Down-regulation of intestinal drug transporters in chronic renal failure in rats

Chronic renal failure (CRF) is associated with an increased bioavailability of drugs by a poorly understood mechanism. One hypothesis is a reduction in the elimination of drugs by the intestine, i.e., drug elimination mediated by protein membrane transporters such as P-glycoprotein (Pgp) and multidrug-resistance-related protein (MRP) 2. The present study aimed to investigate the repercussions of CRF on intestinal transporters involved in drug absorption [organic anion-transportingpolypeptide (Oatp)] and those implicated in drug extrusion (Pgp and MRP2). Pgp, MRP2, MRP3, Oatp2, and Oatp3 protein expression and Pgp, MRP2, and Oatp3 mRNA expression were assessed in the intestine of CRF (induced by five-sixth nephrectomy) and control rats. Pgp and MRP2 activities were measured using the everted gut technique. Rat enterocytes and Caco-2 cells were incubated with sera from control and CRF rats to characterize the mechanism of transporters' down-regulation. Protein expression of Pgp, MRP2, and MRP3 were reduced by more than 40% (p < 0.01) in CRF rats, whereas Oatp2 and Oatp3 expression remained unchanged. There was no difference in the mRNA levels assessed by real-time polymerase chain reaction. Pgp and MRP2 activities were decreased by 30 and 25%, respectively, in CRF rats compared with control (p < 0.05). Uremic sera induced a reduction in protein expression and in activity of drug transporters compared with control sera. Our results demonstrate that CRF in rats is associated with a decrease in intestinal Pgp and MRP2 protein expression and function secondarily to serum uremic factors. This reduction could explain the increased bioavailability of drugs in CRF.     

Effects of haemodialysis on heart rate variability in chronic renal failure

The influence of haemodialysis (HD) on the heart rate variability (HRV) was investigated in nine non-diabetic patients on maintenance haemodialysis. The R-R intervals were measured in recordings during spontaneous quiet breathing and during controlled deep breathing before and after a single HD session. The HRV was expressed as the standard deviation of the mean R-R interval in 3 min ECG recordings. Heart rate variability is the irregularity in the heart rate mainly caused by autonomic control mechanisms. The long-term HRV during quiet breathing was statistically significantly (p less than 0.05) higher after the HD than before. The HRV in the intermediate frequency range of 0.075-0.125 Hz was also significantly increased by the HD. This suggests that some metabolic agents interfering with the heart rate regulation are removed by the haemodialysis, and as a result a better function of the autonomic cardiac control is achieved in uraemic patients.     

曲美他嗪对老年慢性心力衰竭患者心率变异性影响的研究

目的探讨曲美他嗪对老年慢性心力衰竭患者心率变异性影响。方法选择42例老年慢性心力衰竭患者,研究组在对照组传统治疗方法的基础上加用曲美他嗪,于治疗前及治疗后12周对患者心率、射血分数(EF)、6 min步行试验和HRV进行检测,比较检测结果。结果两组心率、EF、6 min步行试验在治疗前均无统计学差异,治疗后研究组心率显著低于对照组,EF和6-MWD显著高于对照组。两组HRV指标治疗前均无统计学差异,治疗后两组的各项指标均出现显著提升,治疗后研究组SDNN、SDANN、r MSSD、p NN50显著高于对照组。结论在常规治疗基础上加用曲美他嗪对老年慢性心力衰竭患者能明显改善HRV与心功能,值得临床应用。     

Impact of a hemodialysis session on cardiac function in patients with chronic renal failure

AIM: To determine the impact of hemodialysis (HD) session on cardiac function in patients with chronic renal failure. MATERIAL AND METHODS: Thirty patients (17 male, 13 female, mean age 49 +/- 11 years) on bicarbonate HD were studied. M-mode echocardiography was performed and ejection fraction (EF) was estimated. Transmitral flow was assessed by Doppler echocardiography. Peak velocity of early (E) and late (A) filling, E/A ratio, isovolumic relaxation time (IVRT) and early deceleration time (DT) were estimated. All the estimations were made one hour before and immediately after HD by one investigator. Flow propagation velocity of early diastolic flow was assessed by color M-mode Doppler echocardiography. RESULTS: A significant decrease of the ejection fraction (delta EF) was observed only in patients with intradialytic hypotension. Hemodialysis resulted in a decrease of early flow velocity from 99.2 +/- 23.8 to 80.6 + 26.0 cm/s (p = 0.0000) and E/A ratio from 1.23 +/- 0.57 to 0.98 +/- 0.43 (p = 0.006). IVRT and DT showed no significant difference. There was a significant positive correlation between the amount of ultrafiltration and deltaE (r = 0.46; p = 0.01), there was no correlation between the amount of ultrafiltration and delta Vp (r = -0.01; p = 0.9). CONCLUSION: The results show that a hemodialysis session influences cardiac function in patients with chronic renal failure. Early diastolic filling considerably decreased in correlation with ultrafiltration. A significant decrease in an ejection fraction was detected only in patients with intradialytic hypotension. Ultrafiltration had no impact on flow propagation velocity of early diastolic flow of the left ventricle assessed by color M-mode Doppler echocardiography.     

Interindividual and intraindividual variability in acetylation: characterization with caffeine

The degree of interindividual and intraindividual variability in acetylator activity was investigated with caffeine used as a probe of enzyme activity. Acetylator phenotype and relative N-acetyltransferase activity were estimated in 46 subjects by measuring the urinary ratio of two metabolites, AFMU/1-MX, after a single 300 mg oral dose of caffeine on five separate occasions. Thirty homozygous slow (rr) and 15 heterozygous rapid (Rr) acetylators were identified. The degree of interindividual variability in acetylator activity was observed to be a mean of 32% (range 27% to 36%) and 20% (range 11% to 29%) in the rr and Rr groups, respectively. The mean intraindividual variation on repetitive measurement was 19% (range 6% to 49%) in the rr and 14% (range 7% to 24%) in the Rr acetylator group. Four subjects had apparent changes in acetylator activity with time such that they were unable to be assigned to any one acetylator group. Two of these four subjects exhibited apparent homozygous rapid acetylator activity intermittently during the 5-week trial. This variability may explain, in part, some of the high degree of patient variability observed in the toxicity, efficacy, and drug-related disease associated with acetylated drugs and environmental toxins.     

藻黄胶囊Ⅱ号延缓慢性肾功能衰竭进展的实验研究

目的 囊Ⅱ号液对人肾小球系膜细胞(GMC)、增殖及分泌纤维连接蛋白(FN)、转化生长因子β1(TGF-β1)的影响.方法 体外人GMC培养,细胞成熟后进行药物孵育,观察细胞增殖情况,检测藻黄胶囊Ⅱ号液对人GMC分泌的FN、TGF-β1的影响.结果 实验研究显示藻黄胶囊Ⅱ号液可明显抑制人GMC的增殖,明显抑制人GMC分泌FN、TGF-β1.结论 藻黄胶囊Ⅱ号液可抑制人GMC的增殖及FN、TGF-β1分泌,提示其可减少肾小球和肾间质细胞外基质的堆积.     

Impact of renal aging on drug therapy

Elderly patients (age ≥ 65 years old) use up to 30% of all commonly prescribed medication, and they suffer more their adverse effects than the general population. In order to minimize this risk, physicians should avoid polypharmacy, dangerous pharmacological interactions and take into account pharmacodynamic and senile pharmacokinetic changes before prescribing any medication to the elderly. The present review article originally describes how renal physiology changes secondary to aging such as dysautonomia, glomerular filtration rate reduction, tubular back-filtration, sodium, calcium and magnesium loss, potassium retention, altered dilution-concentration capability, tubular frailty, genetics, internal milieu and body composition are senile changes that when combined predispose elderly people to suffer from pharmacological adverse effects. Knowledge of these physiological modifications associated with aging and their impact on the pharmacology of particular drugs may help to optimize drug use and to avoid complications in this age group.     

Pseudoclubbing in chronic renal failure

Seven patients with chronic renal failure developed a peculiar abnormality of the fingers referred to as pseudoclubbing. All had radiological evidence of severe secondary hyperparathyroidism and elevated parathormone levels measured by C-terminal assay. Treatment with vitamin D and calcium, parathyroidectomy or renal transplantation resulted in radiological healing but the deformity of the finger tips did not improve. Although these patients represent a group with severe secondary hyperparathyroidism, autonomous secretion of parathormone is not a necessary accompaniment of this disorder.     

Parathyroidectomy in chronic renal failure

In order to establish whether parathyroidectomy altered the natural history of ectopic calcification in patients with renal failure we undertook a detailed analysis of 62 patients with hyperparathyroidism secondary to chronic renal failure who were submitted to parathyroidectomy. Biochemical data (61 patients) and radiological skeletal surveys (42 patients) were studied before and after parathyroidectomy. Transiliac bone biopsies were obtained at (or some time in the previous six months before) parathyroidectomy in 30 and in 36 patients after surgery. Paired bone biopsies were available from 17 of these patients. In the majority of patients secondary hyperparathyroidism was controlled after parathyroidectomy although in seven patients (11 per cent), who underwent subtotal parathyroidectomy, it relapsed after initial improvement. Non-visceral soft tissue calcification disappeared or decreased in 60 per cent of the patients after parathyroidectomy. However, despite marked improvement in subperiosteal erosions and histological osteitis fibrosa, with significant reductions in iPTH and Ca X P product after parathyroidectomy, small peripheral arterial calcification developed or progressed in 56 per cent of the patients. Histological osteomalacia after parathyroidectomy developed after operation in two patients. Both had positive aluminium stains for excess aluminium in their bone. Numbers of osteoclasts and the amount of marrow fibrosis declined in parallel following parathyroidectomy, but woven bone persisted for months or years.     

Adherence monitoring and drug surveillance in chronic opioid therapy

Monitoring adherence with chronic opioid therapies is a critical yet often difficult task. Because chronic opioid therapy is often fraught with complex pharmacological, psychological, social, and legal issues, its application is often controversial or altogether avoided. Improved drug monitoring and surveillance may help reduce some of the reluctance to use chronic opioid therapy in patients with chronic pain states. We review the literature on patient adherence/compliance with chronic administration of opioids as well as novel methods by which adherence with opioid therapy can be measured.     

Secondary hyperparathyroidism in chronic renal failure. Pathophysiology and treatment.

The secondary hyperparathyroidism of chronic renal failure is a result of many factors which result in chronic stimulation of parathyroid hormone secretion and secondary hyperplasia of the parathyroid glands. The secretion and metabolism of parathyroid hormone and its fragments in chronic renal failure are complex and only partially understood. Constant elevated levels of PTH contribute to bone disease and other clinical features of chronic renal failure. Calcium supplementation, high calcium dialysis, control of plasma phosphate and judicious use of the vitamin D metabolites can, to a large extent, prevent or control the development of secondary hyperparathyroidism. Subtotal parathyroidectomy or total parathyroidectomy with autotransplantation is indicated in certain cases, sometimes on an emergency basis. Prevention of postoperative hypocalcemia requires careful management. Successful renal transplantation is usually associated with gradual healing of the bone disease and slow, but sometimes incomplete involution of the parathyroid hyperplasia.     

Human renal organic anion transporters: characteristics and contributions to drug and drug metabolite excretion

The kidney is a key organ for promoting the excretion of drugs and drug metabolites. One of the mechanisms by which the kidney promotes excretion is via active secretion. Secretion of drugs and their metabolites from blood to luminal fluid in the nephron is a protein-mediated process that normally involves either the direct or indirect expenditure of energy. Renal transporters for organic anions are located in the proximal tubule segment of the nephron. The primary transporters of organic anions on the basolateral membrane (BLM) of proximal tubule cells are members of the organic anion transporter (OAT) family (mainly OAT1 and OAT3). The sulfate-anion antiporter 1 (SAT-1; hsat-1) may also contribute to organic anion transport at the basolateral membrane. On the apical membrane, the multi-drug resistance-associated protein 2 (MRP2) is an important transport protein to complete the secretion process. However, there are several transport proteins on the basolateral and apical membranes of proximal tubule cells in human kidneys that have not been fully characterized and whose role in the secretion of organic anions remains to be determined. This review will primarily focus on the human renal basolateral and apical membrane transporters for organic anions that may play a role in the excretion of drugs and drug metabolites.     

慢性肾衰竭患者实施护理路径的临床效果探讨

目的探讨临床护理路径在慢性肾衰患者护理中的应用价值。方法选取160例慢性肾衰竭患者随机分为实验组和对照组,实验组采用临床护理路径干预,对照组采用常规护理措施,测定护理前后患者的尿素氮(BUN)及血肌酐(SCr)变化,护理后评价2组患者健康知识掌握率、基础护理合格率及满意度。结果 2组患者护理后的BUN、SCr均较其护理前显著降低,差异具有统计学意义(P<0.05);护理后,实验组患者BUN、SCr显著低于对照组,差异具有统计学意义(P<0.05)。结论在慢性肾衰患者的护理中应用临床护理路径,可有效降低患者血液中BUN、SCr水平,提高护理质量,值得在临床上推广应用。