Moderate Impairment Of Renal Function Research Articles

Review: HMG CoA reductase inhibitors and renoprotection: the weight of the evidence

Dyslipidemia and the contributions of oxidized low-density lipoproteins (ox-LDL) are independent cardiovascular risk factors. There is growing evidence that dyslipidemia contributes not only to cardiovascular disease but also to the progressive decline of renal function in diabetic and non-diabetic kidney disease. Ox-LDL, by generating inflammation and oxidative stress, contributes to a pro-atherogenic mileu and leads to endothelial dysfunction, subsequent glomerular filtration barrier damage, and progressive renal injury. Chronic kidney disease (CKD), in turn, induces deleterious effects on lipid metabolism. Therefore, by inhibiting cholesterol synthesis and reducing ox-LDL, HMG CoA reductase inhibitors (statins) are attractive therapeutic options to preserve renal function. Current evidence demonstrates a reduction in cardiovascular risk and improved renal outcomes especially in patients with mild to moderate impairment of renal function. Evidence supports a beneficial role of statins thought to extend beyond their lipid-lowering effect, referred to as pleiotropic actions. These actions include modulatory effects on inflammation, oxidative stress and thrombosis, derived from their ability to prevent the formation of isoprenoid intermediates involved in cellular signaling, posttranslational modification of proteins and cellular function. This translates to potential reductions in the rate of decline in GFR in CKD and adverse effects of type 2 diabetes mellitus in the kidney. This review examines the role of statins for reno-protection as well as cardiovascular benefit in patients with CKD.

Remote Renal Injury Following Partial Hepatic Ischemia/Reperfusion Injury in Rats

Liver ischemia/reperfusion has been shown to result in injury of remote organs such as the heart and lungs. Whether or not acute liver injury also results in kidney injury has so far not been adequately addressed. In anesthetized Wistar rats, partial (70%) normothermic hepatic ischemia was applied for 75 min. After 24 h of reperfusion, renal injury was assessed by histology, creatinine and blood urea nitrogen (BUN) serum concentrations, renal expression of proinflammatory genes [quantitative real-time polymerase chain reaction (qRT-PCR)], caspase-3 activation (Western blot), and neutrophil accumulation (myeloperoxidase assay). Twenty-four hours after hepatic ischemia, creatinine (0.57±0.06 vs. 0.32±0.04 mg/dL) and BUN (40.7±15.3 vs. 14.3±2.0 mg/dL) were increased when compared to sham. qRT-PCR revealed higher renal intercellular adhesion molecule-1 gene expression following hepatic ischemia (166 ± 45% when compared to sham) but no differences in renal monocyte chemoattractant protein-1, macrophage inflammatory protein-2, and inducible NO synthase expression. In both groups, kidneys showed no morphological damage and no increase in caspase-3 and myeloperoxidase activity. Severe hepatic ischemia results in a moderate impairment of renal function in rats but does not trigger an inflammatory response in the kidney and does not result in morphological damage of the kidney.

Nierenmanifestationen bei rheumatischen Erkrankungen

Inflammatory rheumatic diseases other than systemic vasculitides and systemic lupus erythematosus are frequently associated with renal abnormalities, which are clinically less apparent due to the subtle course and the often only moderate impairment of renal function. These abnormalities include vascular, glomerular and tubulointerstitial changes. Renal manifestations in the course of rheumatoid arthritis influence the prognosis of the disease. Renal involvement due to AA amyloidosis following long-standing inflammatory joint disease can lead slowly, over years, to end-stage renal disease. A scleroderma renal crisis in the course of systemic sclerosis can potentially result in end-stage renal disease within days. The differential diagnosis of renal abnormalities in a rheumatic patient should include drug induced renal impairment as well as infection.

Magnitude of Underascertainment of Impaired Kidney Function in Older Adults with Normal Serum Creatinine

To estimate in a community-dwelling elderly population the magnitude of renal function misclassification, occurring when persons with normal serum creatinine have reduced glomerular filtration rate (GFR), and to describe the participant characteristics related to misclassification. Cross-sectional. Population-based study of older Italian people. Six hundred sixty participants aged 65 to 92 with normal serum creatinine. GFR was estimated using the Cockcroft-Gault equation and creatinine clearance (CrCl) calculated from 24-hour urine collection. In participants with normal serum creatinine, 39% and 25% had moderate renal function impairment (GFR<60 mL/min) according to the Cockcroft-Gault equation and CrCl calculation, respectively. Prevalence of moderate renal impairment in those aged 65 to 74, 75 to 84, and 85 and older was 18.6%, 58.3%, and 96.8%, respectively (P for trend <.001) according to the Cockcroft-Gault equation, and 15%, 35.7%, and 58.7%, respectively (P for trend <.001) based on the CrCl calculation. In addition, female sex (P<.001) and normal or underweight (P<.05) were factors associated with high risk of misclassification. Serum creatinine alone is one of the most widely used methods of assessing renal function in clinical practice despite its well-known poor correlation with GFR. A large proportion of older persons with impaired renal function are not diagnosed if clinicians rely solely on normal serum creatinine as evidence of normal renal function. Opportunities may be missed for slowing progression of kidney disease, managing comorbidities and complications related to renal impairment, and adjusting drug dosage for renal function.

Comparison of Activated Partial Thromboplastin Time Ratios with Ecarin Clotting Time Ratios for Monitoring Direct Thrombin Inhibitor Therapy: In-Vitro Study and Case Study of Lepirudin Therapy.

The direct thrombin inhibitors lepirudin and argatroban are widely used to treat heparin induced thrombocytopenia (HIT). It has been suggested that the Ecarin™ (Echis carinatus venom) clotting time may be superior to the activated partial thromboplastin time (APTT) for monioring purposes. We have prepared standard curves for lepirudin (Refludan™) and Argatroban covering therapeutic drug levels and corresponding APTT ratios (clotting time/control clotting time). Ecarin™ clotting time ratios were performed to demonstrate the practical application of these curves in the clinical care of patients. We report the case of an 80 year old man with HIT/HITT syndrome that occurred during therapy for deep vein thrombosis (DVT) with a low molecular weight heparin (LMWH). His initial coagulation studies were abnormal due to warfarin and LMWH therapy. The patient had a moderate impairment of renal function. Lepirudin therapy in a bolus dose of 14 mg (patient weight: 103.0 kg) resulted in supratherapeutic blood levels of drug and hematuria (Platelet count: 〉200 x 103). Dosage adjustment to maintain an APTT ratio of 1.5 for five days caused no hematuria, but thromboembolic complications occurred at that ratio. The in-vitro dose response curve for Lepirudin was compared with the Ecarin™ clotting time (ECT) ratio at those same concentration ranges in the same plasma. For comparison, Argatroban dose response curves in-vitro were made as well. ECT ratios were very similar to the APTT ratios in the patient's samples. Representative ratios after the initial bolus, during the infusion period of five days and at the termination of that period are shown in the following table:Comparison of APTT and ECT RatiosAPTT RatioECT Ratio1.431.073.983.082.911.952.741.952.791.902.581.782.442.423.834.78Conclusion: The ECT ratios reflect a steeper dose response curve than that observed with the APTT ratios. This may permit more accurate measurement of blood levels using ECT ratios.

Influence of Low Protein Diet on Nonthyroidal Illness Syndrome in Chronic Renal Failure

Renal failure causes alterations in thyroid hormone metabolism known as nonthyroidal illness syndrome. In the present study we have examined the effect of a low protein diet (LPD) on circulating levels of hormones of the pituitary-thyroid axis, and tumor necrosis factor alpha (TNF-alpha) in patients with chronic renal failure. Seventeen subjects with conservatively treated chronic renal failure (estimated creatinine clearance 39.5+/-11.1 mL/min) were studied before and after 8 wk of dietary intervention (0.6 g/kg of ideal body mass protein, 30% of calories derived from fat, 62% of calories derived from carbohydrates, and 10 mg/kg of phosphorus). Body fat and fat-free mass remained unchanged. Urea and TNF-alpha serum concentrations significantly decreased, whereas T3 and total and free T4 serum concentrations increased significantly. Triiodothyronine level after treatment correlated negatively with baseline urea level. Changes in T3, T4, and fT4 serum concentrations as well as calculated peripheral deiodinase activity correlated negatively with their baseline values. Alterations in TNF-alpha correlated positively with protein intake, whereas changes in T4 and T4/TSH were inversely related to vegetal protein intake. In conclusion, low protein, low phosphorus diet, which is often prescribed to patients with moderate impairment of renal function, exerts a beneficial effect on low T3 syndrome coexisting with renal failure. The effect of low protein diet on the pituitary-thyroid axis is dependent on the degree of renal functional impairment and LPD-induced decrease in TNF-alpha may also contribute to the observed effects of dietary treatment.

Mild renal insufficiency is associated with increased cardiovascular mortality: The Hoorn Study

Cardiovascular mortality is extremely high in end-stage renal disease. Cardiovascular mortality risk also is increased in selected (high-risk) individuals with mild to moderate impairment of renal function. It is not clear whether a similar association exists in the general population and, if so, through what mechanisms. We investigated the association of renal function with all-cause and cardiovascular mortality in a population-based cohort and explored potential mechanisms underlying any such relationship. An age-, sex-, and glucose-tolerance-stratified sample (N = 631) of a population-based cohort aged 50 to 75 years was followed prospectively. After up to 10.2 years of follow-up, 117 subjects had died (50 of cardiovascular causes). At baseline, renal function was estimated by the serum creatinine level, the Cockcroft-Gault formula and Levey's equation. At baseline, the mean age was 64 +/- 7 years, 48% were men, 55% had hypertension, and 27% (by design) had type 2 diabetes. Serum creatinine was 91.7 +/- 19.0 micromol/L; creatinine clearance as estimated by the Cockroft-Gault formula was 72.5 +/- 13.7 mL/min/1.73 m(2), and the glomerular filtration rate (GFR) estimated by Levey's equation was 67.8 +/- 12.1 mL/min/1.73 m(2). Renal function was inversely associated with all-cause and with cardiovascular mortality. Relative risks (95% confidence intervals) were 1.08 (1.04 to 1.13) and 1.11 (1.07 to 1.16) per 5 micromol/L increase of serum creatinine; 1.07 (0.98 to 1.17) and 1.15 (1.01 to 1.31) for each decrease of 5 mL/min/1.73 m(2) creatinine clearance; and 1.15 (1.05 to 1.26) and 1.26 (1.12 to 1.42) for each decrease of 5 mL/min/1.73 m(2) of GFR. These associations remained after adjusting for age, sex, glucose tolerance status, hypertension, prior cardiovascular disease, low-density lipoprotein cholesterol, homocysteine, (micro)albuminuria, von Willebrand factor, soluble vascular adhesion molecule-1 and C-reactive protein. Analyses in diabetic and hypertensive subjects gave similar results. Mild to moderate loss of renal function is strongly associated with an increased risk of cardiovascular mortality. The mechanism behind this association is unclear but does not appear to involve common risk factors such as hypertension, diabetes or hyperhomocysteinemia. Estimation of renal function by relatively simple methods therefore may be a valuable tool for cardiovascular risk assessment over and above that provided by conventional risk factors. Our results were obtained in a general middle-aged to elderly population, and thus have broad applicability.

Prolonged calcium transients and myocardial remodelling in early experimental uraemia.

Cardiovascular disease is the most common cause of premature death in patients with end-stage renal disease, possibly due to a specific 'uraemic cardiomyopathy'. This study was designed to investigate the cardiac changes induced by a moderate impairment of renal function in a model of uraemia. Male Wistar rats (n=11) were rendered uraemic by 5/6 nephrectomy or sham operated (n=11). After 4 weeks, cardiac dimensions were measured from fixed tissue sections using a digital image analysis technique. In parallel groups of animals, cardiac myocytes were isolated and studied for evidence of functional changes attributable to uraemia. After steady-state field stimulation at 0.5 Hz, intracellular Ca(2+) handling (using Fura-2) was investigated. Up to 20 consecutive transients were averaged as the extracellular Ca(2+) was increased. The 5/6 nephrectomy group had a 75% reduction in glomerular filtration rate, and a 2- to 3-fold increase in serum urea and creatinine compared with sham-operated control animals (P<0.0001). However, the blood pressure was found to be similar in each group. Histology of the intact hearts (five pairs) showed a significant increase in tissue cross-sectional area (14%; P<0.04), cross-sectional area of the left ventricle (22%; P<0.04), and a significant increase in left ventricular wall thickness (15%; P<0.03). In the single cardiac cell study, under basal conditions (1-2 mM extra-cellular Ca(2+)) no significant differences in intracellular Ca(2+) were observed, but in high extracellular Ca(2+) the uraemic cells were slower to return to diastolic intracellular Ca(2+) levels (P<0.05). The data provide evidence of altered myocardial structure and function in early experimental uraemia. The changes described are consistent with concentric hypertrophy of the left ventricle, which occurs in the absence of hypertension.

Cardiac Surgery in Patients With Moderate Renal Impairment

There is a paucity of information concerning the results of cardiac surgery in patients with moderate impairment of renal function. We reviewed our recent experience to determine the results of operation and the long-term outcome. Since January 1992, we have performed cardiac surgical procedures utilizing total cardiopulmonary bypass on 57 adult patients with preoperative serum creatinine values > or = 2.0 mg/dL and no history of dialysis. Operative procedures done were coronary artery bypass (39 patients), repeated coronary artery bypass (2), valve replacement with or without coronary artery bypass (12), and other procedures (4). No operative deaths occurred. There were 3 hospital deaths. Only 5 patients required perioperative dialysis; in 5 additional patients, chronic dialysis was begun from 4 to 24 months postoperatively. The surviving patients who were not receiving dialysis had a mean creatinine value of 2.4 mg/dL at most recent follow-up. Adult patients with moderate renal impairment can safely have major cardiac procedures. The majority of patients maintain stable renal function postoperatively. The overall results of cardiac surgery in this patient population are good.

Optimisation of the Treatment of Acute Gout

Most of the drugs prescribed to treat acute gouty attacks were used before the introduction of modern clinical trials. Thus, there are few well-designed studies available to evaluate these drugs. Nevertheless, worldwide clinical experience supports the use of most nonsteroidal anti-inflammatory drugs (NSAIDs), colchicine and corticosteroids in the treatment of acute gout. Colchicine has been widely used but toxicity, especially gastrointestinal adverse effects, are a major concern. Therapeutic regimens involving hourly or 2-hourly administration were based on the short initial half-life of colchicine in plasma. Other therapy schedules, such as early 8-hourly administration, may be equally effective and have fewer adverse effects. Unfortunately, comparative studies to investigate this have not been performed. Colchicine should not be prescribed to patients with either severe renal insufficiency or combined hepatic-renal insufficiency. Doses should be halved in patients with moderate renal function impairment. NSAIDs are the most widely prescribed drugs in the treatment of acute gout. Few comparative data are available, but any of the most potent NSAIDs are probably useful in the control of pain and inflammatory signs of acute gouty arthritis. Pharmacokinetic properties should be taken into account when selecting an NSAID for the treatment of gout, as rapid absorption and a short half-life may help to avoid accumulation in patients with subclinical renal function impairment. Comorbidities should always be kept in mind when prescribing NSAIDs. Patients with previous or recent gastrointestinal bleeding, those receiving anticoagulant therapy or with haemorrhage diathesis, and those with renal insufficiency are at risk of developing severe adverse effects from NSAID administration. Corticosteroids are probably a reasonable choice for patients in whom colchicine and NSAIDs may be hazardous or for those with a history of previous intolerance to these drugs. Few trials using prednisone, prednisolone or triamcinolone acetonide are available, and dosages are prescribed following empirical data. Corticotropin has also been used to treat acute gout. Although it has been proven to be as effective as other corticosteroids or indomethacin, the need for multiple doses, parenteral administration and the high cost are major limitations for its use. Currently, the choice of a drug for the treatment of acute gout will depend on the balance between its efficacy and the potential adverse effects in a particular patient.

Plasma concentrations of an angiotensin-converting enzyme inhibitor, benazepril, and its active metabolite, benazeprilat, after repeated administrations of benazepril in dogs with experimental kidney impairment.

In order to examine the safety of an angiotensin-converting enzyme (ACE) inhibitor in dogs with impaired renal excretion route, benazepril was administered orally, and plasma concentrations of benazeprilat, the active metabolite of benazepril, were determined in dogs with renal mass reduction (1/4th kidney) created by right-side nephrectomy and ligation of branches of the left renal arteries. Five dogs were administered benazepril orally at a given dose (0.5 mg/kg body weight) and 4 other dogs received 20 times that dose (10 mg/kg body weight) once daily for 15 consecutive days before (intact kidney period) and after (1/4th kidney period) creation of kidney impairment. Six control dogs received surgical treatment, but no drug. After creating a 1/4th kidney, plasma urea nitrogen and creatinine concentrations increased to approximately 30 mg/dl and 2.0 mg/dl, respectively, and renal plasma flow and glomerular filtration rate decreased to 37% and 30% of pre-treatment values, respectively. However, these parameters did not change significantly during the 1/4th kidney period both in the 0.5 mg/kg and 10 mg/kg groups. In the 0.5 mg/kg group, plasma benazeprilat concentrations increased to approximately 20 ng/ml to 340 ng/ml 2 hr after each administration, and there were no significant differences between the plasma benazeprilat concentrations during the intact and 1/4th kidney periods. In the 10 mg/kg group, plasma benazeprilat concentrations varied in the individual dog, but did not increase with the days of administration, and were not significantly different on each administration day between the intact and 1/4th kidney periods in either dose group. The AUCs(0-24) of plasma benazeprilat concentrations determined on the 15th administration day were not different between the intact and 1/4th kidney periods in dogs of either dose group. Plasma ACE activities decreased after drug administration in dogs of both groups. Benazepril seemed to have a high safety, and the adjustment of dosage regimen might not be needed in dogs with mild to moderate renal function impairment because the drug was excreted both from the kidneys and liver.

Lipoprotein(a) and apolipoprotein(a) isoforms and proteinuria in patients with moderate renal failure

Atherosclerotic diseases are a major cause of death in patients with renal failure. Increased serum concentrations of lipoprotein(a) [Lp(a)] have been established as a genetically controlled risk factor for these diseases and have been demonstrated in patients with moderate renal failure, suggesting that this lipoprotein contributes to the increased cardiovascular risk seen in these patients. Variable alleles at the apolipoprotein(a) [apo(a)] gene locus are the main determinants of the serum Lp(a) level in the general population. The purpose of this study was to investigate apo(a) isoforms in patients with moderate renal failure and mild proteinuria (less than 1.0 g/day). In 250 consecutive subjects recruited at a hypertension clinic, we assessed the renal function by 24-hour creatinine clearance, proteinuria, and microalbuminuria, as well as the prevalence of atherosclerotic disease, and we also measured apo(a) isoforms, serum albumin, and Lp(a) concentrations. Moderate impairment of renal function (creatinine clearance, 30 to 89 ml/min per 1.73 m2 of body surface area) was found in 97 patients. Lp(a) levels were significantly greater in patients with moderate renal failure (21.7+/-23.9 mg/dl) as compared with patients with normal renal function (15.6+/-16.4 mg/dl, P<0.001), and an inverse correlation was observed between log Lp(a) and creatinine clearance (r = -0.181, P <0.01). However, no difference was found in the frequency of low molecular weight apo(a) isoforms between patients with normal (25.5%) and impaired (27.8%) renal function. Only patients with the smallest size apo(a) isoforms exhibited significantly elevated levels of Lp(a), whereas the large-size isoforms had similar concentrations in patients with normal and impaired renal function. No significant relationship was found between serum Lp(a) and proteinuria. Clinical and laboratory evidence of one or more events attributed to atherosclerosis was found in 9.8% of patients with normal renal function and 25.8% of patients with moderate renal failure (P<0.001). These results indicate that renal failure per se or other genes beside the apo(a) gene locus are responsible for the elevation of serum Lp(a) levels in patients with moderate impairment of renal function. The elevation of Lp(a) levels occurs independently of the level of proteinuria and may contribute to the risk for atherosclerotic disease in these patients.

Uptake and metabolism of lipoproteins from patients with diabetes mellitus type II by glomerular epithelial cells.

Recent studies suggest that dyslipidaemia accelerates the progression of diabetic nephropathy, but the various pathomechanisms underlying such abnormalities are not completely delineated. We isolated, radiolabelled, and characterized very-low-density lipoproteins (VLDL) and low-density lipoproteins (LDL) from eight diabetic patients with moderate impairment of renal function and dyslipidaemia and studied their interaction with LDL receptors in human glomerular epithelial cells. While diabetic VLDL showed no compositional changes, LDL particles contained a higher proportion of triglycerides at the expense of cholesterol in comparison with healthy controls. Despite differences in composition, both VLDL and LDL from patients exhibited reduced receptor affinity and cellular uptake capacity by glomerular epithelial cells. Since LDL composition was altered intracellular cholesterol homeostasis was investigated. Due to reduced cholesterol content and lower uptake capacity, diabetic LDL were less effective in suppressing intracellular sterol synthesis and in activating acylcholesterol acyltransferase than LDL from controls. Electrophoretic mobility of apoB from diabetic patients was enhanced as compared to controls, most probably due to the higher degree of glycation (17 + 1.7 versus 11 + 1%, P < 0.05) but not to oxidation (TBARS 0.5 + 0.2 versus 0.2 + 0.1 mumol/1). Oxidized LDL was not taken up in significant amounts, indicating no scavenger receptor activity in glomerular epithelial cells. The receptor-specific uptake of diabetic VLDL and LDL by glomerular epithelial cells is impaired. Compositional changes of the LDL particle and glycation of the protein moiety may contribute to altered glomerular uptake. However, glycation of the protein moiety may be superior to compositional changes. Because glomerular structures like mesangial matrix and endothelial cells are known for preferential binding of modified lipoproteins, further studies are required to elucidate their potential role in the progression of diabetic glomerulosclerosis.

A short-term antihypertensive treatment-induced fall in glomerular filtration rate predicts long-term stability of renal function

In long-term intervention studies on renal function outcome an initial decline in the glomerular filtration rate (GFR) may occur after starting therapy. If this initial GFR decline is the result of a treatment-induced hemodynamic change reflecting a fall in intraglomerular pressure, it should be reversible after treatment withdrawal, even after long-term treatment. In fact, it could be beneficial for renal function in the long term. We therefore studied systemic and renal hemodynamics in 40 non-diabetic patients with impaired renal function before treatment, during four years treatment with either atenolol or enalapril, and after withdrawal of that treatment. The acute change in GFR 12 weeks after start of treatment varied widely from -11 to + 11 ml/min (mean +/- SD -1.0 +/- 4.1 ml/min, NS). After four years of treatment, withdrawal for 12 weeks resulted in a rise in GFR of +2.2 +/- 5.4 ml/min, P = 0.011, again with a wide range of +14 to -6 ml/min). The initial fall in GFR was related to the rise after withdrawal (r = 0.32, P < 0.05). Interestingly, the acute treatment induced change in GFR correlated with the long-term slope, such that a patient with a greater initial decline in GFR showed a more stable course during the follow up (r = -0.36, P < 0.05). The patients were arbitrarily divided in group A (N = 20), with the largest initial treatment-induced fall in GFR, and group B (N = 20), with the smallest initial fall in GFR. Group A had a significantly less steep slope than group B (-0.41 +/- 1.52 vs. -2.09 +/- 2.79 ml/min/year, P = 0.023) during the four year follow-up. In group A GFR increased again after withdrawal of treatment (+3.8 +/- 5.6 ml/min, P = 0.011) whereas it did not change in group B (+0.5 +/- 4.0 ml/min, NS). As a consequence, GFR post-treatment was not different compared to pre-treatment in group A (-2.5 +/- 7.2 ml/min, NS), whereas it was 5.9 +/- 12.1 ml/min lower in group B (P = 0.023). Patients treated with enalapril had a similar response as patients treated with atenolol. In conclusion, an initial fall in GFR after starting antihypertensive treatment in patients with a mild to moderate renal function impairment (GFR 30 to 90 ml/min) is reversible even after years of treatment, suggesting that this therapy-induced fall is of hemodynamic and not of structural origin. This initial GFR fall was associated with a subsequent stable renal function. These data lead to the hypothesis that the initial fall in GFR in response to antihypertensive therapy reflects renal protection.

Effects of Exercise on Renal Function in Patients with Moderate Impairment of Renal Function Compared to Normal Men

The renal excretory and haemodynamic responses to sustained moderate exertion were investigated in normotensive humans with impaired renal function and normal volunteers. The heart rate increase with exercise was similar in each group. Subjects with impaired renal function showed a significant fall in glomerular filtration rate on exertion, while normals did not. In the presence of renal disease, urine osmolality did not rise with exertion, although it rose markedly in the normal group. Free water clearance became negative after exercise in the normal group only. The diseased kidney is unable to maintain glomerular filtration rate or conserve water under the stress of exertion as well as the normal kidney.

Pharmacokinetics of cefotaxime in patients after liver transplantation

The pharmacokinetics of cefotaxime including formation of its active metabolite desacetyl-cefotaxime were assessed after liver transplantation in three groups of patients (four patients per group): --during the postoperative recovery phase (group 1), --during an episode of allograft nonfunction (group 2), --during an episode of allograft rejection (group 3). All patients received a single dose of 1 g cefotaxime intravenously. Concentrations of cefotaxime and its metabolite were determined in plasma and urine until 6 to 72 h after medication. The terminal half-life of cefotaxime increased and total clearance decreased due to an impairment of drug metabolism, mainly in patients with a nonfunctioning allograft and during rejection. Thus, no desacetyl-cefotaxime was detectable in urine of any patient and none in plasma of 2/4 patients with a nonfunctioning allograft. In addition, a moderate impairment of renal function in several patients contributed to the delayed elimination of cefotaxime and its metabolite. It can be concluded that liver function after transplantation is correlated with the ability to eliminate cefotaxime. Therefore, administration of half the normal dose is recommended particularly in patients with a nonfunctioning allograft or during rejection.

The effects of renal function on the disposition of isradipine.

The effect of renal function on isradipine kinetics was examined in four groups of subjects (N = 55) who had normal or impaired renal function. Each subject received isradipine orally as a 10-mg capsule. Serial blood samples were obtained from 0 to 48 hours postdose and the isradipine plasma concentrations determined by radioimmunoassay. Kinetic parameters, Cmax, lambda 3, t 1/2, AUC, CL'o (oral clearance), and CLo (oral clearance standardized to body weight) were determined. Marked intersubject variability of the pharmacokinetic parameters was observed. No statistically significant differences (P greater than .05) were found for AUC, Cl'o, and Clo parameters when renal impairment groups were compared with controls. AUC values were lower (P less than .05), however, for the group with severe renal function impairment than for groups with mild or moderate renal function impairment. No significant correlations (r = -.23, P greater than .05; and r = .13, P greater than .05, respectively) were found between creatinine clearance (CLCR) and CLo and between age and CLo. Considering the interpatient variability in isradipine disposition and the lack of significant differences in CLo between groups, no clear-cut dosing regimen alterations, based on single-dose data, are warranted in renal impairment.

Clinical pharmacokinetics of oral buspirone in patients with impaired renal function.

12 patients with mild to moderate impairment of renal function and 12 healthy subjects each received 20mg buspirone as a single dose in this acute study. Six anuric patients with chronic renal failure were given two 20mg doses of buspirone, the first 2 days before haemodialysis (between dialyses) and the second during hemodialysis (2 hours before dialysis began). The differences between the median pharmacokinetic values of buspirone for healthy subjects, patients with mild to moderate renal impairment, and anuric patients were not statistically significant. Similarly, there were no significant differences between values in mild to moderate renal failure vs healthy subjects. Some of the median pharmacokinetic values for the active buspirone metabolite 1-(2-pyrimidinyl)-piperazine (1-PP), however, differed significantly for anuric patients, compared with healthy subjects or patients with mild to moderate renal impairment. When assessed between and during haemodialysis, the anuric patients had significantly (p less than 0.05) greater pharmacokinetic median values: half-life (t 1/2) = 15.2 vs 9.8 hours; area under the concentration-time curve (AUC) = 604 vs 404 nmol/L.h; and mean residence time (MRT) = 9.28 vs 6.96 hours. No firm recommendation for specific dosage can be made based on the present data. However, it does appear that in patients with mild to moderate renal impairment, the pharmacokinetics of buspirone and its active metabolite 1-PP are similar to those in individuals with normal renal function. For anuric patients higher concentrations of the 1-PP metabolite are attained while they are not undergoing haemodialysis. A dosage reduction of 25 to 50% might be necessary when buspirone is given to anuric patients.

腎機能低下を示す高血圧患者に対するＢＫＵ反復投与時の薬物動態

The pharmacokinetics of the alpha-blocking agent urapidil have been elucidated only in subjects with normal renal function. In the present study, BKU-15 (sustained-release capsules containing 15mg of urapidil) was administered for 7 consecutive days to 7 hypertensive patients with mild to moderate impairment of renal function. Treated were 3 males and 4 females between the ages of 24 to 74 years, and the dosing regimen was BKU-15 s. i. d. at 8: 00 a. m. on days 1 and 7, and b. i. d. at 8: 00 a. m. and 5: 00 p.m. on days 2 to 6.The minimum plasma concentration of urapidil determined at 8: 00 a. m. stabilized by day 5, measuring 74.0±19.8ng/ml on day 7. The pharmacokinetic parameters calculated after administration on day 7 were as follows: Cmax 205.5±31.0ng/ml; Tmax 4.3±0.3hrs; kel 0.1±0.02/hr; t1/2 8.4±1.5hrs. The absorption rate constant, minimum plasma concentration, and Cmax of urapidil were comparable to the corresponding values in healthy subjects given a 2-fold dose (Ebihara et al.), whereas elimination was delayed by a factor of two.A decrease in blood pressure was observed at 2 to 10 hours after administration of BKU-15. There was no significant change in heart rate. Two patients complained of hot flushes and throbbing in the temporal region, which might be related to the pharmacological effects of the drug. Severe nausea was noted in another patient.It is thus considered that BKU-15 b. i. d, may be adequate as the initial dosage in treating hypertensive patients with impaired renal function.

Improvement in renal function following ureteric reimplantation for vesicoureteric reflux.

Summary— Ten children with vesicoureteric reflux who had moderate impairment of renal function before corrective surgery have been analysed retrospectively. A significant improvement in renal function occurred after successful anti‐reflux surgery. The possible reasons for this improvement are discussed with emphasis on the functional rather than the morphological effects of reflux.