Normal Renal Function Subjects Research Articles

Pharmacokinetic evaluation of single-dose migalastat in non-Fabry disease subjects with ESRD receiving dialysis treatment, and use of modeling to select dose regimens in Fabry disease subjects with ESRD receiving dialysis treatment.

Fabry disease (FD) is an X-linked lysosomal disorder leading to multiorgan dysfunction, including renal impairment and the risk of significant accumulation for renally excreted drugs. Migalastat, an approved therapy in FD patients with amenable variants, is primarily eliminated in urine; however, its use had not been studied in patients with end-stage renal disease (ESRD) receiving dialysis therapy. This study investigated the pharmacokinetics (PK), dialyzability, and tolerability of 123 mg migalastat in non-FD subjects with ESRD on stable hemodialysis/hemodiafiltration (EudraCT 2018-003684-57). Results were analyzed by population PK and physiologically based PK (PBPK) modeling and intended to propose dose regimens resulting in negligible migalastat trough levels in plasma and comparable concentrations above the threshold in target tissues in FD patients with ESRD. Subjects with ESRD received 123 mg migalastat 24 hours before dialysis and, following an 8-day washout, immediately before dialysis. Matched controls with normal renal function (NRF) received migalastat 123 mg. Migalastat concentrations were measured in plasma, urine, and dialysate, and modeled to select regimens providing similar disposition to NRF. Migalastat was extracted by hemodialysis/hemodiafiltration (74%/72%). PBPK modeling predicted that 123 mg every other week (QOW) with regular dialysis 2-3 times weekly in ESRD subjects produced: a fraction of time above EC50 similar to FD patients with NRF; adequate Cmax for intracellular trafficking of mutant α-galactosidase A to the lysosome; and Ctrough levels near the lower limit of quantification (LLOQ) similar to NRF subjects receiving 123 mg every other day. Migalastat 82 mg weekly produced a greater fraction of time above EC50 and longer duration of concentrations above the LLOQ, potentially resulting in accumulation in tissues. Migalastat was well extracted by hemodialysis/hemodiafiltration. Migalastat 123 mg QOW is the proposed dose regimen for further evaluation in FD patients with ESRD, which could inform expansion of treatment options. Trial registration: EU Clinical Trials Register, EudraCT number 2018-003684-57.

Venetoclax pharmacokinetics in subjects with end-stage renal disease undergoing hemodialysis.

e19042 Background: Venetoclax is a first-in-class Bcl-2 inhibitor approved for the treatment of chronic lymphocytic leukemia (CLL) and acute myeloid leukemia(AML) and is currently being investigated as a treatment for t(11;14)-positive relapsed/refractory multiple myeloma (MM). Renal insufficiency is a common comorbidity in patients with hematologic malignancies, and no clinical study has been conducted to assess how end stage renal disease might affect venetoclax pharmacokinetics. This study aimed to assess the pharmacokinetics of venetoclax after oral administration of a single 100 mg dose of venetoclax in subjects with normal renal function and end-stage renal disease, including those undergoing hemodialysis. Methods: Venetoclax was administered as a single 100 mg dose to 7 healthy female subjects with normal renal function (eGFR > 90 ml/min) and 6 female subjects with end-stage renal disease (ESRD) (eGFR < 15 ml/min) both prior to hemodialysis (Period 1) and between hemodialysis days (Period 2). Intensive PK and protein binding samples were collected from all subjects. Arterial and venous samples were collected from ESRD subjects during hemodialysis to assess the effect of hemodialysis on the pharmacokinetics of venetoclax. Pharmacokinetic parameters were estimated using non-compartmental methods. Results: There was no difference in plasma venetoclax concentrations between arterial and venous samples, suggesting that hemodialysis did not affect the PK of venetoclax. The fraction unbound (fu) of venetoclax increased approximately 2-fold for subjects with ESRD compared to subjects with normal renal function.The unbound Cmax and AUC0-48 of ESRD subjects, between dialysis days were comparable to unbound Cmax and AUC0-48 observed in the normal renal function subjects. The harmonic mean t1/2 between groups (normal renal function vs. ESRD) ranged from 11 and 12.2 hours, demonstrating that end-stage renal disease did not affect the half-life of venetoclax. Conclusions: End-stage renal disease does not alter unbound venetoclax plasma concentrations and no dose adjustment is neededfor patients with renal insufficiency based on pharmacokinetics. Clinical trial information: NCT04810598 .

Non-Invasive Evaluation of Kidney Elasticity and Viscosity in a Healthy Cohort.

Introduction:There is currently a lack of published data on kidney elasticity and viscosity. Non-invasive techniques, such as two-dimensional shear-wave elastography (2D-SWE PLUS) and viscosity plane-wave ultrasound (Vi PLUS), have surfaced as new detection methods, which, thanks to efficient processing software, are expected to improve renal stiffness and viscosity measurements. This study aims to be the first one to assess the normal range values in normal renal function subjects and to investigate the factors that impact them. Methods: We conducted a cross-sectional study employing 50 participants (29 women and 21 men) with a mean age of 42.22 ± 13.17, a mean estimated glomerular filtration rate (eGFR) of 97.12 ± 11 mL/min/1.73 m2, a mean kidney length of 10.16 ± 0.66 cm, and a mean body mass index (BMI) of 24.24 ± 3.98. With a C6-1X convex transducer and the Ultra-FastTM software available on the Hologic Aixplorer Mach 30 ultrasound system, we acquired five measurements of renal cortical stiffness and viscosity (achieved from five distinct images in the middle part of the subcapsular cortex) from each kidney. The ten measurements' median values correlated with the participant's demographical, biological, and clinical parameters. Results: The mean kidney elasticity was 31.88 ± 2.89 kiloPascal (kPa), and the mean viscosity was 2.44 ± 0.57 Pascal.second (Pa.s) for a mean measurement depth 4.58 ± 1.02cm. Renal stiffness seemed to be influenced by age (r = -0.7047, p < 0.0001), the measurement depth (r = -0.3776, p = 0.0075), and eGFR (r = 0.6101,p < 0.0001) but not by BMI (r = -0.2150, p = 0.1338), while viscosity appeared to be impacted by age (r= -0.4251, p = 0.0021), eGFR (r = 0.4057, p = 0.0038), the measurement depth (r= -0.4642, p = 0.0008), and BMI (r= -0.3676, p = 0.0086). The results of the one-way ANOVA used to test the differences in the variables among the three age sub-groups are statistically significant for both 2D-SWE PLUS (p < 0.001) and Vi PLUS (p = 0.015). The method found good intra-operator reproducibility for the 2D-SWE PLUS measurements, with an ICC of 0.8365 and a 95% CI of 0.7512 to 0.8990, and for the Vi PLUS measurements, with an ICC of 0.9 and a 95% CI of 0.8515 to 0.9397. Conclusions: Renal stiffness and viscosity screening may become an efficacious, low-cost way to gather supplemental diagnostic data from patients with chronic kidney disease (CKD). The findings demonstrate that these non-invasive methods are highly feasible and not influenced by gender and that their values correlate with renal function and decrease with age progression. Nevertheless, more research is required to ascertain their place in clinical practice.

Renal function trajectories in hepatitis C infection: differences between renal healthy and chronic kidney disease individuals

Associations between hepatitis C virus (HCV) and chronic kidney disease (CKD) have been reported; however, differences of renal progression between general and CKD population remain to be elucidated in prospective studies. A total of 1179 participants, who have tested for anti-HCV antibody, were enrolled and prospectively followed for 3 years. The risks associated with HCV infection, in terms of incidence of CKD, annual estimated glomerular filtration rate (eGFR) changes and 50% decline of eGFR at 3-year from baseline, were compared between normal renal function subjects and CKD patients. Overall, 111 of 233 (47.6%) CKD patients and 167 of 946 (17.7%) non-CKD subjects had HCV infection. The crude incidence rates of CKD were 226.9 per 1000 person-years and 14.8 per 1000 person-years in in HCV and non-HCV infected patients, respectively. The adjusted hazard ratio of HCV infection for incident CKD was 7.9 (95% CI 5–12.7). The HCV-infected normal renal function subjects were independently associated with increased risks of eGFR decline in the 1-year, 2-year and 3-year, respectively. The risk associations remained significant in 50% decline of eGFR at 3 years models and in different subgroup analyses. The increases of risks of eGFR decline were also notorious among overall HCV-infected CKD patients. However, the risk associations were less prominent in subgroup analyses (elderly, women and diabetic patients). The findings highlighted the importance of viral diagnosis with not only prognostic but also public health implications for preserving kidney function.

The use of anticoagulants in chronic kidney disease: Common point of view of cardiologists and nephrologists.

In patients diagnosed with chronic kidney disease (CKD), atrial fibrillation (AF) is associated with an increased risk of thromboembolism and stroke. Moreover, patients with CKD - especially those in end-stage renal disease - also present an increased risk of bleeding. Oral anticoagulation is the most effective form of thromboprophylaxis in patients with AF and an increased risk of stroke. However, the underuse of these drugs was observed, mainly due to safety reasons and restricted evidence on efficacy. Much evidence suggests that non-vitamin K-dependent oral anticoagulant agents significantly reduce the risk of stroke, intracranial hemorrhage, and mortality, with lower to similar major bleeding rates compared with vitamin K antagonists, such as warfarin, in normal renal function subjects. Thus, they are currently recommended for that group of patients. However, their metabolism is largely dependent on the kidneys for elimination, and current knowledge in this area is limited due to patients with a decreased glomerular filtration rate are usually excluded from clinical trials. The present review article focuses on currently available data on oral anticoagulants in patients with moderate to advanced chronic kidney disease and those with end stage renal disease.

Association between macular degeneration and mild to moderate chronic kidney disease: A nationwide population-based study.

Chronic kidney disease (CKD) and macular degeneration (MD) are 2 grave diseases leading to significant disability secondary to renal failure and blindness. The 2 diseases share not only common risk factors but also similar pathogenic mechanisms to renal and retinal injuries. Previous epidemiological studies indicated association between these 2 diseases. However, this concept is challenged by recent investigations. Patients with mild to moderate CKD (n = 30,696) between January 1, 1995 and December 31, 2005 were selected from the Taiwan National Health Insurance Database. Controls (n = 122,784) were matched by age, gender, diabetes mellitus type 2, and hypertension status (1:4 ratios). The risk of MD was compared between the 2 groups. The mean age of patients was 54.9 ± 15.7 years. The proportion of MD was 2.7% in mild to moderate CKD patients and 1.9% in normal controls (P < 0.001); and, 0.39% and 0.26% (P < 0.001) in advanced MD. Mild to moderate CKD patients had higher risk for MD [adjusted odds ratio (OR), 1.301; 95% confidence interval (CI), 1.200–1.411; P < 0.001] than normal renal function subjects. The association was more pronounced for advanced MD. From all age strata (10 years increase), the presence of CKD in those patients aged less than 40 years had highest OR for all MD (OR = 2.125, 95% CI: 1.417–3.186, P < 0.001). The results were consistent in interaction terms, highlighting the importance of CKD in young age patient for risk of MD. The high risk for MD in mild to moderate CKD patients remains significant after adjustment for personal habits (alcohol drinking and smoking, model 1; OR: 1.371; 95% CI: 1.265–1.486; P < 0.001), comorbidities (dyslipidemia, cerebrovascular disease, and peripheral vascular disease, model 2; OR: 1.369; 95% CI: 1.264–1.484; P < 0.001) and all these factors (model 3; OR: 1.320, 95% CI: 1.218–1.431, P < 0.001). This association was consistent in the subanalysis, excluding those patients with diabetic retinopathy. Proper diagnosis and timely intervention should be warranted to retard visual loss of these patients.

Pharmacokinetics of Treprostinil Diolamine in Subjects With End-Stage Renal Disease On or Off Dialysis

Treprostinil diolamine sustained release (UT-15C SR) is being evaluated as an oral therapy for pulmonary arterial hypertension. This study evaluated the pharmacokinetics (PKs) of treprostinil following administration of UT-15C SR in subjects with end-stage renal disease (ESRD) compared with healthy subjects with normal renal function (NRF) and the effect of hemodialysis on the PK parameters of treprostinil. Eight ESRD subjects (requiring dialysis, mean creatinine clearance = 11.5 mL/min) received 2 single doses of 1 mg of UT-15C SR (separated by 2 weeks), with the first dose given immediately after dialysis and the second given 4 hours before the start of dialysis. Eight NRF subjects received a single dose of 1 mg of UT-15C SR. The median Cmax, AUC0-inf, and t1/2 of treprostinil were 680 pg/mL, 3240 hours pg/mL, and 2.35 hours, respectively, in ESRD subjects dosed after dialysis and were 551 pg/mL, 3152 hours pg/mL, and 2.05 hours, respectively, in ESRD subjects dosed before dialysis. In comparison, corresponding values were 730 pg/mL, 3726 hours pg/mL, and 3.54 hours, respectively, in NRF subjects. UT-15C SR of 1 mg was well tolerated by NRF and ESRD subjects. The most frequent adverse event was headache and nausea. There was no substantial difference in treprostinil PKs between ESRD and NRF subjects following administration of UT-15C SR tablets. Hemodialysis did not have clinically important effect on treprostinil PK in ESRD subjects.

Pathogenesis of Secondary Hyperparathyroidism

Chronic renal failure is the primary cause of secondary hyperparathyroidism (SHPT). Patients with mineral metabolism disorders commonly present with low serum calcium levels, hyperphosphatemia, and calcitriol deficiency. In normal renal function subjects, parathyroid cells have a low turnover and rarely undergo mitoses. In uremic conditions, however, parathyroid glands become hyperplasic and leave quiescence. During the last ten years, new molecular mechanisms have been investigated to better understand the pathogenesis of SHPT: the emerging role of the Calcium Sensing Receptor (CaSR); the importance of the parathyroid expression of the Vitamin D receptor (VDR); the growing evidence on the central role of the Fibroblast Growth Factor 23 (FGF-23). In contrast, the discovery of a parathyroid phosphate sensor or receptor has yet to be made.

Pharmacocinétique de l'amprénavir chez deux patients infectés par le VIH-1 et présentant une insuffisance rénale sévère et terminale

Amprenavir is an HIV-1 protease inhibitor which is hepatically metabolized (> 80%) with a low renal elimination. It has thus been suggested that no dosage adjustment is necessary in patients with renal dysfunction. However, no data are available on the pharmacokinetics of amprenavir in patients with renal insufficiency. We report on the pharmacokinetics of amprenavir in two HIV patients with severe and end-stage renal insufficiency. Amprenavir pharmacokinetics did not differ in our patients as compared with normal renal function subjects. Furthermore, amprenavir was not dialysable (FHD < 25%). As a result, the drug may be administered at its normal dose in patients with renal failure, even when severe. In dialysis patients, amprenavir may be administered before or after the session.

Inorganic fluoride kinetics and renal tubular function after sevoflurane anesthesia in chronic renal failure patients receiving hemodialysis.

Although sevoflurane is used in clinical anesthesia, its effects on renal function and inorganic fluoride (F-) kinetics in patients with chronic renal failure (CRF) have not been determined. We investigated F- kinetics and renal tubular function in sevoflurane anesthesia in CRF patients having hemodialysis. Five patients dialyzed and five with normal renal function undergoing parathyroidectomy or thyroidectomy were anesthetized with sevoflurane (1.0%-2.5%) and nitrous oxide in oxygen. Serum and urine levels of F-, blood urea nitrogen (BUN), serum creatinine (Cr), serum and urine beta 2-microglobulin (BMG) levels, and urine N-acetyl-beta-D-glucosaminidase (NAG) level were measured. BUN, Cr, and serum and urine BMG levels were significantly higher in the CRF patients than in the controls. There were no differences in serum F- level, rate of elimination, and area under the curve of serum F- levels between the two groups. However, the CRF patients had a significantly lower level of urine F- than control subjects. These data suggest that the F- kinetics in the CRF patients is different from that in normal renal function subjects. This clinical study with a limited number of patients may facilitate further studies to define the mechanisms of differences in the F- kinetics between normal subjects and CRF patients having hemodialysis after sevoflurane anesthesia.

Nephrotoxicity: A comparison in humans of gentamicin and gentamicin C 1 administration

The relative nephrotoxicities of the gentamicin complex (Garamycin) and gentamicin C 1 were studied using “acute” (intravenous infusion, five normal renal function subjects) and 3-day (multiple injections for 3 days, five normal renal function subjects) administration of the drug. Inulin, creatinine, and para-aminohippurate (PAH) clearances, renal concentrating capacity, urinary alkaline phosphatase, N-acetyl-β- d-glucosaminidase and β-glucuronidase enzyme excretions, and quantitative urinary sediment counts were measured before and during treatment. Although transient elevations of urinary enzymes occurred with both drugs, these were judged neither excessive nor abnormal. Renal function indicators showed no change after drug administration and there were no significant differences between drugs. Also, urinary sediment showed no changes from normal, and the gentamicin C 1 administration was not significantly different from results after gentamicin complex administration. By the presently rather imprecise criteria defining the lower limits of nephrotoxicity, neither drug when administered by the present recommendations for the upper dose limits for therapy with gentamicin complex was shown to be toxic. The 3-day multiple-dosing schemes for both drugs results in a total dose comparable to chronic dosing for 7–10 days at more usual doses and were judged to be comparable.