Effect of candesartan cilexetil (TCV-116) in rats with chronic renal failure.
(17/1427)
BACKGROUND: Inhibition of the renin-angiotensin system by both angiotensin II type 1 receptor antagonists (AT1As) and angiotensin I-converting enzyme inhibitors (ACEIs) shows renoprotective effects in rats with chronic renal failure when treatment is started in the early phase of renal injury. In this study, we examined the renal protective effects of candesartan cilexetil (TCV-116), an AT1A, and enalapril, an ACEI, in the progressive phase of renal injury in 5/6 nephrectomized rats. METHODS: Candesartan cilexetil (1 mg/kg/day) and enalapril (10 mg/kg/day) were orally administered once a day for 4 weeks (the short-term experiment) or 16 weeks (the long-term experiment) to 5/6 nephrectomized rats beginning 15 weeks after the nephrectomy, that is, after they had already showed marked proteinuria. RESULTS: In vehicle-treated rats, proteinuria, glomerulosclerosis, and interstitial fibrosis developed. Moreover, enhanced expression of transforming growth factor-beta1 (TGF-beta1) in the injured glomeruli was observed. These adverse changes progressed with time, and in the short-term experiment, both drugs inhibited them. In the long-term experiment, the progressive proteinuria and the elevation of blood pressure were similarly attenuated by both drugs. However, candesartan cilexetil significantly inhibited the progression of glomerulosclerosis, the expression of TGF-beta1, and interstitial fibrosis, whereas enalapril did not. CONCLUSION: These results indicate that candesartan cilexetil shows potent and long-term preventive effects against the progression of previously developed renal injury. (+info)
Metallothionein protects against the nephrotoxicity produced by chronic CdMT exposure.
(18/1427)
Metallothionein (MT) is a low-molecular-weight, cysteine-rich, metal-binding protein. Induction of MT has been proposed to be an important adaptive mechanism in decreasing Cd toxicity. MT has been shown to protect against CdCl2-induced lethality and hepatotoxicity; however, MT does not protect against acute CdMT-induced nephrotoxicity. This study was aimed at clarifying the role of metallothionein in chronic CdMT-induced renal injury. Wild type and MT-I/II knockout (MT-null) mice were therefore given sc injections of CdMT (25 and 100 microg Cd/kg) or saline daily, 6 times/week for 6 weeks, and renal injury was evaluated. Multiple injections of CdMT to wild-type mice resulted in renal Cd concentrations up to 120 microg/g kidney, along with a 100-fold increase in renal MT (450 microg/g kidney). In contrast, renal Cd concentration in MT-null mice administered multiple injections of CdMT reached a much lower level than in wild-type mice (<10 microg/g kidney). Although less Cd accumulated in their kidneys, MT-null mice were more susceptible than wild-type mice to CdMT-induced nephrotoxicity, as indicated by increased urinary excretion of protein and N-acetyl-beta-D-glucosaminidase, as well as by elevated blood urea nitrogen levels. At the higher daily dose of CdMT (100 microg Cd/kg), kidneys of MT-null mice were enlarged. Chronic CdMT administration eventually damaged the entire kidney, which included glomerular swelling, interstitial inflammation, edema, tubular cell degeneration, and atrophy. In contrast to a single injection of CdMT that produces proximal tubular necrosis, chronic injection of CdMT results in tubular cell apoptosis in both wild-type and MT-null mice. These data indicate that chronic CdMT administration produces similar renal injury to that observed after chronic CdCl2 administration, and that intracellular MT protects against nephrotoxicity produced by chronic CdMT administration. (+info)
Inhibition of apoptosis induced by ischemia-reperfusion prevents inflammation.
(19/1427)
Ischemia followed by reperfusion leads to severe organ injury and dysfunction. Inflammation is considered to be the most important cause of tissue injury in organs subjected to ischemia. The mechanism that triggers inflammation and organ injury after ischemia remains to be elucidated, although different causes have been postulated. We investigated the role of apoptosis in the induction of inflammation and organ damage after renal ischemia. Using a murine model, we demonstrate a relationship between apoptosis and subsequent inflammation. At the time of reperfusion, administration of the antiapoptotic agents IGF-1 and ZVAD-fmk (a caspase inactivator) prevented the early onset of not only renal apoptosis, but also inflammation and tissue injury. Conversely, when the antiapoptotic agents were administered after onset of apoptosis, these protective effects were completely abrogated. The presence of apoptosis was directly correlated with posttranslational processing of the endothelial monocyte-activating polypeptide II (EMAP-II), which may explain apoptosis-induced influx and sequestration of leukocytes in the reperfused kidney. These results strongly suggest that apoptosis is a crucial event that can initiate reperfusion-induced inflammation and subsequent tissue injury. The newly described pathophysiological insights provide important opportunities to effectively prevent clinical manifestations of reperfusion injury in the kidney, and potentially in other organs. (+info)
Relating protein intake to nutritional status in haemodialysis patients: how to normalize the protein equivalent of total nitrogen appearance (PNA)?
(20/1427)
BACKGROUND: The protein equivalent of total nitrogen appearance (PNA) is assumed to be a reliable estimate of dietary protein intake in haemodialysis patients. Protein requirements are related to body size. In order to standardize PNA to individual differences in body size, PNA is normalized to various terms related to the patient's body weight. It is not clear which is the most appropriate method to normalize PNA. METHODS: We calculated five commonly used variants of normalized PNA and related them to indices of nutritional status in 57 stable chronic haemodialysis patients, 57 +/- 15 (mean +/- SD) years of age. PNA, determined by direct dialysate quantification, was normalized to actual post-dialysis dry body weight (DBW), normal body weight (DBWnormal), lean body mass (LBM), normal lean body mass (LBMnormal), and 'normalized' body weight (N). Nutritional status was assessed using an index of nutrition composed of anthropometry derived parameters and plasma albumin concentration. RESULTS: PNA(DBW) (0.85 +/- 0.14 g/kg/d) tended to be higher than PNA(DBWnormal) (0.81 +/- 0.14 g/kg/d). PNA(LBM) (1.17 +/- 0.19 g/kg/d) did not differ from PNA(LBMnormal) (1.19 +/- 0.21 g/kg/d). PNA(N) (1.06 +/- 0.14 g/kg/d) was significantly higher than PNA(DBW) and PNA(DBWnormal), but lower than PNA(LBM) and PNA(LBMnormal). Actual PNA (61 +/- 13 g/d) correlated significantly with DBW (r=0.52) and LBM (r=0.63) indicating that large patients eat more protein. Interestingly, actual PNA correlated with plasma albumin (r=0.33) and with the overall index of nutrition (r=0.27) as well. PNA(DBW) correlated negatively with relative DBW (r=-0.32), expressed as a percentage of normal values, indicating that PNA(DBW) is relatively high in underweight patients. In contrast, PNA(DBWnormal) correlated positively with all nutritional parameters as well as with the overall index of nutrition (r=0.33). PNAN and PNA(LBM) did not correlate with the nutritional status, but PNA(LBMnormal) correlated positively with relative DBW (r=0.50) and with overall nutritional status (r=0.34). PNA(DBWnormal) and PNA(LBMnormal) in well-nourished patients showed overlap with the values in patients with evident malnutrition, despite the positive correlation of the normalized PNA values with nutritional status. CONCLUSIONS: Normalizing PNA by DBWnormal and LBMnormal appeared to be the most appropriate method to standardize protein intake in haemodialysis patients. Since actual PNA is the purest estimate of protein intake that correlated with nutritional status, we recommend to evaluate actual PNA as well in studies that relate protein intake to patient outcome. (+info)
Early predictors of transplant-related mortality (TRM) after allogeneic bone marrow transplants (BMT): blood urea nitrogen (BUN) and bilirubin.
(21/1427)
Transplant-related mortality (TRM) following allo- geneic bone marrow transplantation (BMT) remains a major concern and early identification of patients at risk may be clinically relevant. In this study we describe a predictive score based on bilirubin and blood urea nitrogen (BUN) levels on day +7 after BMT. The patient population consisted of 309 consecutive patients who underwent BMT from sibling (n = 263) or unrelated donors (n = 46) for hematologic disorders between December 1990 and December 1996. Of 27 laboratory tests taken on day +7 after BMT, serum bilirubin (P = 0.02) and BUN (P = 0.007) were found to be independent predictors of TRM in multivariate analysis. The median levels of bilirubin (0.9 mg/dl) and of BUN (21 mg/dl) were then used as a cut-off and a score of 1 was given for values equal/greater than the median. There were 216 patients with scores 0-1 (low risk) on day +7 (bilirubin <0.9 and/or BUN <21) and 93 patients with score 2 (high risk) (bilirubin >/=0.9 and BUN >/=21): the latter had more grade III-IV acute graft-versus-host disease (P = 0.03), slower neutrophil (P = 0.02) and slower platelet engraftment (P = 0.002). The actuarial 5 year TRM is 22% for low risk vs44% for high risk patients (P = 0.0003). For HLA-identical siblings TRM is 20% vs35% (P = 0.01), for unrelated donors it is 20% vs 65% (P = 0.01). Day +7 score was highly predictive of TRM on multivariate analysis (hazard ratio 1.9, P < 0.01), after adjustment for year of transplant (P < 0.00001), unrelated vs sibling donors (P = 0.001), patient age (P = 0.01) and diagnosis (P = 0.01). These results were validated on an independent group of 82 allogeneic BMT recipients in a pediatric Unit who showed an actuarial TRM of 16% for low risk vs 46% for high risk patients (P = 0.002). This study suggests that it may be possible to identify patients with different risks of TRM on day +7 after BMT: high risk patients could be eligible for programs designed to intensify prophylaxis of post-transplant complications. (+info)
Rebound kinetics of beta2-microglobulin after hemodialysis.
(22/1427)
BACKGROUND: Evaluation of beta2-microglobulin (beta2m) removal during hemodialysis using predialysis and immediate postdialysis plasma concentrations is only valid in the absence of postdialysis rebound. Postdialysis rebound of beta2m has not been studied extensively, and its importance in the determination of beta2m clearance is unknown. METHODS: We evaluated the kinetics of urea and beta2m in a crossover study of 10 chronic hemodialysis patients using dialyzers with similar urea mass transfer-area coefficients containing either low-flux cellulose acetate or high-flux cellulose triacetate membranes. Kinetics were examined during and following a 210 minute treatment by measuring plasma concentrations predialysis at regular intervals during therapy and at 0, 2, 10, 20, 30, and 60 minutes postdialysis. Clearances of urea and beta2m were also determined directly from the arterial and venous concentration differences across the dialyzer at 60 minutes after starting dialysis. RESULTS: By design, urea removal was similar for both low-flux and high-flux dialyzers as assessed by the urea reduction ratio and Kt/V. Postdialysis urea rebound was similar for low- and high-flux dialyzers; the rebound in the plasma urea nitrogen concentration (expressed as a percentage of the intradialytic decrease in plasma concentration) was 9.2 +/- 1.9% (mean +/- SEM) at 30 minutes postdialysis and 13.0 +/- 1.4% at 60 minutes postdialysis for a single pool urea Kt/V of 1.16 +/- 0.05. The plasma beta2m concentration increased by 11.1 +/- 3.0% during the treatment using the low-flux dialyzer but decreased by 27.1 +/- 4.0% during the treatment using the high-flux dialyzer. When using the high-flux dialyzer, the rebound of beta2m was 44.8 +/- 21.4% at 30 minute postdialysis and 45.9 +/- 15.9% at 60 minutes postdialysis. The clearance of beta2m for the high-flux dialyzer calculated from predialysis and immediate postdialysis plasma concentrations using a single-compartment model (28.2 +/- 4.4 ml/min) was higher (P < 0.05) than that determined directly across the dialyzer (18.3 +/- 2.0 ml/min). If either the 30- or 60-minute postdialysis plasma beta2m concentration was used instead, the calculated beta2m clearance (16. 5 +/- 4.8 ml/min or 15.6 +/- 2.8 ml/min, respectively) was similar to that determined directly across the dialyzer. CONCLUSIONS: Postdialysis rebound of beta2m when using high-flux dialyzers is substantial; neglecting postdialysis rebound results in an overestimation of beta2m clearance when calculated using a single-compartment model. (+info)
Effects of level of energy intake and energy demand on growth hormone, insulin, and metabolites in Targhee and Suffolk ewes.
(23/1427)
Yearling ewes (n = 32) were used in a 2x2x2 factorial experiment to determine effects of breed (Targhee vs. Suffolk), energy intake (1x vs. 3x NEm requirements, and physiological status (nonpregnant, nonlactating vs. lactating) on serum GH, insulin, NEFA, glucose, and blood urea nitrogen (BUN) concentrations. Blood collections were made in two periods that began 21 and 32 d after ewes lambed. Lactating ewes had more GH peaks (P<.10), higher (P<.01) mean GH concentration, and greater (P<.01) area under the GH curve (AUC) than nonlactating ewes. The AUC was greater (P<.01) in ewes fed 1x NEm than in ewes fed 3x NEm. Energy intake had no effect on serum GH before feeding (P>.23) when evaluated within physiological statuses. After feeding, GH concentrations were greater (P<.10) for ewes fed 1x NEm than for those fed 3x NEm. Insulin and glucose did not differ (P>.23) between energy intake levels. Insulin and glucose were greater (P<.001) in nonlactating than in lactating ewes when evaluated within breed. Lactating and Targhee ewes fed 1x NEm had greater (P<.001) NEFA concentration than nonlactating and Targhee ewes fed 3x NEm, respectively. Ewes fed 3x NEm and Targhee ewes had greater (P<.005) BUN concentrations than ewes fed 1x NEm and Suffolk ewes, respectively. Physiological status seems to play a more important role in the regulation of GH than does energy intake. Higher BUN concentrations in Targhee than in Suffolk ewes demonstrates one metabolic event that distinguishes a breed's adaptation to the environment in which it originated. (+info)
Ontogenic maturation of the somatotropin/insulin-like growth factor axis.
(24/1427)
The ontogeny of the somatotropin/insulin-like growth factor system was examined in well-fed pigs under basal conditions and during a short-term challenge of porcine ST (pST). The study was conducted with two replicates of eight castrate male pigs from 3.8 kg BW (10 d of age) to 92 kg BW (129 d of age). Pigs were reared individually with ad libitum access to milk replacer through 23 d of age. Thereafter, pigs were fed a corn, soybean meal, and dry skim milk diet formulated to exceed nutrient requirements by approximately 30%. Pigs were randomly assigned to receive daily i.m. injections of either 0 (buffer) or 120 microg/kg BW of pST for a duration of 4 d starting at 10, 19, 33, 43, 63, 83, and 125 d of age. Blood was collected via jugular venipuncture on d 0 and 4 of the challenge. Circulating levels of IGF-I were not dramatically affected by age, but levels of IGF-II were low from 10 to 19 d of age and then increased through later stages of growth. Circulating concentrations of IGF binding protein (BP)-3 increased with age (P < .05), but levels of IGFBP-2, a 30-kDa IGFBP, and IGFBP-4 were unchanged (P > .10). The pST challenge reduced plasma urea nitrogen at all ages, but the magnitude of the response was less in younger pigs compared with the maximum response in pigs greater than 30 kg BW (63 d of age). The IGF-I response to the pST challenge also increased from approximately 30% in young pigs to a threefold increase in older pigs. Regardless of age, concentrations of IGF-II were minimally affected by the pST challenge. Circulating levels of IGFBP-3 increased and IGFBP-2 levels decreased in response to the pST challenge, and the magnitude increased with age. The high nutritional status of pigs in the early phases of growth diminished the postnatal changes in IGF-I and IGFBP-2, but not IGF-II or IGFBP-3. Overall, data demonstrate a developmental regulation of the ST/IGF system, with pST challenges altering circulating concentrations of IGF-I, IGFBP-3, and IGFBP-2 coincident with changes in amino acid metabolism. (+info)