studied in older adults. However, limited data are available on inappropriate drug dosing in those with dementia or cognitive impairment and renal impairment. Objectives: We aimed to examine the prevalence of, and factors associated with, inappropriate drug dosing in older patients with dementia or cognitive impairment and renal impairment. Methods: We adhered to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guideline and the Cochrane Handbook for Systematic Reviews of Interventions. We searched Medline, Embase, CINAHL, and PubMed for studies on inappropriate drug dosing in older patients with dementia or cognitive impairment and renal impairment, published from 1 January 2000 to 31 August 2024, with English language restriction following the PICOS search strategy. Two reviewers independently screened all titles and abstracts, extracted data from included studies, and undertook quality assessment using the Joanna Briggs Institute (JBI) tool. Descriptive statistics were used to summarise and present findings. Results: In total, eight retrospective cohort studies were included. Of the total number of patients with dementia who had renal impairment (n = 5250), there were 2695 patients (51.3%; range: 0-60%) who had inappropriate drug dosing. Drugs commonly prescribed in inappropriate doses in patients with dementia who had renal impairment included memantine, baclofen, nonsteroidal anti-inflammatory drugs (NSAIDs), metformin, digoxin, morphine, and allopurinol. The studies did not identify statistically significant risk factors for inappropriate drug dosing. Conclusions: Inappropriate drug dosing among older adults with dementia or cognitive impairment and renal impairment appears to occur frequently. While our findings should be interpreted with caution owing to the small number of studies and substantial heterogeneity, proactive prevention, recognition, and management of inappropriate drug dosing in this population is warranted.

Effect of Renal and Hepatic Impairment on the Pharmacokinetics of Pritelivir and Its Metabolites.

Two trials were performed to evaluate the effect of renal and hepatic impairment on the pharmacokinetics of pritelivir and its metabolites. The renal impairment trial included subjects with mild, moderate, and severe impairment, while the hepatic impairment trial included subjects with moderate impairment. Both trials recruited a matched control group of healthy subjects. Following a single oral dose of 100 mg of pritelivir, mild and moderate renal impairment and moderate hepatic impairment did not have a clinically relevant effect on the pharmacokinetics of pritelivir. In subjects with severe renal impairment, pritelivir exposure (area under the plasma concentration-time curve from time 0 to infinity (AUC0- inf) was 57% higher compared with controls. Pritelivir plasma protein binding was similar in subjects and controls with renal impairment, while the free fraction was higher in subjects with moderate hepatic impairment, increasing unbound pritelivir exposure by 23%. For the metabolites pyridinyl phenyl acetic acid (PPA), amino thiazole sulfonamide (ATS), and PPA-acyl glucuronide, generally higher exposure was observed with increasing degree of renal impairment (ie, moderate to severe), but not with mild impairment. A modest effect of moderate hepatic impairment was observed for PPA and ATS. Pritelivir was safe and well tolerated in healthy subjects and subjects with renal or hepatic impairment.

Pharmacokinetics and Safety of Pemafibrate in Patients with both Dyslipidemia and Severe Renal Impairment: A Phase 4 Study.

AIMS: Per the package insert, pemafibrate was contraindicated for use in patients with severe renal impairment despite its biliary excretion. To validate this, we evaluated the pharmacokinetics and safety of pemafibrate for 12 weeks in patients with hypertriglyceridemia and renal impairment. METHODS: In this phase 4, multicenter, placebo-controlled, double-blind, parallel-group, comparative study, 21 patients were randomly assigned to pemafibrate 0.2 mg/day or placebo within Groups A (estimated glomerular filtration rate [eGFR] ＜30 mL/min/1.73m2 without hemodialysis; pemafibrate n=4; placebo, n=2), B (hemodialysis; pemafibrate, n=4; placebo, n=1), and C (eGFR ≥ 30 and ＜60 mL/min/1.73m2 without hemodialysis; pemafibrate, n=8; placebo, n=2) for 12 weeks. Area under the concentration vs time curve within the dosing interval (τ) (AUCτ) of pemafibrate was measured after 12-week administration. RESULTS: The AUCτ (geometric mean) of pemafibrate was 7.333 and 7.991 ng·h/mL in Groups A+B and C, respectively; in Groups A+B to C at 12 weeks, the geometric mean ratio of pemafibrate AUCτ was 0.92 (90% confidence interval [CI]: 0.62, 1.36). The upper limit of the 90% CI was ≤ 2.0 (predetermined criterion). There was no consistent trend in the AUCτ and maximum plasma concentration of pemafibrate with/without statin use. Renal impairment degree did not affect the incidence of adverse events. No safety concerns were observed. CONCLUSION: Pemafibrate repeated administration in patients with severe renal impairment did not increase pemafibrate exposure.

Role of Urinary Matrix Metalloproteinase-7 (MMP-7) as an Early Marker of Renal Dysfunction in Diabetic Individuals: A Cross-Sectional Study.

BACKGROUND AND OBJECTIVES: The matrix metalloproteinase 7 (MMP-7) level gets heightened in the urine samples of diabetic individuals with impaired renal function. Renal biopsy is seldom offered because of its invasive nature. These concerns spurred the investigation of relationships between urine MMP-7 levels and the renal function of diabetic individuals. Studies exploring this aspect are scarce. We aimed to evaluate the glycemic and renal parameters of female and male individuals with or without type 2 diabetes mellitus (T2DM) or kidney disease. We also assessed the correlation of urine MMP-7 with various parameters. METHODS: This prospective, analytical, cross-sectional study was conducted at Kalinga Institute of Medical Sciences (KIMS), Bhubaneswar, India, from February 2020 to January 2023. Female and male individuals 18-85 years of age diagnosed with either T2DM, hypertension, or kidney disease were assessed for their glycemic indices and renal parameters. Those with both renal disease and T2DM were placed in group A. The diabetic individuals without kidney disease constituted group B. People in group C had neither kidney disease nor T2DM. Patients in group D had kidney disease but were not diabetics. The parameters of the male and female participants in each of the four groups were assessed and compared, including: age, body mass index (BMI), fasting blood sugar (FBS), glycosylated hemoglobin (HbA1c), serum urea, serum creatinine, estimated glomerular filtration rate (eGFR), urine albumin, urine creatinine, urine albumin-creatinine ratio (ACR), serum sodium, serum potassium, and urine MMP-7 levels. Furthermore, we correlated urine MMP-7 with all these traits. We used R software (version 4.4.0, Vienna, Austria) for data analysis. RESULTS: Two hundred eighty-seven (87.5%) of the 328 individuals we screened were eligible. Of them, group A had the maximum number (94) of participants, followed by B (75), C (65), and D (53). Males comprised 60.3% (n = 173) of the study population. The median age of the participants was 52.0 (44.0-61.1) years. The intergroup variations were statistically significant (p < 0.001) owing to their glycemic status and renal function. The gender-basis comparison of FBS and HbA1c yielded non-significant differences. On the contrary, assessment of the renal parameters revealed significant differences (p < 0.001) between females and males. The study population had a median urine MMP-7 level of 19.9 (1.1-50.5) µg/L. Significant associations with urine MMP-7 were found with serum creatinine (r = 0.91, p < 0.001), urine ACR (r = 0.86, p < 0.001), and eGFR (r = -0.84, p < 0.001). CONCLUSION: Our study portrayed that male diabetics, in comparison to female diabetics, had greater levels of urine ACR, urine MMP-7, eGFR, and serum creatinine. Moreover, urine ACR, eGFR, and serum creatinine strongly correlated with the urine MMP-7 level.

Application of Physiologically Based Pharmacokinetic Model to Delineate the Impact of Aging and Renal Impairment on Ceftazidime Clearance.

The impact of physiological changes during aging on drug disposition has not always been thoroughly assessed in clinical studies. This has left an open question such as how and to what extent patho- and physiological changes in renal function can affect pharmacokinetics in the geriatric population. The objective of this work was to use a physiologically based pharmacokinetic (PBPK) model to quantify the impact of aging and renal impairment (RI) separately and together on ceftazidime pharmacokinetics (PK). The predicted plasma concentrations and PK parameters from the PBPK model were compared to the observed data in individuals of different ages with or without RI (16 independent studies were investigated in this analysis). Apart from clearance in one study, the predicted ceftazidime PK parameters of young adults, elderly, and in individuals with different levels of renal function were within 2-fold of the observed data, and the observed concentrations fell within the 5th-95th prediction interval from the PBPK model simulations. The PBPK model predicted a 1.2-, 1.5-, and 1.8-fold increase in the plasma exposure (AUC) ratio in individuals aged 40, 60, and 70 years old, respectively, with normal renal function for their age compared to 20-year-old individuals with normal renal function. The impact of RI on ceftazidime was predicted to be less marked in older individuals (a 1.04-, 1.43-, and 2.55-fold change in mild, moderate, or severe RI compared to a healthy age-matched control) than in younger individuals (where a 1.47-, 2.03-, and 3.50-fold increase was predicted in mild, moderate, or severe RI compared to a healthy age-matched control). Utilization of the applied population-based PBPK approach allows delineation of the effects of age from renal disease and can better inform future study design and dosing recommendations in clinical study of elderly patients depending on their age and renal function.

VEPTP inhibition with an extracellular domain targeting antibody did not restore albuminuria in a mouse model of diabetic kidney disease.

Diabetic kidney disease (DKD) is the leading cause of end-stage kidney disease. DKD is a heterogeneous disease with complex pathophysiology where early endothelial dysfunction is associated with disease progression. The Tie2 receptor and Angiopoietin 1 and 2 ligands are critical for maintaining endothelial cell permeability and integrity. Tie2 signaling is negatively regulated by the endothelial specific transmembrane receptor Vascular Endothelial Protein Tyrosine Phosphatase (VEPTP). Genetic deletion of VEPTP protects from hypertension and diabetes induced renal injury in a mouse model of DKD. Here, we show that VEPTP inhibition with an extracellular domain targeting VEPTP antibody induced Tie2 phosphorylation and improved VEGF-A induced vascular permeability both in vitro and in vivo. Treatment with the VEPTP blocking antibody decreased the renal expression of endothelial activation markers (Angpt2, Edn1, and Icam1) but failed to improve kidney function in db/db uninephrectomized ReninAAV DKD mice.

Impact of multiple comorbidities on long-term mortality in older patients following transcatheter aortic valve replacement.

Background: Older candidates for transcatheter aortic valve replacement (TAVR) frequently present with both cardiac and noncardiac comorbidities. There are few risk scores that evaluate a wide range of comorbidities. Methods: Patients who underwent TAVR for severe aortic stenosis were retrospectively evaluated. A new prediction model (Cardiac and nonCardiac Comorbidities risk score: 3C score) was determined based on coefficient in the multivariate Cox regression analysis for two-year all-cause mortality. C-statistics were assessed to compare the predictive abilities of the 3C score, the Charlson Comorbidities Index (CCI) score, the European System for Cardiac Operative Risk Evaluation (EuroSCORE) II, and the Model for End-stage Liver Disease eXcluding International normalized ratio (MELD-XI) score. Results: The present study included 226 patients (age, 86 ± 5 years; males, 38 %). The values of the CCI score, EuroSCORE II, and MELD-XI score were 2 (1-3), 3.36 (2.12-4.58), and 5.35 (3.05-8.55), respectively. Multivariate Cox regression analysis identified two cardiac (left ventricular ejection fraction [LVEF] <40 % [2 points]; pulmonary hypertension [1 point]) and three noncardiac comorbidities (hepatobiliary system impairment [3 points]; estimated glomerular filtration rate <30 ml/min/1.73 m2 [1 point]; cachexia [1 point]). The C-statistics of the 3C score, EuroSCORE II, MELD-XI score, and CCI score were 0.767 (0.666-0.867), 0.610 (0.491-0.729), 0.580 (0.465-0.696), and 0.476 (0.356-0.596), respectively (p < 0.001). Conclusions: Among cardiac and noncardiac comorbidities, special attention should be given to hepatobiliary system impairment and reduced LVEF in older patients following TAVR. The 3C score may contribute to the risk stratification.

Predictive value of fine fibrillatory wave for declining eGFR in patients with persistent atrial fibrillation: Long-term follow-up study.

BACKGROUND: Renal dysfunction has been identified as a risk factor for both stroke and bleeding events in atrial fibrillation (AF) patients, yet the mechanisms remain unclear. We examines the connection between fine fibrillatory wave and estimated glomerular filtration rate (eGFR) decline, alongside chronic kidney disease (CKD). METHODS: Persistent AF patients admitted to Jinan University's First Affiliated Hospital from January 2019 to June 2023 were enrolled. Kaplan-Meier analysis explored kidney endpoints for coarse and fine fibrillatory wave. A multivariate Cox model estimated adjusted hazard ratios (HR) and 95 % confidence intervals (95 % CI) to determine the correlation between fine fibrillatory wave and eGFR decline, as well as CKD. RESULTS: Of the 3521 AF patients, 229 were ultimately included in the analysis of this study. The median age of these patients was 75 years, with 58 % being male. The median follow-up time was 23 months, and the mean eGFR was 70 ± 19 mL/min/1.73 m2. Multivariate COX regression analysis revealed fine fibrillatory wave (HR = 8.311, 95 % CI 3.418-20.211, p < 0.001) as an independent risk factor associated with a ≥ 30 % decline in eGFR. Among 166 AF patients with eGFR >60 mL/min/1.73 m2, 40 cases (24 %) experienced a decline to <60 mL/min/1.73 m2. In comparison to coarse fibrillatory wave, the risk of fine fibrillatory wave causing eGFR decline to <60 mL/min/1.73 m2 was approximately 4.6 times higher (HR = 4.645, 95 % CI 2.127-10.142, p<0.001). CONCLUSIONS: Fine fibrillatory wave was independently associated with the risk of eGFR decline ≥30 % and eGFR decline to <60 mL/min/1.73 m2.

Anticoagulant therapy in renal insufficiency theme: Anticoagulation in complex situations.

Many patients with impaired renal function have concurrent indications for anticoagulant therapy, including atrial fibrillation and venous thromboembolism. For mild chronic kidney disease, data from clinical trials and existing guidelines can be applied to clinical management. The benefits and harms of anticoagulation therapy in patients with more advanced renal impairment are nuanced, as both thrombotic and bleeding risk are increased. Until recently, data regarding anticoagulants in severe renal impairment were primarily observational, but emerging evidence includes a few small clinical trials and the emergence of novel agents hypothesized to have improved efficacy and safety in this population. In this review, we summarize existing data on anticoagulation in patients with chronic kidney disease. We suggest a framework for anticoagulation decision-making in the burgeoning worldwide population of patients with chronic kidney disease.

The effect of severe renal impairment on the pharmacokinetics, safety and tolerability of mitiperstat.

AIMS: Mitiperstat is a novel, highly potent myeloperoxidase inhibitor being evaluated in patients with cardio-metabolic disease (phase 2). These patients often have impaired renal function, which may affect mitiperstat pharmacokinetics. This study assessed mitiperstat pharmacokinetics, safety and tolerability in participants with severe renal impairment and normal renal function, to inform inclusion of participants with estimated glomerular filtration rate (eGFR) < 30 mL/min/1.73 m2 in phase 3. METHODS: Participants with severe renal impairment (eGFR ≥15 and <30 mL/min/1.73 m2) who were not on dialysis (n = 10) and group-matched controls (eGFR ≥90 mL/min/1.73 m2; n = 10) received a single mitiperstat 2.5 mg oral tablet. Blood samples were collected at intervals for 2 weeks and urine samples for 24 h post-dose. RESULTS: Total apparent mitiperstat clearance was 10.83 L/h in the severe renal impairment cohort and 25.62 L/h in the control cohort. The area under the plasma concentration-time curve was 2.37-fold higher (90% confidence interval [CI]: 1.79, 3.12) in the severe renal impairment cohort than in the control cohort, with longer elimination half-life and similar maximum concentration. Non-renal clearance was similar between the cohorts. CONCLUSIONS: Mitiperstat apparent clearance was approximately twofold lower in individuals with severe renal impairment than in those with normal renal function. Lower clearance was driven by reduced renal clearance; non-renal clearance was similar. Mitiperstat was generally well tolerated by participants with severe renal impairment and normal renal function. These findings, together with efficacy and safety/tolerability data from phase 2b, will guide the dosing regimen for phase 3.

A Novel Formulation of Ketorolac Tromethamine (NTM-001) in Continuous Infusion in Adults with and without Renal Impairment: A Randomized Controlled Pharmacologic Study.

INTRODUCTION: There is a medical need for a safe, effective nonopioid postoperative analgesic for older subjects, including those with mild to moderate renal impairment. METHODS: Participants (≥ 65 years) were stratified by no, mild, or moderate renal impairment defined as creatinine clearance 60-89 mL/min for mild and 30-59 mL/min for moderate. Subjects were randomized to receive a loading dose of 6.25 mg of ketorolac tromethamine drug candidate NTM-001 followed by a 1.75 mg/h continuous intravenous (IV) infusion over 24 h or an IV bolus injection of ketorolac tromethamine (KETO-BOLUS) of 15 mg every 6 h. There were four treatment periods of 24 h for each subject with a minimum 7-day washout between them. This was a crossover study so subjects served as their own controls. Blood drawn from the subjects was used to plot concentration-time profiles against target profiles. Adverse events were monitored. RESULTS: Thirty-nine subjects enrolled. Concentration-time profiles showed low intersubject variability. Model-predicted curves for those with renal impairment closely matched observed plasma concentrations. Continuous infusion maintained higher mean plasma concentrations than the bolus regimen. No serious or unexpected adverse events were observed. No deaths occurred. CONCLUSIONS: NTM-001 was considered safe and well tolerated in this population of participants ≥ 65 years, including in those with mild or moderate renal impairment. There were fewer adverse events in the continuous infusion group. The predictable pharmacologic properties and blood concentration levels suggest that continuous IV infusion of ketorolac can be used as an effective postoperative pain reliever in older subjects.

Controlling postoperative pain can lead to faster recovery. Ketorolac tromethamine is a nonsteroidal anti-inflammatory drug (NSAID), like ibuprofen and naproxen, that can be as effective as morphine without the same risks. In hospitals, ketorolac is usually administered intravenously (IV) either continuously or as a bolus injection. A bolus of ketorolac may result in adverse gastrointestinal side effects. In this study, a new formulation of ketorolac tromethamine, NTM-001, was administered IV as a continuous 24 h infusion compared to IV boluses of ketorolac tromethamine every 6 h in volunteers. Volunteers were older (≥ 65 years) and had no, mild, or moderate kidney dysfunction. One randomized group received a starting IV dose of 6.26 mg followed by a continuous IV infusion of 1.75 mg/h of over 24 h. The other group received single NTM-001 IV bolus injections of ketorolac tromethamine 15 mg every 6 h over 24 h (4 doses, 60 mg) over the 24 h. After completing the first study, subjects waited at least a week and then switched groups, giving the study a crossover design so it could be observed how each subject responded to both regimens. Blood drawn from the subjects was tested for standard pharmacokinetic (PK) parameters. The data show that blood concentrations of NTM-001 can be reliably predicted. Side effects were mild and the continuous infusion reduced side effects. No unexpected adverse events occurred. These data show that NTM-001 can be used safely in older individuals, including those with mild or moderate kidney impairment.

Albumin-to-Globulin Ratio Combined with Neutrophil-to-Lymphocyte Ratio as a Prognostic Predictor in Multiple Myeloma with Renal Impairment.

Background: The albumin-to-globulin ratio (AGR) and neutrophil-to-lymphocyte ratio (NLR) have been recently regarded as promising prognostic factors in various malignancies. The present study investigated the prognostic value of combining the AGR and NLR (ANS) for risk assessments in multiple myeloma (MM) with renal impairment (RI). Methods: From 2011 to 2018, 79 patients with MM and RI were enrolled in this study. Receiver operating curves (ROCs) were constructed to determine optimal AGR and NLR thresholds for predicting overall survival (OS) and progression-free survival (PFS) during follow up. The prognostic values of AGR, NLR, and ANS were evaluated with Cox regression and Kaplan-Meier methods. We also created a predictive nomogram for prognostic evaluations of OS and PFS, and the predictive accuracy was assessed with a concordance index (c-index). Results: The ROC curves analyses showed that the optimal cut-off levels were 2.27 for NLR and 1.57 for AGR. A high NLR and a high ANS were significantly associated with worse OS and PFS. However, a high NLR combined with a low AGR was associated with worse OS. Multivariate analyses demonstrated that both the NLR and ANS were independent predictors for both OS and PFS and that a low AGR was an independent predictor of a reduced OS. The nomogram accurately predicted OS (c-index: 0.785) and PFS (c-index: 0.786) in patients with MM and RI. Conclusion: ANS may serve as a potential prognostic biomarker in patients with MM and RI. The proposed nomograms may facilitate prognostic predictions for patients with MM and RI.

Expanding Role of Endogenous Biomarkers for Assessment of Transporter Activity in Drug Development: Current Applications and Future Horizon.

The evaluation of transporter-mediated drug-drug interactions (DDIs) during drug development and post-approval contributes to benefit-risk assessment and helps formulate clinical management strategies. The use of endogenous biomarkers, which are substrates of clinically relevant uptake and efflux transporters, to assess the transporter inhibitory potential of a drug has received widespread attention. Endogenous biomarkers, such as coproporphyrin (CP) I and III, have increased mechanistic understanding of complex DDIs. Other endogenous biomarkers are under evaluation, including, but not limited to, sulfated bile acids and 4-pyridoxic acid (PDA). The role of endogenous biomarkers has expanded beyond facilitating assessment of transporter-mediated DDIs and they have also been used to understand alterations in transporter activity in the setting of organ dysfunction and various disease states. We envision that endogenous biomarker-informed approaches will not only help to formulate a prudent and informed DDI assessment strategy but also facilitate quantitative predictions of changes in drug exposures in specific populations.

Right Ventricular and Right Atrial Strain Are Associated with Kidney Dysfunction in Acute Heart Failure.

BACKGROUND: In acute heart failure (HF), low cardiac output and venous congestion are pathophysiological mechanisms that contribute to renal function impairment. This study investigated the association between advanced echocardiographic measures of right ventricular and atrial function and renal impairment in patients with acute HF. METHODS AND RESULTS: A total of 377 patients hospitalized for acute HF were prospectively evaluated. Estimated glomerular filtration rate (eGFR) on admission was measured using the 2021 Chronic Kidney Disease Epidemiology Collaboration creatinine equation. Advanced echocardiographic assessment was performed on admission. Patients with eGFR < 45 mL/min/1.73 m2 were more likely to have chronic heart failure, chronic atrial fibrillation, and type 2 diabetes mellitus compared to patients with eGFR ≥ 45 mL/min/1.73 m2. Patients with lower eGFR had lower cardiac output, higher mean E/e' ratio, larger right ventricular (RV) size, worse RV free wall longitudinal strain, more impaired right atrial (RA) reservoir strain, and more frequent severe tricuspid regurgitation. RV free wall longitudinal strain and RA reservoir strain were the only independent echocardiographic associates of low eGFR, whereas cardiac output was not. CONCLUSIONS: Impaired RV and RA longitudinal strain were independently associated with eGFR < 45 mL/min/1.73 m2 in acute HF, while reduced cardiac output was not. This suggests that RV and RA dysfunction underlying venous congestion and increased renal afterload are more important pathophysiological determinants of renal impairment in acute HF than reduced cardiac output.

Prognosis of concurrent renal impairment at diagnosis of multiple myeloma: a systematic review.

BACKGROUND: Multiple myeloma is a malignant tumour of the blood in which abnormal proliferation of plasma cells leads to bone destruction, renal impairment, anaemia, and hypercalcaemia. Renal impairment caused by multiple myeloma is a common and serious condition; however, the prognosis of multiple myeloma at the time of diagnosis remains unclear. METHOD: We conducted searches for literature in PubMed, Web of Science, Cochrane, Embase, CNKI, Wanfang, and VIP databases up to 30 April 2023. Progression-free survival and overall survival with and without renal impairment at the time of multiple myeloma diagnosis were compared, and prognostic indicators were analysed. RESULTS: Six studies were finally included. Among patients with multiple myeloma, 319 had renal impairment, and 1166 had no renal impairment. Compared to the control group, no significant difference was observed in overall or progression-free survival in patients with multiple myeloma complicated with renal impairment. CONCLUSION: The limited low-quality evidence available does not support an association between prognosis and multiple myeloma complicated by kidney injury.