Various Degrees Of Renal Insufficiency Research Articles

Correlation between diabetic nephropathy and diabetic retinopathy as a long term complications of diabetes mellitus

Abstract Background/aim: Diabetes mellitus is a metabolic disorder of multiple etiologies characterized by a lack of insulin, with a consequent disordered metabolism of glucose, fats, and proteins. A number of complications, such as diabetic nephropathy and retinopathy, may develop as a result of long-term diabetes. The aim of this study aimed to determine the correlation between diabetic nephropathy and diabetic retinopathy as long-term complications of diabetes mellitus. Materials and methods: Retrospective, descriptive, and analytical research was conducted at the department of Endocrinology, Clinical Center, University of Sarajevo. The study included 158 patients hospitalized in time between 1st of January and 31st of December 2012. Results: New-onset diabetes was found in 38%, and diabetes type 2 patients 132 (83.5%), female 105 (66.5%) while older than 60 years were 100 (63.3%). Upon discharge from hospital 83,7% of patients were discharged with glycemia <10 mmol / l. We found that 47,5% of patients had HbA1c> 10%. Reduced kidney function, different degrees of failure was at 66.5%. More than half (62.7%) patients had proteinuria as a sign of diabetic nephropathy. Diabetic retinopathy was diagnosed with different types in 54.4%. Conclusion: Diabetes leads to an increase in nitrogen compounds, and the development of diabetic nephropathy manifests as various degrees of renal insufficiency. The duration of diabetes and occurrence of diabetic retinopathy were significantly interrelated. The correlation between the degree of renal failure and changes in the ocular fundus has not been proven, but more severe renal insufficiency is associated with a higher incidence of diabetic retinopathy compared to patients with less impaired renal function.

Spectrum of cancer patients receiving renal biopsy

The frontier of onco-nephrology, particularly renal complications of cancer and treatment, remains unexplored. We revisit the fundamental tool of diagnosing kidney disease, renal biopsy, in cancer patients with renal manifestation. Patients who received renal biopsy from July 2015 to July 2019 were analyzed. Primary outcomes included end-stage renal disease (ESRD), mortality, and catastrophic outcome defined as either ESRD or mortality. A Cox proportional hazards model and Kaplan-Meier technique were used to assess the association with outcome measurements and survival analyses. Immunosuppression after renal biopsy and response to the treatment were evaluated. Among the 77 patients, the median age was 66 years (interquartile range [IQR] 59-73 years) and 46 (59.7%) were male. At the time of renal biopsy, 57 patients (74%) had various degrees of renal insufficiency. Tubulointerstitial damage score, quantified by renal pathology, were associated with higher hazards of ESRD (hazard ratio [HR], 1.77; 95% confidence interval [95% CI], 1.20 to 2.61; P=0.004) and catastrophic outcome (HR, 1.30; 95% CI, 0.99 to 1.70; P=0.058). The response rate to immunosuppression was lower in those diagnosed with tubulointerstitial nephritis (1 of 4 patients, 25%) than those with glomerulopathy (10 of 20 patients, 50%). Renal biopsy may improve diagnostic accuracy and assist in treatment guidance of cancer patients with renal manifestation. Renal biopsy should be encouraged with clinical indication. Collaboration between oncologists and nephrologists is of paramount importance to provide more comprehensive care for caner patients.

PP45 - Octogenarians – A growing population in cardiac surgery

Octogenarians are a growing population of patients who are candidates for cardiac surgery. The author analyses a single centre experience with patients over 80 years of age who underwent cardiac surgery. A retrospective observational study was performed at the University Hospital in the period from 2011 to 2015. During that period 2139 heart operations were performed; authors compared preoperative, intraoperative and postoperative data of 1890 patients younger than 80 with group of octogenarian (123 patients over 80 years underwent cardiac procedures). There where 123 (6%) patients 80 years old or older. Sixty-five percent (65%) of the procedures were elective, 29% emergency and 6% urgent. Coronary artery bypass grafting was performed in 37% of patients, aortic valve replacement surgery in 31%, interventions involving the mitral valve in 3%, two procedures (CABG+AVR, CABG+MVR or AVR+MVR) in 22% and other procedures in 6%. The mean age of the patients was 81 (80-88 range). Octogenarian had a statistically higher Euroscore (p<0,001), more COPD (p<0,05), diabetes mellitus type 2 (p<0,05) and malignancies (p<0,01). There was no statistical difference in the operation time, CPB time and clamp time. Postoperative (cumulative) time in ICU was higher in octogenarian group (p<0,01); ventilator time was longer (p<0,01) there were more respiratory complications (p<0,01) and tracheotomies (p<0,05). Octogenarian received more transfusions. (p<0,01). Although their physical status was heavily burdened with preoperative comorbidities (8 patients had a cerebrovascular insult (7%), 16 (13%) some kind of vascular surgery, 10 (8%) COPD, 34 (28%) atrial fibrillation, 28 (23%) myocardial infarction, 96 (78%) hypertension, 29 (24%) diabetes, 24 (20%), various degrees of renal insufficiency, 2 patients (1.63%) were on haemodialysis, mortality was low- one patient died (0,8%). Octogenarians are a growing population of patients undergoing cardiac surgery. These patients often present multiple comorbidities that put them in a higher risk category. However, improvements in surgical technique, CPB technology and perioperative management enable us to perform cardiac surgery procedures in a safe manner.

Evaluation of the Single-dose Pharmacokinetics of Bilastine in Subjects with Various Degrees of Renal Insufficiency

BackgroundBilastine is a novel second-generation H1 antihistamine, which has not shown sedative or cardiotoxic effects in clinical trials and in post-marketing experience so far, developed for the symptomatic treatment of allergic rhinoconjunctivitis and urticaria. It has recently been granted marketing authorization for these therapeutic indications in adults and adolescents at a once-daily oral dose of 20 mg in several European countries.ObjectiveThis study was conducted to determine the pharmacokinetics of bilastine at a single oral dose of 20 mg in renally impaired subjects. The need for a dose adjustment in patients with renal insufficiency was assessed by comparing the exposure to bilastine in these subjects with the estimated exposure of a dose corresponding to the safety margin.MethodsThe study was an open-label, single-dose, parallel-group study of the pharmacokinetics and safety of a single dose of bilastine. The study was conducted as an in-patient setting at a clinical pharmacology facility. A total of 24 male or female subjects aged 18–80 years were to be enrolled in four groups of six subjects each. The groups were as follows: (1) healthy [glomerular filtration rate (GFR) >80 mL/min/1.73 m2]; (2) mild renal insufficiency (GFR 50–80 mL/min/1.73 m2); (3) moderate renal insufficiency (GFR 30–50 mL/min/1.73 m2); and (4) severe renal insufficiency (GFR ≤30 mL/min/1.73 m2). A single 20 mg bilastine tablet was administered in a fasted state. Blood and urine samples were collected from pre-dose up to 72 h post-dose for bilastine pharmacokinetic analysis. Pharmacokinetic results were summarized using appropriate descriptive statistics.ResultsThere was a clear trend of increasing area under the plasma concentration–time curve (AUC) and maximum plasma concentration (Cmax) through the groups 1–4. The mean AUC from time zero to infinity (AUC∞) ranged from 737.4 to 1708.5 ng·h/mL in healthy subjects and severely impaired subjects, respectively. No significant differences among groups in median time to reach Cmax (tmax) or in the mean terminal disposition rate constants for bilastine were found. Renal and plasma clearance paralleled GFR. In all groups of renally impaired subjects the corresponding 90 % confidence interval of both AUC∞ and AUC from time zero to time of last measurable plasma concentration (AUClast) were not within the 0.8–1.25 interval, indicating that bioequivalence between groups could not be demonstrated. The majority of bilastine was excreted within the first 12 h, and elimination was essentially complete by 72 h.ConclusionAn oral dose of bilastine (20 mg) was well-tolerated in renal insufficiency, despite the increase in exposure. The oral plasma clearance to renal clearance ratio [(CLP/F)/CLR] was approximately equal in the different groups, suggesting that renal excretion was the main elimination route for bilastine, and no alternative elimination routes were used even in severe renal insufficiency. Although exposure to bilastine was higher in renally impaired subjects, it remained well within the safety margins, thus allowing the conclusion that a 20-mg daily dose can be safely administered to subjects with different degrees of renal insufficiency without the need for dose adjustments.

Light Chain Deposition Disease After Renal Transplantation

Light Chain Deposition Disease After Renal Transplantation

Effect of Renal Insufficiency on the Pharmacokinetics of Sitagliptin, a Dipeptidyl Peptidase-4 Inhibitor

Sitagliptin is an oral, once-daily, potent, and highly selective dipeptidyl peptidase–4 inhibitor for the treatment of type 2 diabetes (1). In subjects with normal renal function (creatinine clearance >80 ml/min), 75–80% of an oral dose was excreted unchanged in urine. Renal clearance was ∼350 ml/min, indicating that active secretion of sitagliptin rather than only filtration is involved in renal excretion. Thus, renal excretion is the primary mechanism of elimination for sitagliptin (2). The purpose of this study was to evaluate the pharmacokinetics of single doses of sitagliptin in patients with various degrees of renal insufficiency (RI). This was an open-label, two-part study in 30 otherwise healthy male and female subjects (18–75 years of age) with BMI ≤40 kg/m2. Subjects were assigned to one of five groups ( n = 6/group), based on the following criterion for degree of RI: mild (creatinine clearance 50–80 ml/min), moderate (30–50 ml/min), severe ( 80 ml/min). Healthy subjects ( n = 145) from 11 other studies were included in a historical control group to supplement those studied here. Creatinine clearance values were based on measured 24-h urinary creatinine excretion (this study) or calculated using the Cockroft-Gault formula (historical controls). Because sitagliptin plasma concentrations were expected to increase with RI, a 50-mg dose was expected to be well …

A dose-escalating and pharmacologic study of bortezomib in adult cancer patients with impaired renal function

2032 Background: Bortezomib is a highly selective and reversible inhibitor of the proteasome with activity in multiple myeloma and other malignancies. Patients (pts) with renal impairment have been treated in previous trials, but there has not been a systematic investigation into the effects of renal dysfunction on dosing. Study objectives were to characterize the pharmacokinetic (PK) and pharmacodynamic (PD) profile of bortezomib, and to determine the maximum tolerated dose (MTD) in adults with advanced malignancy and renal insufficiency ranging in severity from mild to dialysis dependence. Methods: Fifty-one pts have received intravenous bortezomib at 0.7 mg/m2 up to the approved dose of 1.3 mg/m2 on days 1,4, 8, and 11 every 3 weeks. Pts were stratified by 24-hour creatinine clearance (CrCL) normalized to a body surface area of 1.73 m2 into five cohorts per the table . Doses were escalated in cohorts of three pts in groups B-E. Blood samples were assayed for bortezomib concentration, as well as the PD endpoint of 20S inhibition. Results: Escalation of bortezomib doses to 1.3 mg/m2 was well tolerated in all groups with CrCL ≥ 20 mL/min/1.73 m2. There has been only one instance of dose limiting toxicity (group C at 1.3 mg/m2) which did not prevent successful completion of this cohort. No patients discontinued therapy due to renal deterioration. Doses of 0.7 mg/m2 were tolerable in Group D patients (CrCL&lt; 20 mL/min/1.73 m2 ). Five dialysis pts have been treated; 3 at 0.7 mg/m2, and 2 at 1.0 mg/m2. All tolerated therapy well, and accrual to Groups D and E continues. PK and PD assays are underway and the analysis will be reported in full. Conclusions: This study is the first comprehensive evaluation of bortezomib in pts with various degrees of renal insufficiency including dialysis dependence. Bortezemib at the approved dose of 1.3 mg/m2 on this schedule is well tolerated by pts with CrCL ≥ 20 mL/min/1.73 m2. Results of this trial will allow for dosing recommendations for bortezomib use in pts with renal insufficiency. [Table: see text] [Table: see text]

Clinical Pharmacokinetics of Losartan

Losartan is the first orally available angiotensin-receptor antagonist without agonist properties. Following oral administration, losartan is rapidly absorbed, reaching maximum concentrations 1-2 hours post-administration. After oral administration approximately 14% of a losartan dose is converted to the pharmacologically active E 3174 metabolite. E 3174 is 10- to 40-fold more potent than its parent compound and its estimated terminal half-life ranges from 6 to 9 hours. The pharmacokinetics of losartan and E 3174 are linear, dose-proportional and do not substantially change with repetitive administration. The recommended dosage of losartan 50 mg/day can be administered without regard to food. There are no clinically significant effects of age, sex or race on the pharmacokinetics of losartan, and no dosage adjustment is necessary in patients with mild hepatic impairment or various degrees of renal insufficiency. Losartan, or its E 3174 metabolite, is not removed during haemodialysis. The major metabolic pathway for losartan is by the cytochrome P450 (CYP) 3A4, 2C9 and 2C10 isoenzymes. Overall, losartan has a favorable drug-drug interaction profile, as evidenced by the lack of clinically relevant interactions between this drug and a range of inhibitors and stimulators of the CYP450 system. Losartan does not have a drug-drug interaction with hydrochlorothiazide, warfarin or digoxin. Losartan should be avoided in pregnancy, as is the case with all other angiotensin-receptor antagonists. When given in the second and third trimester of pregnancy, losartan is often associated with serious fetal toxicity. Losartan is a competitive antagonist that causes a parallel rightward shift of the concentration-contractile response curve to angiotensin-II, while E 3174 is a noncompetitive "insurmountable" antagonist of angiotensin-II. The maximum recommended daily dose of losartan is 100mg, which can be given as a once-daily dose or by splitting the same total daily dose into two doses. Losartan reduces blood pressure comparably to other angiotensin-receptor antagonists. Losartan has been extensively studied relative to end-organ protection, with studies having been conducted in diabetic nephropathy, heart failure, post-myocardial infarction and hypertensive patients with left ventricular hypertrophy. The results of these studies have been sufficiently positive to support a more widespread use of angiotensin-receptor antagonists in the setting of various end-organ diseases. Losartan, like other angiotensin-receptor antagonists, is devoid of significant adverse effects.

Interpretation of erythropoietin levels in patients with various degrees of renal insufficiency and anemia

Chronic renal failure leads to hyporegenerative anemia due to erythropoietin deficiency. The creatinine clearance and hemoglobin levels, at which anemia treatment with recombinant erythropoietin should be started, are unclear. Interpretation of serum erythropoietin levels in the context of renal insufficiency remains controversial and was addressed in this study. Three hundred and ninety-five patients were randomly chosen out of over 5000 consecutive patients investigated by coronary angiography at a single center between 1997 and 2001. Laboratory values and clinical information were prospectively collected in a central registry. Serum samples were frozen before angiography and now used to measure serum erythropoietin levels and evaluate the relationship between erythropoietin and hemoglobin levels in the context of various degrees of renal insufficiency. The patients with the lowest renal function (creatinine clearance <20 mL/min) had significantly lower hemoglobin levels than the group with normal renal function. However, erythropoietin levels were identical indicating a lower set point for erythropoietin regulation. Above a creatinine clearance of 40 mL/min a significant inverse correlation between erythropoietin and hemoglobin levels was observed and described with the formula erythropoietin [U/L]= 2.5 x (140 - hemoglobin [g/L]) or alternatively Deltaerythropoietin (U/L) =-2.5 xDeltahemoglobin (g/L). Below 40 mL/min no significant correlation was found. A cut-off level for an altered set point of erythropoietin regulation was determined at 40 mL/min creatinine clearance. Above this cut-off hemoglobin negatively regulates erythropoietin. Below the cut-off erythropoietin levels remain stable. Pathophysiologic concepts for this finding and clinical implications in patients with moderate renal failure are discussed.

Anticoagulant efficacy of PEG-Hirudin in patients on maintenance hemodialysis

Heparins are currently the anticoagulants of choice in long-term hemodialysis (HD). Because of their shortcomings, including the increasing incidence of heparin-induced thrombocytopenia (HIT II), alternative anticoagulation is necessary. The study objectives were to provide safe and effective HD by investigating an appropriate PEG (polyethylene glycol)-Hirudin dosage regimen in patients on HD, as well as to compare the safety, tolerability, and efficacy of PEG-Hirudin with that of unfractionated heparin (UFH). Twenty patients (12 males, 8 females, mean age 57.8 years) with end-stage renal disease (ESRD) took part in the study. Dialysis sessions lasting a mean of 4.3 hours (QB 250 to 300 mL/min, QD 500 mL/min) were performed 3 times a week with a Gambro GFS plus 16 dialyzer. Ten patients (group I) received UFH at 3 regular dialysis sessions (HD1-3) followed by 5 dialysis sessions using PEG-Hirudin (HD4-8). Another 10 patients (group II) received UFH at 3 regular dialysis sessions (HD1-3) followed by 10 sessions on PEG-Hirudin (HD4-13). The starting dose of PEG-Hirudin was a single bolus injection of 80 microg/kg BW (HD4), except for the first patient, who received 50 microg/kg BW followed by a 12 microg/kg bolus. Before each of the following sessions (HD5-13), an individualized PEG-Hirudin dose of between 26 to 65 microg/kg body weight (BW) (mean dose 41 microg/kg BW) was injected. PEG-Hirudin plasma and blood concentrations derived from anti-Iia activity and ecarin clotting time (ECT), respectively, activated partial thromboplastin time (aPTT), bleeding time, and arteriovenous (AV) fistula compression time were investigated to calculate the pharmacokinetic parameters or to assess anticoagulant efficacy. Mean predialysis PEG-Hirudin plasma concentrations increased up to a maximum of 488 ng/mL in group I (HD8) and up to 536 ng/mL in group II (HD8). Mean plasma concentrations measured at 5 minutes after the 1st (HD4), 5th (HD8), and 10th (HD13) PEG-Hirudin injection ranged from 1076 to 1298 ng/mL. Mean post-dialysis plasma levels ranged from 818 to 995 ng/mL. Mean predialysis aPTT was not affected by UFH, but was prolonged by 46 to 56 seconds by PEG-Hirudin. Five minutes after injecting PEG-Hirudin or UFH, mean aPTT was prolonged to a maximum of 85 and 188 seconds, respectively. Mean post-dialysis aPTT values ranged from 60 to 68 seconds after PEG-Hirudin and 34 to 46 seconds after UFH. PEG-Hirudin was well tolerated; no serious adverse events or bleeding complications were observed. Safety assessments yielded no significant difference between the two anticoagulants. This pilot study confirmed the usefulness and tolerability of a PEG-Hirudin dose regimen consisting of a single, fixed bolus dose of 80 microg/kg BW injected before starting the first dialysis session (HD4) and followed by a dose titration period over at least 4 sessions (HD5-8), which again was followed by a fixed maintenance dose period (HD9-13). On the basis of PEG-Hirudin data from patients with various degrees of renal insufficiency but not undergoing hemodialysis and prior recombinant-hirudin (r-hirudin) experience, patients were titrated into an EC-controlled dose range that proved to be efficacious enough to prevent clotting and safe enough to prevent bleeding. Due to the favorable pharmacokinetic properties of PEG-Hirudin, a residual anticoagulant effect is maintained in the intervals between dialysis sessions, and this permanent state of anticoagulation may prevent vascular access complications as well as other vascular events.

Does Continuous Venovenous Hemodiafiltration Concomitant with Radiological Procedures Provide a Significant and Safe Removal of the Iodinated Contrast Ioversol?

Background: The purpose of our study was to investigate whether continuous venovenous hemodiafiltration (CVVHDF) concomitant with radiological procedures (RxP) was feasible, well tolerated and could significantly remove iodinated contrast media (CM). Methods: 26 patients with various degrees of renal insufficiency who were submitted to RxP were included in the study. The CVVHDF session was started immediately before CM administration. All the patients were evaluated for feasibility and tolerability; furthermore a pharmacokinetic study was done on 12 patients to calculate the amount of CM eliminated. The baseline incidence of CM nephropathy was studied in 25 consecutive historical controls. Results: The CM administered was 208 ± 146 g; the fractional removal of CM was 9.2 ± 4.9% during RxP and 30.9 ± 20.7% during the whole CVVHDF session. Hemodynamic tolerance was excellent. The incidence of CM nephropathy in the experimental and control groups was 37 and 24%, respectively. Conclusions: CVVHDF during RxP is feasible and well tolerated but ioversol removal is modest. This fact together with the high incidence of renal function impairment, the complexity of the procedure and its intrinsic risks, and the large amount of resources needed discourage the routine use of CVVHDF as a prophylactic tool to avoid CM nephropathy.

The adverse renal effects of prostaglandin-synthesis inhibition in the fetus and the newborn

To summarize experimental animal data and to provide a limited literature review on the adverse renal effects of nonsteroidal anti-inflammatory drugs (NSAIDs) on the developing fetus and the maturing newborn. The experimental data were obtained from anesthetized, ventilated, six- to eight-day-old rabbits that received an intravenous bolus of either acetylsalicylic acid (ASA), ibuprofen (IBU) or indomethacin (INDO). In one set of experiments, ASA was also tested in 12-week-old (young adult) rabbits. Renal function was monitored with inulin and para-aminohippuric acid clearances measuring glomerular filtration rate (GFR) and renal blood flow. The renal vascular resistance was calculated. All three nonspecific cyclo-oxygenase-1 or -2 (COX-1/2) inhibitors caused remarkably similar reversible, oliguric, acute renal failure (ARF). In young adult animals, the side effects were attenuated. The underlying pathophysiology is related to the carefully maintained low GFR of the fetus and the newborn, dependent on a delicate interplay between vasoconstriction (angiotensin II) and vasodilation (prostaglandins [PGs]). When PG-synthesis is inhibited, the vasoconstriction is relatively unopposed, causing ARF. The renal effects of fetal exposure to NSAIDs are discussed, as are new insights into the role of COX-1/2 for a normal nephrogenesis. COX-nil or COX-inhibited animals have long lasting renal structural injury. Fetuses exposed in utero to significant amounts of NSAIDs have at birth various degrees of renal insufficiency and structural renal defects with a very high mortality. All NSAIDs, both specific and nonspecific COX inhibitors, have renal side effects in the immediate post-natal period and should, therefore, be given with the utmost caution. NSAIDs given during pregnancy for the prevention of toxemia, polyhydramnios and premature labour may affect fetal renal function and structure. In animal experiments, IBU was not less nephrotoxic than INDO, as suggested recently by human premature neonates.

Rapid activation of the complement system by cuprophane depends on complement component C4

Rapid activation of the complement system by cuprophane depends on complement component C4

Pharmacokinetics of sertindole and dehydrosertindole in volunteers with normal or impaired renal function.

To study the effect of renal impairment on the pharmacokinetics of sertindole. A single 4 mg oral dose of sertindole was given to normal subjects (n = 6) and subjects with various degrees of impaired renal function (n = 18) classified into mild, moderate, and severe/hemodialysis based on their creatinine clearance). The relationships between the pharmacokinetic parameters and the degree of renal impairment were investigated using regression analysis with creatinine clearance as an explanatory variable along with body weight. Subjects were also genotyped for CYP2D6-A or 2D6-B mutations. The mean CL/f and t1/2 values of sertindole ranged from 14 to 31 1.h-1 and from 73 to 93 h, respectively, and were not significantly related to creatinine clearances. There was no indication of any influence of creatinine clearance on the fraction of sertindole (0.994-0.995) binding to plasma proteins. The total fraction of the sertindole dose removed by dialysis was less than 0.1% Subjects with B/B genotype (n = 2) for CYP2D6 were associated with a distinctly lower clearance of sertindole (6.3 vs 25.3 1.h-1) than subjects with wt/wt genotype for CYP2D6. Since the pharmacokinetics of sertindole are unchanged by renal impairment, dosage adjustment does not appear to be necessary for subjects with various degrees of renal insufficiency or subjects with renal failure requiring hemodialysis.

Determination of the glomerular filtration rate by identification of sinistrin kinetics.

A computer-based method of system identification and estimation of parameter variance for two-compartment models matched to dynamic sinistrin concentration profiles for the determination of glomerular filtration rate is described. Thereby a procedure for the judgment of the optimal sampling time horizon is presented. Since single-injection techniques are suspected of yielding systematic overestimation of the glomerular filtration rate, a method is demonstrated confirming that such a technique employing sinistrin kinetics can be used to correctly determine the glomerular filtration rate. The validation of the system parameters gained by the single-injection method is made through prediction of the concentration contour under a constant infusion regimen in the same subject on a different occasion. This was performed in healthy controls and in patients with various degrees of renal insufficiency. Upon consideration of the dependence of the clearance estimates and their variances on the protocol duration in test subjects examined from four to ten hours, an adaptive design of the protocol length is developed.

Pharmacokinetics of FCE 22891 in patients with various degrees of renal insufficiency

Pharmacokinetics of FCE 22891 in patients with various degrees of renal insufficiency

Pharmacokinetics of Temocapril and Enalapril in Patients with Various Degrees of Renal Insufficiency

Temocapril is a novel ACE inhibitor that is cleared via dual excretion routes in humans. Borderline or mildly hypertensive patients with normal renal function [group 1, creatinine clearance (CLCR) > 70 ml/min (4.2 L/h), n = 12], moderate renal impairment [group 2, CLCR 30 to 70 ml/min (1.8 to 4.2 L/h), n = 12] or severe renal impairment [group 3, CLCR < 30 ml/min (1.8 L/h), n = 12] received a single oral dose of either temocapril 1 mg (n = 6, each group) or enalapril 5mg (n = 6, each group). These 2 drugs gave similar values for the area under the plasma concentration-time curve (AUC) of the active diacids. The maximum plasma concentration of enalapril diacid was increased 2- and 6-fold in moderate and severe renal impairment, respectively, whereas that of temocapril diacid was not altered. The AUC of enalapril diacid increased 13-fold at CLCR values < 30 ml/min, but that of temocapril diacid increased only 2-fold. The duration of plasma ACE inhibition due to enalapril was greatly prolonged by the impairment of renal function, whereas that due to temocapril was affected very little. Urinary recovery of temocapril diacid was decreased markedly in patients with severe renal dysfunction, most probably because the diacid was excreted through the biliary route. On the other hand, urinary recovery of enalapril diacid remained fairly high even in patients with severe renal impairment, because of extremely high plasma diacid concentrations resulting from the lack of biliary excretion. These observations suggest that temocapril is beneficial in the treatment of hypertension in patients with severely impaired renal function.

Influence of renal function on the pharmacokinetics of lomefloxacin compared with other fluoroquinolones

Fluoroquinolones have similar chemical structures but wide differences in their pharmacokinetic profiles. Disparity in fluoroquinolone elimination is most evident in patients with various degrees of renal insufficiency. Ofloxacin is almost exclusively eliminated by the kidney, whereas pefloxacin is predominantly cleared by the liver. The fluoroquinolones eliminated by both renal and nonrenal routes (hepatic and transintestinal) include norfloxacin, ciprofloxacin, enoxacin, fleroxacin, temafloxacin, and lomefloxacin. The primary renal mechanism of elimination for norfloxacin, ciprofloxacin, enoxacin, fleroxacin, temafloxacin, and lomefloxacin is glomerular filtration and tubular secretion. Both total clearance and renal clearance significantly correlate with creatinine clearance for these fluoroquinolones, and creatinine clearance is a useful clinical marker on which to base dosage adjustments. For some fluoroquinolones, dosage adjustments are recommended when creatinine clearances fall below 30–40 mL/min. This is especially evident for lomefloxacin, temafloxacin, norfloxacin, ciprofloxacin, enoxacin, and fleroxacin. There is very little removal of fluoroquinolones from the plasma during hemodialysis due to their extensive tissue distribution.

Relationship between renal function and disposition of oral cefixime

The pharmacokinetics of cefixime following a single oral dose of 200 mg have been investigated in 6 normal subjects and in 22 patients with various degrees of renal insufficiency. Serum and urine samples were collected between 0 and 72 h and were subjected to two methods of analysis: bioassay and HPLC. There was a linear relationship between the two sets of results from 228 samples. This result suggests that none of the metabolites, which may accumulate in uraemic patients, has antibacterial activity. In normal subjects, the peak serum level (Cmax) was 2.50 micrograms.ml-1 at 2.83 h (tmax); the apparent elimination half-life (t1/2) was 3.73 h; the apparent total body clearance (CL.f-1) was 154 ml.min-1, the mean renal clearance (CLR) was 39.1 ml.min-1 and the apparent fraction of the dose recovered in 24 h urine was 0.22. In uraemic patients, Cmax and tmax were slightly increased and t1/2 was increased to 12-14 h in patients with an endogenous creatinine clearance below 20 ml.min-1. The apparent volume of distribution was decreased. Apparent total and renal clearances were lower in proportion to the degree of renal insufficiency. Linear relationships were found between CL/f, CLR and creatinine clearance (CLCR). The findings suggest that the dose of cefixime needs to be reduced only in patients with severe renal failure.

Pharmacokinetics and hemostasis following administration of a new, injectable oxacephem (6315-S, flomoxef) in volunteers and in patients with renal insufficiency

Flomoxef is a new oxacephem of broad antibacterial activity. The compound is mainly excreted through the kidneys. Two dose finding studies in patients with various degrees of renal insufficiency revealed that the dosage of flomoxef has to be reduced exactly according to the renal function. Although the N-methylthiotetrazole group has been replaced by a hydroxyethyl group, an inhibitory effect of flomoxef on vitamin K metabolism persisted. This effect was, however, less pronounced than with latamoxef. Only patients with low vitamin K stores are endangered. For those in whom low vitamin K stores are suspected repeated controls of prothrombin time are advised during the treatment. In contrast to latamoxef the platelet system was not affected by flomoxef. With the exception of loose stools in some patients no other clinical side effects during treatment were observed.