Pharmacokinetics of Teneligliptin in Subjects With Renal Impairment.

The pharmacokinetics of teneligliptin was compared in renally impaired and healthy subjects. Subjects were assigned to one of four groups of eight subjects, according to the stage of disease [mild, moderate, severe or end stage renal disease (ESRD)], while matched healthy subjects were allocated to one of two reference groups. Mild, moderate and severe renal impairment had no effect on maximum plasma concentration (Cmax ) following a single oral dose of 20 mg teneligliptin, as defined in the FDA guideline. AUC0-∞ was increased in all groups relative to the reference group but this was unrelated to the degree of renal impairment. Mean plasma protein binding was <80% in all groups. Overall, teneligliptin was well tolerated by subjects with renal impairment or ESRD. Dialysis is not expected to affect the efficacy or safety of teneligliptin. These results indicate that dose adjustment may not be needed when teneligliptin is administered to subjects with mild, moderate or severe renal impairment or ESRD.

Effects of renal impairment on the pharmacokinetics, pharmacodynamics and safety of rivaroxaban, an oral, direct Factor Xa inhibitor.

AIM: This study evaluated the effects of impaired renal function on the pharmacokinetics, pharmacodynamics and safety of rivaroxaban (10mg single dose), an oral, direct Factor Xa inhibitor. METHODS: Subjects (n= 32) were stratified based on measured creatinine clearance: healthy controls (≥80ml min(-1) ), mild (50-79mlmin(-1) ), moderate (30-49mlmin(-1) ) and severe impairment (<30mlmin(-1) ). RESULTS: Renal clearance of rivaroxaban decreased with increasing renal impairment. Thus, plasma concentrations increased and area under the plasma concentration-time curve (AUC) LS-mean values were 1.44-fold (90% confidence interval [CI] 1.1, 1.9; mild), 1.52-fold (90% CI 1.2, 2.0; moderate) and 1.64-fold (90% CI 1.2, 2.2; severe impairment) higher than in healthy controls. Corresponding values for the LS-mean of the AUC for prolongation of prothrombin time were 1.33-fold (90% CI 0.92, 1.92; mild), 2.16-fold (90% CI 1.51, 3.10 moderate) and 2.44-fold (90% CI 1.70, 3.49 severe) higher than in healthy subjects, respectively. Likewise, the LS-mean of the AUC for Factor Xa inhibition in subjects with mild renal impairment was 1.50-fold (90% CI 1.07, 2.10) higher than in healthy subjects. In subjects with moderate and severe renal impairment, the increase was 1.86-fold (90% CI 1.34, 2.59) and 2.0-fold (90% CI 1.44, 2.78) higher than in healthy subjects, respectively. CONCLUSIONS: Rivaroxaban clearance is decreased with increasing renal impairment, leading to increased plasma exposure and pharmacodynamic effects, as expected for a partially renally excreted drug. However, the influence of renal function on rivaroxaban clearance was moderate, even in subjects with severe renal impairment.

Increased type IIA secretory phospholipase A(2) expression contributes to oxidative stress in end-stage renal disease.

End-stage renal disease (ESRD) patients exhibit increased in vivo oxidative stress conceivably contributing to cardiovascular mortality. The type IIA secretory phospholipase A(2) (sPLA(2)) has proatherogenic activity. We explored the hypothesis that sPLA(2) contributes to oxidative stress generation and endothelial dysfunction in ESRD patients and transgenic (tg) mice. Patients with ESRD had increased in vivo oxidative stress as assessed by plasma isoprostane levels (p < 0.001). Active sPLA(2) in plasma was substantially increased compared with healthy controls (1,156 +/- 65 versus 184 +/- 5 ng/dL, p < 0.001) and correlated with plasma isoprostanes (r = 0.61, p < 0.001). Correspondingly, human sPLA(2) tg mice display increased generation of reactive oxygen species within aortic vascular smooth muscle cells, leading to severe endothelial dysfunction (maximal vasodilation in response to 10 micromol/L acetylcholine, sPLA(2) 36 +/- 8%, controls 80 +/- 2% of phenylephrine-induced vasoconstriction). Increased vascular oxidative stress in sPLA(2) tg mice is dependent on the induction of vascular cyclooxygenase (COX)2 expression. Conversely, ESRD patients show increased formation of COX2-derived prostaglandins (p < 0.05) correlated with plasma sPLA(2) (r = 0.71, p < 0.05). Our data indicate that increased expression of sPLA(2) might represent a novel causative risk factor contributing to the increased cardiovascular disease morbidity and mortality in ESRD.

Kidney transplantation in children: impact of young recipient age on graft survival.

BACKGROUND: It has been suggested that recipient age may have an effect on renal graft survival due to its potential influence on the competence of the immune system. A comparison of graft survival between children and elderly adults, however, has never been performed. METHODS: Forty patients /=65 years using a case-control analysis. Apart from age, matching criteria were the number of HLA mismatches and the date of transplantation. RESULTS: The mean age differed by 57 years between study and control group (10 +/- 5 vs 67 +/- 2, P < 0.001). There was no difference in the number of initially non-functioning grafts, sex distribution, immunosuppression, number of HLA mismatches on the HLA-DR, -B and -A locus, cold ischaemia time and the number of patients with panel-reactive antibodies. The only difference was a lower donor age in the study group (17 +/- 14 vs 35 +/- 16, P < 0.001) compared with the control group. During the follow-up of 109 +/- 54 and 79 +/- 49 months, respectively, acute rejections were more frequent in the study group (25 vs 12, P < 0.01). There was no significant difference in graft survival between both groups when death with functioning graft was excluded. CONCLUSIONS: This study which compares two groups of patients with a mean age difference of 57 years could not demonstrate an effect of young recipient age on graft survival, though the incidence of acute rejections appeared to be significantly higher in the paediatric population. Thus paediatric renal transplanted patients do not seem to have a disadvantage regarding graft survival due to their young recipient age.

Improved survival in patients with type 1 diabetes mellitus after renal transplantation compared with hemodialysis: a case-control study.

BACKGROUND: Diabetes mellitus is the leading cause of renal failure worldwide. The question of which treatment modality-hemodialysis versus renal transplantation-is associated with the lowest risk of cardiovascular morbidity and mortality in the diabetic end-stage renal disease (ESRD) population has not yet been investigated in a controlled trial. METHODS: We therefore conducted a case-control study of patients with ESRD caused by type 1 diabetes mellitus. The case patients were diabetics who received a renal graft between 1978 and 1997, whereas the controls were registered for renal transplantation but stayed on maintenance hemodialysis without ever undergoing transplantation. The groups were matched for age, sex, duration of diabetes, length of hemodialysis (up to the registration), and date of registration for renal transplantation. RESULTS: Kaplan-Meier life table analysis, based on 46 case patients and 46 controls, demonstrated a highly significant (P=0.0001) poorer survival in the control group compared with the case group. Logistic regression showed that hemodialysis was a significant risk factor for death (P=0.0002) and cardiovascular morbidity (P=0.0023). Patients with cardiovascular complications such as coronary artery and peripheral vascular events were significantly more frequent in the control group. Additionally tested risk factors for cardiovascular complications (serum cholesterol, arterial blood pressure, number of antihypertensive drugs, serum calcium, serum phosphate, and glucose control [hemoglobin A(1c)]) showed no significant correlation to survival or morbidity in either group by logistic regression. CONCLUSIONS: Renal transplantation is associated with a significantly improved survival compared with hemodialysis in patients with ESRD caused by type 1 diabetes mellitus. This seems to be a result of a reduced incidence of cardiovascular complications after renal transplantation.

Contrast media nephropathy: intravenous CT angiography versus intraarterial digital subtraction angiography in renal artery stenosis: a prospective randomized trial.

BACKGROUND: Spiral computed tomographic angiography (CTA) is a noninvasive method to diagnose renal artery stenosis (RAS). In digital subtraction angiography (DSA), contrast media (CM) is injected directly into the renal artery; in CTA, a greater amount of CM is injected intravenously, potentially leading to an increased incidence of CM nephropathy. METHODS: We investigated 80 patients with suspected RAS randomized to either CTA or DSA prospectively. The following parameters were determined: serum creatinine level and single-shot inulin clearance for evaluation of renal function and urine alpha1-microglobulin and beta-N-acetyl-glucoseaminidase (beta-NAG) as markers for tubular toxicity. Data from 16 patients undergoing angioplasty in the same session were excluded. RESULTS: In the CTA and DSA groups, 163 +/- 13 and 104 +/- 56 mL of CM (mean +/- SD; P < 0.0001) were administered, respectively. Mean serum creatinine levels increased from 1.78 +/- 1.61 to 1.92 +/-1.73 mg/dL (157 +/- 142 to 170 +/- 153 micromol/L; P = 0.00001) in the CTA group and from 1.52 +/- 1.23 to 1.60 +/- 1.28 mg/dL (134 +/- 109 to 141 +/- 113 micromol/L; P = 0.01) in the DSA group. Mean inulin clearance decreased from 63 +/- 28 to 58 +/- 23 mL/min (P = 0.01) and 65 +/- 26 to 62 +/- 26 mL/min (P < 0.01), median beta-NAG levels increased from 4.6 to 6.0 U/g creatinine (P = not significant) and 2.5 to 8.0 U/g creatinine (P < 0.001), and median alpha1-microglobulin levels increased from 13 to 17 microg/g creatinine (P < 0.025) and 11 to 21 microg/g creatinine (P = not significant) in the CTA and DSA groups, respectively. CM nephropathy occurred in 3 of 33 patients in the CTA group and 2 of 31 patients in the DSA group. The increase in creatinine level was reversible in all patients within 7 days. CONCLUSION: On this study, CTA performed for the detection of RAS is not associated with an increased risk for CM nephropathy compared with intraarterial DSA despite a greater dose of CM.

Angiography for renal artery stenosis: no additional impairment of renal function by angioplasty.

The aim of this study was to compare renal function between patients with renal angiography and patients with renal angiography and angioplasty (AP) for renal artery stenosis (RAS). Forty-seven patients with suspected RAS were prospectively investigated by digital subtraction angiography (DSA) using non-ionic low osmolar contrast media (CM). In 22 patients RAS was detected and in 16 cases an angioplasty was performed in the same session. The following parameters were determined 1 day prior to and after the DSA, respectively: serum creatinine (S-Crea, micromol/l) and single-shot inulin clearance (In-Cl, ml/min) for the evaluation of renal function; and urine alpha 1-microglobuline (AMG, microg/g Crea) and beta-N-acetyl-glucoseaminidase (beta-NAG, U/g Crea) as markers of tubular toxicity. Serum creatinine was measured additionally 2 days after CM had been injected. In both groups with and without AP 174+/-65 and 104+/-56 ml of CM ( p<0.0005) were used, respectively. There were no differences with regard to renal function or risk factors for CM nephrotoxicity between both groups. In the group with AP S-Crea and In-Cl (each: mean+/-SD) did not change significantly (before DSA: 171+/-158 and 61+/-24, after DSA: 189+/-177 and 61+/-25, respectively), beta-NAG (median) rose from 4 to 14 ( p<0.05) and AMG from 8 to 55 (n.s., because of high SD). In the group without AP S-Crea increased from 134+/-109 to 141+/-113 ( p<0.01), In-Cl dropped from 65+/-26 to 62+/-26 ( p<0,01), beta NAG (median) rose from 4 to 8 ( p=0.01), and AMG from 7 to 10 (n.s.). A rise in baseline S-Crea by more than 25% or 44 micromol/l occurred in 4 and 2 patients in the group with and without AP, respectively. Creatinine increase was reversible in all cases within 7 days. In this study using sensitive methods to detect changes of renal function and tubular toxicity no additional renal function impairment in DSA with angioplasty for RAS compared with DSA alone could be demonstrated. Our data suggest that AP performed for RAS has a beneficial effect on renal function.