Rationale for the administration of systemic 5-FU in combination with heated intraperitonal oxaliplatin.

BACKGROUND: Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (HIPEC) with oxaliplatin (OX) is the standard of care for selected patients with peritoneal carcinomatosis of colorectal origin. Because 5-FU is mandatory to improve efficacy of OX when used by systemic route, several teams now empirically combine intravenous (IV) 5-FU with HIPEC OX, but this practice has yet to be supported by preclinical data. Using a murine model, we studied the impact of IV 5-FU on peritoneal absorption of HIPEC OX. METHODS: Under general anesthesia, 24 Sprague-Dawley rats were submitted to 4 different doses of IV 5-FU (0, 100, 400 and 800 mg/m2) and a fixed dose of HIPEC OX (460 mg/m2) perfused at 40 °C during 25 min. At 25 min, samples in different compartments were harvested (peritoneum, portal vein and systemic blood) and the concentrations of 5-FU and OX were measured by high performance liquid chromatography. RESULTS: Peritoneal absorption of OX was significantly higher (17.0, 20.1, 34.9 and 38.1 nmol/g, p < 0.0001) with increasing doses of 5-FU (0, 100, 400 and 800 mg/m2, respectively). Peritoneal absorption of OX reached a plateau between 400 and 800 mg/m2 of IV 5-FU. CONCLUSION: IV 5-FU enhances peritoneal absorption of HIPEC OX. The most efficient dose of IV 5-FU to be used in combination with HIPEC OX seems to be 400 mg/m2.

Behavioral, pharmacological and molecular characterization of the saphenous nerve partial ligation: a new model of neuropathic pain.

The saphenous partial ligation (SPL) model is a new, easily performed, rodent model of neuropathic pain that consists of a unilateral partial injury to the saphenous nerve. The present study describes behavioral, pharmacological and molecular properties of this model. Starting between 3 and 5 days after surgery, depending on the modality tested, animals developed clear behaviors indicative of neuropathic pain such as cold and mechanical allodynia, and thermal and mechanical hyperalgesia compared with naive and sham animals. These pain behaviors were still present at 1 month. Signs of allodynia also extended to the sciatic nerve territory. No evidence of autotomy or bodyweight loss was observed. Cold and mechanical allodynia but not thermal and mechanical hyperalgesia was reversed by morphine (4 mg/kg i.p.). The cannabinoid receptor agonist WIN 55,212-2 (5 mg/kg i.p.) improved signs of allodynia and hyperalgesia tested except for mechanical hyperalgesia. Gabapentin (50 mg/kg i.p.) was effective against cold and mechanical allodynia but not hyperalgesia. Finally, amitriptyline (10 mg/kg i.p.) failed to reverse allodynia and hyperalgesia and its administration even led to hyperesthesia. Neurobiological studies looking at the expression of mu opioid receptor (MOR), cannabinoid CB(1) and CB(2) receptors showed a significant increase for all three receptors in ipsilateral paw skin, L3-L4 dorsal root ganglia and spinal cord of neuropathic rats compared with naive and sham animals. These changes in MOR, CB(1) and CB(2) receptor expression are compatible with what is observed in other neuropathic pain models and may explain the analgesia produced by morphine and WIN 55,212-2 administrations. In conclusion, we have shown that the SPL is an adequate model that will provide a new tool for clarifying peripheral mechanisms of neuropathic pain in an exclusive sensory nerve.

Cytochrome P450 and liver diseases.

Cytochrome P-450 (CYPs) are involved in the metabolism of drugs, chemicals and endogenous substrates. The hepatic CYPs are also involved in the pathogenesis of several liver diseases. CYP-mediated activation of drugs to toxic metabolites induces hepatotoxicity. Well-known examples include acetaminophen and halothane. In some instances, covalent binding of the toxic metabolite to CYP leads to the formation of anti-CYP antibodies and immune-mediated hepatotoxicity (hydralazine, tienilic acid). Anti-CYP2D6 antibodies are also present in the serum of patients with type II autoimmune hepatitis, but the mechanism leading to their presence and their pathogenic significance remains unclear. Several studies support a role for CYP2E1 in the pathogenesis of alcoholic liver disease and non-alcoholic steatohepatitis. In these conditions, enhanced CYP2E1 activity is associated with lipid peroxidation and the production of reactive oxygen species with secondary damage to cellular membranes and mitochondria. Because of its ability to activate carcinogens, a role for CYP2E1 as a cofactor for hepatocellular carcinoma has also been postulated. On the other hand, drug metabolism is impaired in patients with liver disease, particularly that mediated by CYPs. The content and activity of CYP1A, 2C19 and 3A appear to be particularly vulnerable to the effect of liver disease while CYP2D6, 2C9 and 2E1 are less affected. The pattern of CYPs isoenzymes alterations also differs according to the etiology of liver disease. A strong relationship between the activity of CYPs and the severity of cirrhosis has been demonstrated, but the usefulness of measuring CYP activity to assess hepatic functional reserve remains uncertain.

The influence of moderate hypoalbuminaemia on the renal metabolism and dynamics of furosemide in the rabbit.

1. The present study aimed to investigate the influence of hypoalbuminaemia on the pharmacokinetics and pharmacodynamics of furosemide. Hypoalbuminaemia was produced by repeated plasmapheresis, to attain plasma albumin concentrations of 21.6 +/- 0.9 g l-1, compared with 33.0 +/- 0.6 g l-1 in controls (P < 0.001). The per cent of bound furosemide in hypoalbuminaemic rabbits (90.8 +/- 0.7%) was lower than that in control rabbits (97.4 +/- 0.5%, P < 0.001). The kinetics of intravenous furosemide (2.5 mg kg-1) were studied in control (n = 6) and hypoalbuminaemic rabbits (n = 6). 2. To assess the effect of hypoalbuminaemia on extrarenal clearance of furosemide, functional anephria was induced by ligating the renal pedicles of 12 rabbits, which were segregated in two groups, with and without hypoalbuminaemia. 3. In the control group, total, urinary and metabolic clearances of furosemide were 11.8 +/- 1.0, 5.0 +/- 0.4 and 6.8 +/- 0.6 ml min-1 kg-1, respectively. Compared with control rabbits, in hypoalbuminaemic rabbits, total clearance of furosemide increased by 40% (P < 0.001), result of the enhancement of furosemide metabolic clearance (C1m) from 5 to 10 ml min-1 kg-1 (P < 0.01). In hypoalbuminaemic rabbits, urinary excretion of furosemide was reduced by 26% (2451 +/- 115 vs 1818 +/- 134 micrograms h-1, P < 0.01). In anephric rabbits, furosemide total clearance was 1.77 +/- 0.12 ml min-1 kg-1, value not affected by hypoalbuminaemia, confirming that the increase in C1m induced by hypoalbuminaemia occurs in the kidneys. 4. Compared with controls, in hypoalbuminaemic rabbits, the rate of urinary excretion (142 +/- 9 vs 74 +/- 8 ml h-1, P < 0.001) and the rate of excretion of sodium (18.6 +/- 0.9 vs 9.9 +/- 0.9 mmol h-1, P < 0.001) were very much reduced. However, the dose-response curves were not different. 5. In conclusion, hypoalbuminaemia is associated with an increase in renal metabolic clearance of furosemide, possibly because of the increase in furosemide unbound concentration, and a decrease in the diuretic/natriuretic effect of furosemide, secondary to a reduction in furosemide tubular secretion. Thus, albumin facilitates the renal secretion of organic anions but not their metabolism.

Catabolism in critical illness: estimation from urea nitrogen appearance and creatinine production during continuous renal replacement therapy.

Thirty-eight intensive care unit (ICU) patients (26 men and 12 women with a mean age of 57.0 +/- 16.6 years) with acute renal failure (ARF) treated by venovenous continuous renal replacement therapy (CRRT) were evaluated while in relatively steady metabolic control. Twenty-seven were undergoing continuous venovenous hemodialysis, nine were undergoing continuous venovenous hemodiafiltration, and two were undergoing continuous venovenous hemofiltration. Periods of analysis varied between 24 and 408 hours (mean duration, 82.7 +/- 70.6 hours; median, 72 hours). Their mean Acute Physiology and Chronic Health Evaluation II (APACHE II) score within 24 hours of admission to the ICU was 21.3 +/- 6.3 and survival rate was 31.6%. Urea nitrogen and creatinine concentrations were determined every 6 to 12 hours in both serum (Cun and Cc, respectively) and effluent (spent dialysate and/or ultrafiltrate). The mean effluent rate was 1,472 +/- 580 mL/h and blood flow rate, 166 +/- 32 mL/min. Urine was collected daily for urea nitrogen and creatinine measurement. Urea nitrogen appearance rate (UnA) and creatinine production rate (Pc), calculated from urea nitrogen (UnMR) and creatinine mass removal (CMR) from both the effluent and the urine, using Garred mass balance equations and the Forbes-Bruining formula, allowed normalized protein catabolic rate (nPCR) and estimates of lean body mass (LBM) to be derived. Creatinine metabolic degradation rate (Dc), estimated by the Mitch formula, was included in the calculation. The lowest body weight recorded during the study period was considered as dry weight (BW). The creatinine index (CI) was also obtained. For each parameter, the results are presented as mean, median, and range values: UnMRe (from effluent), 13.6 +/- 7.2, 12.5, 1.6 to 32.6 mg/min; UnMRu (from urine), 0.13 +/- 0.40, 0, 0 to 2.30 mg/min; UnA, 13.6 +/- 7.0, 12.5, 3.8 to 32.1 mg/min; nPCR, 1.75 +/- 0.82, 1.60, 0.61 to 4.23 g/kg/d; CMRe (from effluent), 942.0 +/- 362.3, 918.0, 211.2 to 1,641.6 mg/d; CMRu (from urine), 44.4 +/- 138.8, 0, 0 to 698.5 mg/d; Dc, 94.6 +/- 49.9, 81.9, 31.0 to 294.1 mg/d; Pc total, 1,067.1 +/- 409.7, 1,053.7, 261.5 to 1,988.2 mg/d; LBM, 38.3 +/- 11.9, 37.9, 15.0 to 65.0 kg; LBM/BW ratio, 49.5% +/- 14.0%, 50.3%, 22.5% to 86.0%; and CI, 13.7 +/- 4.7, 14.2, 4.1 to 25.8 mg/kg/d. When Pc was estimated from the Cockcroft-Gault equations (as Pc'), the mean value for Pc and Pc' was similar (1,067.1 +/- 409.7 v 1,284.9 +/- 484.1 mg/d), but there were relatively large differences for the majority of cases. A positive correlation was observed between UnA and Pc (R = 0.42). Serum albumin and LBM/BW correlated poorly (R = 0.20). Outcome was weakly related to UnA and to nPCR (R = 0.29 and R = 0.31, respectively). Urea nitrogen appearance appears widely variable in critically ill ARF patients. This simple approach can provide useful information for an easy estimate of net protein catabolism in critically ill patients with ARF undergoing CRRT.

Arginine vasopressin disposition in the conscious rabbit.

To characterize the urinary kinetics of AVP, and the influence of regional blood flow on the metabolic degradation of AVP, multiple doses of AVP were administered to conscious rabbits. AVP systemic clearance (ClT) was not influenced by changes in dose, in spite of a decrease in AVP urinary clearance following the highest dose. Hepatic blood flow was inversely associated with AVP concentrations, and despite a decrease in hepatic plasma flow of 37% (p < 0.05), following the high dose of AVP, ClT remained unchanged. These results indicate that AVP plasma kinetics are first order and plasma flow independent, and urinary kinetics are zero order.

Continuous veno-venous hemodiafiltration for the treatment of spontaneous tumor lysis syndrome complicated by acute renal failure and severe hyperuricemia.

We describe a case of Burkitt's lymphoma presenting as spontaneous tumor lysis syndrome (TLS) complicated by severe hyperuricemia and anuric acute renal failure presumed to be secondary to uric acid nephropathy. The patient was treated with continuous veno-venous hemodiafiltration (CVVHDF) using a dialysate flow rate of 2.5 l/h, and a replacement fluid rate of 1.5 l/h (administered in pre-dilution). Mean clearances during CVVHDF for urea, creatinine, uric acid, and phosphorus were, respectively, 55.8 +/- 3.8, 48.9 +/- 2.6, 45.1 +/- 2.6 and 47.0 +/- 3.3 ml/min (or 80, 70, 65 and 68 l/day, respectively). Serum urea, creatinine, uric acid, and phosphorus decreased from 42 to 9 mmol/l, 533 to 189 micromol/l, 1980 to 372 micromol/l, and 2.0 to 1.4 mmol/l, respectively, after 48 hours of CVVHDF. Previously, we reported the use of continuous arteriovenous hemodialysis (CAVHD) at a high dialysate flow rate of 4 l/h for the treatment of acute renal failure and TLS, which provided excellent continuous clearances of small molecular weight solutes. This last modality was very efficient and prevented deleterious rebound in serum solute concentrations frequently observed in TLS after intermittent hemodialysis (IHD). It was concluded that high-dialysate flow rate CAVHD was a more potent form of treatment than conventional IHD. With recent advances in technology, veno-venous continuous renal replacement therapies are becoming more popular than arterio-venous modalities since they are safer and less cumbersome. Furthermore, flow rates being precisely regulated, solute clearances can be steadily maintained. With CVVHDF flow rates as used in this report, we achieved excellent solute clearances and metabolic control. We propose CVVHDF as an ideal treatment for acute renal failure in TLS. In our opinion, CVVHDF is an advantageous alternative to treat TLS complicated by acute renal failure.

Native arterio-venous fistula for hemodialysis: What to expect early after creation?

Abstract: Native arterio-venous fistulas (AVFs) are preferred for hemodialysis vascular access over synthetic grafts and long-term catheters. However, prevalence rates of native AVFs are variable around the world and have increased only slightly in United States since the DOQI guidelines. To increase rates of native AVFs, pre-operative vascular mapping by ultrasound has been found of major help for appropriate selection of the vessels. The minimal desirable lumen diameter of the artery should be > 2 mm and > 2.5 to 3 mm for the vein at the anatomosis. Early failure can be reduced to less than 10% when the feeding artery is > 2 mm, even in diabetics. If sizes of the vessels are smaller than those targets at the wrist, moving to the upper arm should be considered. The interval between creation and first cannulation varies from 2 weeks to 4 months. There might not be much advantage to wait for more than 4 weeks; however, in large dialysis units, observing a delay of 4 to 6 weeks may be worthwhile to avoid initial problems such as infiltrations and lacerations. Access flow monitoring is essential since it is a reliable predictor of vascular access dysfunction, reducing associated morbidity and costs. Early monitoring of recently created native AVFs has shown that the increase in intra-access blood flow occurs very soon after construction and becomes maximal after a few weeks. A recent prospective study involving all new native AVFs monitored by ultrasound-dilution between weeks 6 and 10 after creation, and every 3 to 6 weeks over 4 months, showed no statistically significant difference in access blood flow between the initial and final measurements (respective values of 1132 +/- 681 and 1097 +/- 644 ml/min). Access flow was higher in males, and in brachio-cephalic compared to radio-cephalic AVFs. Over the long-term, AVFs are associated with longer patency and lower complication rates, and efforts should be directed at further increasing their prevalence.

Emerging evidence of the impact of kidney disease on drug metabolism and transport.

Several lines of emerging evidence indicate that kidney disease differentially affects uptake and efflux transporters and metabolic enzymes in the liver and gastrointestinal (GI) tract, and uremic toxins have been implicated as the cause. In patients with kidney disease, even drugs that are eliminated by nonrenal transport and metabolism could lead to important unintended consequences if they are administered without dose adjustment for reduced renal function. This is particularly so in the case of drugs with narrow therapeutic windows and may translate into clinically significant variations in exposure and response.

NPT2a gene variation in calcium nephrolithiasis with renal phosphate leak.

A decrease in renal phosphate reabsorption with mild hypophosphatemia (phosphate leak) is found in some hypercalciuric stone-formers. The NPT2a gene encodes a sodium-phosphate cotransporter, located in the proximal tubule, responsible for reclaiming most of the filtered phosphate load in a rate-limiting manner. To determine whether genetic variation of the NPT2a gene is associated with phosphate leak and hypercalciuria in a cohort of 98 pedigrees with multiple hypercalciuric stone-formers, we sequenced the entire cDNA coding region of 28 probands, whose tubular reabsorption of phosphate normalized for the glomerular filtration rate (TmP/GFR) was 0.7 mmol/l or lower. We performed genotype/phenotype correlations for each genetic variant in the entire cohort and expressed NPT2a variant RNAs in Xenopus laevis oocytes to test for cotransporter functionality. We identified several variants in the coding region including an in-frame 21 bp deletion truncating the N-terminal cytoplasmic tail of the protein (91del7), as well as other single-nucleotide polymorphisms that were non-synonymous (A133V and H568Y) or synonymous. Levels of TmP/GFR and urine calcium excretion were similar in heterozygote carriers of NPT2a variants compared to the wild-type (wt) homozygotes. The transport activity of the H568Y mutants was identical to the wt, whereas the N-terminal-truncated version and the 91del7 and A133V mutants presented minor kinetic changes and a reduction in the expression level. Although genetic variants of NPT2a are not rare, they do not seem to be associated with clinically significant renal phosphate or calcium handling anomalies in a large cohort of hypercalciuric stone-forming pedigrees.

Role of the kidneys in the metabolism of furosemide: its inhibition by probenecid.

The site where furosemide is metabolized and the location where probenecid reduces furosemide metabolism remain poorly defined. The liver appears to play a minor role, and there is indirect evidence suggesting that the kidneys could be responsible for the metabolism of furosemide. To assess the role of the kidneys in the metabolism of furosemide, its intravenous kinetics have been studied in control and anephric rabbits, after the ligation of the renal pedicles. Two additional groups of rabbits, control and anephric, have received probenecid before the administration of furosemide. In the control group, the total clearance of furosemide was 18.65 +/- 1.01 mL/ min per kg; urinary and metabolic clearances of furosemide were 7.95 +/- 0.65 and 10.70 +/- 1.11 mL/min per kg, respectively. In anephric rabbits, total clearance was reduced by 85% to 2.69 +/- 0.26 mL/min per kg (P < 0.001), secondary to the abolition of furosemide renal excretion and to the reduction in metabolic clearance from 10.70 +/- 1.11 to 2.69 +/- 0.26 mL/min per kg (P < 0.001). The pretreatment with probenecid reduced the total clearance of furosemide by 80%, to 3.62 +/- 0.24 mL/min per kg (P < 0.001), because of a reduction of 90 and 75% in urinary and metabolic clearances, respectively. The administration of probenecid to anephric rabbits did not reduce further the metabolic clearance. It is concluded that the kidneys are responsible for 85% of furosemide total clearance, either via excretion (43%) or biotransformation (42%), and that probenecid inhibits both processes.

Dialysate leaks in peritoneal dialysis.

Dialysate leakage represents a major noninfectious complication of peritoneal dialysis (PD). An exit-site leak refers to the appearance of any moisture around the PD catheter identified as dialysate; however, the spectrum of dialysate leaks also includes any dialysate loss from the peritoneal cavity other than via the lumen of the catheter. The incidence of dialysate leakage is somewhat more than 5% in continuous ambulatory peritoneal dialysis (CAPD) patients, but this percentage probably underestimates the number of early leaks. The incidence of hydrothorax or pleural leak as a complication of PD remains unclear. Factors identified as potentially related to dialysate leakage are those related to the technique of PD catheter insertion, the way PD is initiated, and weakness of the abdominal wall. The pediatric literature tends to favor Tenckhoff catheters over other catheters as being superior with respect to dialysate leakage, but no consensus on catheter choice exists for adults in this regard. An association has been found between early leaks (< or =30 days) and immediate CAPD initiation and perhaps median catheter insertion. Risk factors contributing to abdominal weakness appear to predispose mostly to late leaks; one or more of them can generally be identified in the majority of patients. Early leakage most often manifests as a pericatheter leak. Late leaks may present more subtly with subcutaneous swelling and edema, weight gain, peripheral or genital edema, and apparent ultrafiltration failure. Dyspnea is the first clinical clue to the diagnosis of a pleural leak. Late leaks tend to develop during the first year of CAPD. The most widely used approach to determine the exact site of the leakage is with computed tomography after infusion of 2 L of dialysis fluid containing radiocontrast material. Treatments for dialysate leaks include surgical repair, temporary transfer to hemodialysis, lower dialysate volumes, and PD with a cycler. Recent recommendation propose a standard approach to the treatment of early and late dialysate leaks: 1-2 weeks of rest from CAPD, and surgery if recurrence. Surgical repair has been strongly suggested for leakage causing genital swelling. Delaying CAPD for 14 days after catheter insertion may prevent early leakage. Initiating CAPD with low dialysate volume has also been recommended as a good practice measure. Although peritonitis and exit-site infections are the most frequent causes of technical failure in peritoneal dialysis (PD), dialysate leaks represent one of the major noninfectious complications of PD. In some instances, dialysate leakage may lead to discontinuation of the technique (1). Despite its importance, the incidence, risk factors, management, and outcome of dialysate leakage are poorly characterized in the literature. We will review the limited available information on this topic in the next few sections.

Role of plasma protein binding on renal metabolism and dynamics of furosemide in the rabbit.

To investigate the influence of furosemide plasma protein binding on its kinetics and dynamics, the kinetics of furosemide was studied in the presence of a protein binding displacer, warfarin, and in hypoalbuminemic rabbits. Compared with controls, in anesthetized rabbits pretreated with warfarin, the unbound fraction of furosemide increased from 1.8 +/- 0.4% to 7.0 +/- 0.4% (p <.001), and its metabolic clearance increased by 30%, whereas furosemide urinary excretion decreased by 48% (p <.05). Experiments in nephrectomized rabbits showed that the increase in metabolic clearance was secondary to an increase in its renal metabolic clearance (p <.05). Compared with controls, in warfarin pretreated rabbits, sodium excretion and diuresis were decreased by 30% (p <.05). However, when furosemide was injected mixed with albumin, warfarin-induced kinetic and dynamic alterations of furosemide were reversed. Compared with control rabbits, in conscious hypoalbuminemic rabbits, furosemide unbound fraction was enhanced from 1.2 +/- 0.1% to 5.5 +/- 0.5% (p <. 001), and its urinary excretion, diuresis, and sodium excretion were reduced by 22% (p <.05). The administration of warfarin to hypoalbuminemic rabbits further increased the fraction of unbound furosemide, and diminished its urinary excretion and diuretic effect. In conclusion, 1) binding of furosemide to plasma proteins, and not albumin per se, facilitates its renal secretion and pharmacological response; 2) the decrease in furosemide binding, secondary to drug displacement and/or hypoalbuminemia, can be a cause of resistance to the diuretic; and 3) when furosemide binding is decreased, the administration of furosemide mixed with albumin enhances its renal secretion and diuretic effect.

Folic acid and pyridoxal-5'-phosphate losses during high-efficiency hemodialysis in patients without hydrosoluble vitamin supplementation.

OBJECTIVES: To determine the serum status in folate, pyridoxal-5'-phosphate (the active moiety of pyridoxine), cobalamin, and total homocysteine of chronic dialysis patients not routinely supplemented with B-complex vitamins and to evaluate induced intradialytic losses during high-efficiency hemodialysis. DESIGN: A cross-sectional study. SETTING: A university medical center providing tertiary care. PATIENTS: Thirty-six chronic dialysis patients (23 men and 13 women, mean age 57+/-13 years) treated since 3.8+/-2.2 years by hemodialysis and not supplemented with hydrosoluble vitamins. METHODS: Thrice-weekly hemodialysis was performed using CT-190G (Baxter, IL) or F-20 (Hospal, St-Leonard, Canada) reused dialyzers with a mean blood flow rate of 371+/-40 mL/min, a dialysate flow rate of 500 mL/min, and a mean session time of 3.7+/-0.4 hours. Prehemodialysis serum vitamin B(12) and homocysteine, and predialysis and postdialysis serum folate, pyridoxal-5'-phosphate, and urea were measured. Blood-side folate and pyridoxal-5'-phosphate clearances were calculated. RESULTS: Predialysis serum total homocysteine was above normal in all patients, with values ranging from 14.4 to 158.0 micromol/L (mean 40.2+/-29.6 micromol/L, median 33.5 micromol/L). Whereas the majority, 21 patients, had evidence of coronary, cerebrovascular, and/or peripheral vascular diseases, there was no difference in total homocysteine in patients with or without vascular disease (respectively, 40.8+/-37.0 micromol/L v 39.4+/-15.1 micromol/L, P = NS). Predialysis serum concentrations of pyridoxal-5'-phosphate were reduced in 20 patients (56%) and were in the lower normal range for 14 patients. Predialysis and postdialysis serum folate concentrations were 12.4+/-6.1 nmol/L and 8.6 +/- 3.6 nmol/L, whereas predialysis and postdialysis serum pyridoxal-5'-phosphate concentrations were 11.1+/-7.5 nmol/L and 8.0 +/-5.9 nmol/L. Percent reduction ratios were 68.4% +/- 6.6% for urea, 26.3%+/-16.0% for folates, and 27.9%+/-14.2% for pyridoxal-5'-phosphate. Blood-side clearances reached 134.7+/-22.2 mL/min for folates and 54.4+/-38.2 mL/min for pyridoxal-5'-phosphate. There was no significant difference in predialysis serum folate and pyridoxal-5'-phosphate in patients with or without evidence of vascular disease. CONCLUSION: This study confirms that: (1) total serum homocysteine levels are very high in chronic hemodialysis patients not supplemented with B-complex vitamins; (2) folate is significantly cleared or lost during high-efficiency hemodialysis; and (3) pyridoxal-5'-phosphate, the active moiety of pyridoxine, is depleted in most chronic hemodialysis patients without supplementation and that high-efficiency hemodialysis contributes to its depletion.

Stereoselective disposition of propranolol in rabbits. Role of presystemic organs and dose.

The kinetics of propranolol enantiomers are stereoselective when high doses of the racemic drug are given po. To document whether the dose and/or the route of administration determines the stereoselective kinetics of propranolol enantiomers, conscious rabbits received 40, 80, or 120 mg/kg po or 0.5 or 10 mg/kg iv doses of racemic propranolol, and serial blood samples were obtained to assay propranolol enantiomers. At low po and iv doses, the kinetics of the propranolol enantiomers were identical. After the 120 mg/kg po dose, the kinetics of the enantiomers were stereoselective, i.e. the AUC0-->infinity for (S)-(-)-propranolol was greater than the AUC0-->infinity for (R)-(+)-propranolol (p < 0.05). The iv injection of 10 mg/kg generated zero-order kinetics, and (S)-(-)-propranolol was eliminated faster than the antipode. Propranolol enantiomer plasma protein binding was not stereoselective. In vitro, after the incubation of 5.8 or 58 microM (RS)-propranolol with cells of the intestinal mucosa or the liver, (R)-(+)-propranolol was more rapidly metabolized than (S)-(-)-propranolol at both concentrations in the intestine and at the higher concentration in the liver. Incubation of the individual enantiomers (2.9 and 29 microM) showed that in the intestine the intrinsic clearance of (R)-(+)-propranolol was greater than that of (S)-(-)-propranolol but in the liver there was preferential saturation of (S)-(-)-propranolol clearance. In conclusion, at low po or iv doses the kinetics of (RS)-propranolol are not stereoselective because the liver overshadows the effect of the intestine, and at high po doses the kinetics of propranolol enantiomers are stereoselective because of hepatic saturation of (S)-(-)-propranolol clearance.

Renal replacement in end-stage renal disease patients over 75 years old.

BACKGROUND: Over the last decade, the age of dialysis patients has been increasing steadily in several units in Canada. Our main objective was to assess prevalence, co-morbidity and outcome of ESRD patients over 75 years old at the beginning of dialysis treatment in our center. As a group, they were compared to younger dialysis patients treated simultaneously. METHODS: In the last 5 years, all cases beginning dialysis in our institution who were above 75 years of age were reviewed, as well as cases aged between 50 and 60 years who started dialysis during the same period. Between January 1996 and December 2000, among a total of 429 new chronic dialysis patients, 67 ESRD patients over 75 years (15.6%) and 66 patients between 50 and 60 years (15.4%) began dialysis treatment. RESULTS--PRIMARY AND SECONDARY: Diabetes was present in 37% of elderly and in 56% of the younger patients. Younger patients had been referred earlier to our nephrologists than the older ones (42 vs. 27%). Elderly were more frequently treated by hemodialysis than peritoneal dialysis (81 vs. 19%) when compared to their younger counterparts (65 vs. 35%). Long-term catheters for hemodialysis were used more often in elderly patients. No renal transplantation were performed in older patients while 7 younger patients received a renal graft. Survival rates after 1 and 3 years were, respectively, 93 and 74% for patients between 50 and 60 years, whereas it decreased to 80 and 45% for those over 75 years (p = 0.002). More than 50% of patients older than 75 years died within 2 years after starting dialysis; their mean survival was 31 months; patients starting dialysis between 50 and 60 years survived on the average 44 months during the study period. According to the multivariate logistic regression model, risk factors for increased mortality in the older group were: number of hospitalization days during the past 3 months (OR 34.8, 95% CI 8.3-145.7, p < 0.001) and lower weight (OR 16.6, 95% CI 2.0-139.0, p = 0.001). CONCLUSION: We may conclude that, in our hands, life expectancy of patients who began dialysis above 75 years is significantly shorter than for patients for whom dialysis is initiated between age 50 and 60 years, especially if they have a low weight, lose weight and/or require hospitalization.