Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0036690 (sepsis)
 59,461 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

103 patients who received a cyclosporine-treated primary cadaver kidney transplant (TX) at our center between 1985 and 1989, whose graft survived for more than 1 year and who accepted to undergo voiding cystography after TX were analyzed and grouped according to the highest grade (regardless to whether active or passive) of vesicourteral reflux (VUR): group 0, absent (n = 14); group 1-2, grade I or II (n = 62); group 3, grade III (n = 27). Patient follow-up ranged from 5 to 10 (median 7) years. Patient and graft survivals and prevalence of hypertension (defined as the persistent need of antihypertensive therapy), did not differ significantly between groups (Mantel-Cox test p: n.s. in all cases). GFR (Cockroft and Gault) and proteinuria were evaluated with ANOVA for repeated measures at 1, 2, 3, 4 and 5 years in the 96 patients (group 0: 13, group 1-2: 56, group 3: 27) whose grafts lasted for 5 years or more. Neither GFR values (p: n.s.) nor GFR behaviour over time (p: n.s.) differed between groups, although a progressive decline of GFR was noted in all groups (p < 0.002). Proteinuria neither showed any significant differences between groups in values (p: n.s.) or behaviour over time (p: n.s.), nor any trend in behaviour over time in all groups as a whole (p: n.s.). Finally, in the first 5 years after TX the 3 groups did not differ for number of urinary tract infections (UTIs) (mean value for all patients: 2.5, range 0-22, episodes/pt/5 years) (p: n.s.), or for number of UTIs with leukocyturia (mean 0.6, range 0-6, episodes/pt/5 years) (p: n.s.), or for number of febrile UTIs (mean 0.3, range 0-5, episodes/pt/5 years) (p: n.s.), or for number of UTIs with sepsis (mean 0.1, range 0-2, episodes/pt/5 years) (p: n.s.). The same results were obtained when, instead of episodes/ pt/5 years, percentages of patients without or with 1 or more of such episodes in the same period were considered. In conclusion, VUR does not seem to be hazardous for the transplanted kidney in the medium to long-term.
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PMID:Vesicoureteral reflux after kidney transplantation: clinical significance in the medium to long-term. 920 64

Excess NO generation plays a major role in the hypotension and systemic vasodilatation characteristic of sepsis. Yet the kidney response to sepsis is characterized by vasoconstriction resulting in renal dysfunction. We have examined the roles of inducible nitric oxide synthase (iNOS) and endothelial NOS (eNOS) on the renal effects of lipopolysaccharide administration by comparing the effects of specific iNOS inhibition, -N6-(1-iminoethyl)lysine (L-NIL), and 2,4-diamino6-hydroxy-pyrimidine vs. nonspecific NOS inhibitors (nitro- -arginine-methylester). cGMP responses to carbamylcholine (CCh) (stimulated, basal) and sodium nitroprusside in isolated glomeruli were used as indices of eNOS and guanylate cyclase (GC) activity, respectively. LPS significantly decreased blood pressure and GFR (112+/-4 vs. 83+/-4 mmHg; 2.66+/-0.29 vs. 0. 96+/-0.22 ml/min, P < 0.05) and inhibited the cGMP response to CCh. GC activity was reciprocally increased. L-NIL and 2, 4-diamino-6-hydroxy-pyrimidine administration prevented the decrease in GFR (2.71+/-0.28 and 3.16+/-0.18 ml/min, respectively), restored the normal response to CCh, and GC activity was normalized. In vitro application of L-NIL also restored CCh responses in LPS glomeruli. Neuronal NOS inhibitors verified that CCh responses reflected eNOS activity. L-NAME, a nonspecific inhibitor, worsened GFR (0.41+/-0.15 ml/min), a reduction that was functional and not related to glomerular thrombosis, and eliminated the CCh response. No differences were observed in eNOS mRNA expression among the experimental groups. Selective iNOS inhibition prevents reductions in GFR, whereas nonselective inhibition of NOS further decreases GFR. These findings suggest that the decrease in GFR after LPS is due to local inhibition of eNOS by iNOS, possibly via NO autoinhibition.
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PMID:Inhibition of constitutive nitric oxide synthase (NOS) by nitric oxide generated by inducible NOS after lipopolysaccharide administration provokes renal dysfunction in rats. 921 22

Renal involvement remains a major complication of multiple myeloma, particularly in advanced disease. A retrospective analysis was performed of the modes of presentation, treatment and outcome of all patients with multiple myeloma treated in our renal unit between 1987 and 1996. Thirty-four patients were identified: in 26 (76%) the diagnosis of myeloma was made only after referral. Light chains were the most common paraprotein in both serum and urine. Twenty-one (62%) patients underwent renal biopsy: myeloma cast nephropathy was the predominant histological finding in 16 cases. Thirty-one (91%) patients had severe renal failure (GFR < 20 mL/min), with 28 (82%) requiring dialysis within 2 weeks of admission. Despite treatment of presumed precipitaing causes of acute deterioration in renal function, only 1 of these 28 patients subsequently became independent of dialysis. Most had advanced stage myeloma: 29 (85%) were Durie-Salmon stage II or III. Hypercalcemia, sepsis and pathological fractures were the principal complications. Median survival overall was 5 months. The main causes of death were withdrawal of renal replacement therapy (overwhelming myeloma, severe debilitation) and sepsis. Nineteen (56%) patients received long-term (> 1 month) renal replacement therapy with a median survival of 8 months. However, five of these (26%) have survived for more than 12 months on dialysis and report a good quality of life.
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PMID:Multiple myeloma and renal failure: one center's experience. 971 78

Acute renal failure (ARF) during sepsis is associated with increased nitric oxide (NO) and oxygen radicals, including superoxide (O(2)(-)). Because O(2)(-) reacts with NO in a rapid manner, it plays an important role in modulating NO levels. Therefore, scavenging of O(2)(-) by superoxide dismutase (SOD) may be critical for preserving NO bioavailability. In mice, substantial renal extracellular SOD (EC-SOD) expression implies its important role in scavenging O(2)(-) in the kidney. We hypothesized that during endotoxemic ARF, EC-SOD is decreased in the kidney, resulting in increased O(2)(-) and thus decreased vascular NO bioavailability with resultant renal vasoconstriction and ARF. In the present study, normotensive endotoxemic ARF was induced in mice using lipopolysaccharide (LPS; 5 mg/kg ip). Sixteen hours after LPS, glomerular filtration rate (GFR; 50 +/- 16 vs. 229 +/- 21 microl/min, n = 8, P < 0.01) and renal blood flow (RBF; 0.61 +/- 0.10 vs. 0.86 +/- 0.05 ml/min, n = 8, P < 0.05) were subsequently decreased. EC-SOD mRNA and protein expression in endotoxemic kidneys were decreased at 16 h compared with controls. A catalytic antioxidant, metalloporphyrin, reversed the deleterious effects of endotoxemia on renal function as GFR (182 +/- 40 vs. 50 +/- 16 microl/min, n = 6, P < 0.01) and RBF (1.08 +/- 0.10 vs. 0.61 +/- 0.10 ml/min, n = 6, P < 0.05) were preserved. Similar results were obtained with tempol, a chemically dissimilar antioxidant. Specific inhibition of inducible nitric oxide synthase (iNOS), l-N(6)-(1-iminoethyl)-lysine, reversed the renal protective effect on GFR and RBF observed with antioxidant treatment during endotoxemia. In summary, renal EC-SOD expression is decreased during endotoxemia. Antioxidant therapy preserved GFR and RBF during endotoxemia. The reversal of this protective effect by inhibition of iNOS suggests the importance of the bioavailability of NO for preservation of renal function during early endotoxemia.
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PMID:Interaction among nitric oxide, reactive oxygen species, and antioxidants during endotoxemia-related acute renal failure. 1255 64

We report on survival, rejection, lymphoma and renal function following cardiac transplant using a steroid-free maintenance immunosuppressive regimen. We have performed 73 cardiac transplants in 71 children under 16 yr of age in the last 12 yr. There were eight perioperative and four late deaths giving actuarial survival of 88, 88, 85 and 70% at 1, 2, 5 and 10 yr, respectively. A total of 11 (15.3%) children had one episode of rejection (grade 3) in the first 6 months; one died and one was re-transplanted because of rejection. There was only one episode of late rejection (8 yr post-transplant) because of low drug levels in a patient with lymphoma and sepsis. This patient did not survive. Three other children (5.6%) also developed lymphoma and recovered but one died subsequently of graft failure. Four children have developed severe renal failure (glomerular filtration rate GFR <30 mL/min/m2). Two have not survived and one is expected to commence dialysis soon. The remainder have mild to moderate renal impairment. We report excellent survival and low rejection rates without use of long-term steroids. However the doses of cyclosporin used have had a significant effect on renal function in many cases.
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PMID:Pediatric cardiac transplant: results using a steroid-free maintenance regimen. 1258 30

Abnormalities in the beta(2)-adrenergic control of organ function have been implicated in the pathogenesis of several disease states, such as septic shock. The objectives of the present study were to define the contribution of beta(2)-adrenoceptors (beta(2)-AR) to normal renal physiology and to investigate whether overexpression of renal beta(2)-AR might be potentially beneficial in preventing progressive renal damage associated with endotoxemia. Adenoviral transgenes containing the human beta(2)-AR (Adeno-beta(2)-AR) were constructed and delivered into the rat kidney by means of intraparenchymal injections. Administration of 10(9) total viral particles of Adeno-beta(2)-AR induced an approximately threefold increase in beta(2)-AR density in the renal tissue, which 2 wk after delivery, enhanced GFR and sodium reabsorption compared with control rats. The enhanced GFR was abolished by the addition of the beta(2)-AR antagonist, ICI 118,551. Administration of lipopolysaccharide (LPS) caused a reduction in GFR, beta(2)-AR density, and cAMP together with enhanced TNF-alpha mRNA in the kidney. In rats overexpressing beta(2)-AR, the reduction in baseline GFR and elevation of TNF-alpha mRNA and leukocyte infiltration into the kidney associated with the endotoxin were blocked. These findings suggested the possibility that a renal-specific overexpression of beta(2)-AR preserves basal renal function in response to a ligand-independent beta(2)-AR activation and that the delivery of Adeno-beta(2)-AR gene is a potential novel therapeutic strategy for treatment of acute renal failure associated with sepsis.
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PMID:beta(2)-Adrenoceptor activation attenuates endotoxin-induced acute renal failure. 1474 78

It is known that, among human patients with sepsis, acute renal failure (ARF) dramatically increases mortality rates to 50 to 80%. However, the pathogenesis of septic ARF is not fully understood. An increase in endotoxin-induced mortality rates for leptin-deficient ob/ob mice was recently demonstrated. In comparison with ob/ob mice, db/db mice, which are deficient in the long isoforms of leptin receptors (Ob/Rb), demonstrate lower mortality rates after exposure to the endotoxin LPS. In db/db mice, mRNA for the short isoforms of leptin receptors is constitutively expressed in the kidney, lung, liver, and macrophages. It is known that plasma leptin levels increase in rodents after exposure to LPS, and this was demonstrated for db/db mice. Because ob/ob and db/db mice are both obese, factors other than obesity must be involved in the increased mortality rates for ob/ob mice. In this study, the hypothesis that the short forms of leptin receptors might offer protection against endotoxin-induced lethality at least in part by providing protection against ARF was examined. Serum leptin levels were significantly increased with LPS treatment in wild-type and db/db mice but not ob/ob mice. GFR decreased significantly 16 h after the homozygous ob/ob mice received intraperitoneal injections of 0.3 mg/kg LPS (0.37 +/- 0.04 ml/min per g kidney versus 0.83 +/- 0.06 ml/min per g kidney, n = 6, P < 0.01); the mean arterial pressure (MAP) remained unchanged. For ob/ob littermates (+/?ob), there was no significant change in either MAP or GFR when the mice were challenged with the same time interval (16 h) and dose of LPS. In contrast to ob/ob mice, there was no significant change in GFR or MAP when homozygous db/db mice or their littermates received injections of an even higher dose of LPS (0.4 mg/kg). Mouse recombinant leptin had no effect on GFR when ob/ob mice received 0.3 mg/kg LPS injections. However, renal function (serum creatinine levels, 0.4 +/- 0.1 mg/dl versus 0.9 +/- 0.1 mg/dl, P < 0.01) and MAP (68 +/- 4 mmHg versus 51 +/- 2 mmHg, n = 6, P < 0.01) were significantly improved with leptin replacement when the ob/ob mice developed hypotensive ARF with a higher dose of LPS (0.5 mg/kg). In summary, the previously reported increased susceptibility to LPS of ob/ob mice, compared with db/db mice, may be attributable at least in part to increased susceptibility to ARF.
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PMID:Role of leptin deficiency in early acute renal failure during endotoxemia in ob/ob mice. 1497 66

Sepsis is a major cause of acute renal failure (ARF) and death. Thromboxane A2 (TxA(2)) may mediate decreases of renal blood flow (RBF) and/or GFR associated with LPS-induced sepsis. This study tested whether TxA(2) receptor blockade, with the use of TxA(2) receptor knockout (TP-KO) mice or a selective TP receptor antagonist (SQ29,548), would alleviate LPS-induced renal vasoconstriction and ARF. Under basal conditions, anesthetized TP-KO mice displayed a lower mean arterial pressure than wild-type (WT) mice (102 versus 94 mmHg; P < 0.05). RBF, renal vascular resistance (RVR), GFR, and urine flow did not differ among groups under basal conditions, suggesting little tonic influence of TxA(2) on renal TP receptors in health. In endotoxemic WT mice, 14 h after LPS (Escherichia coli LPS 8.5 mg/kg intraperitoneally), mean arterial pressure was reduced to 85 mmHg (P < 0.001), as were RBF (5.0 versus 9.3 ml/min per g kidney wt; P < 0.001) and GFR (0.38 versus 1.03 ml/min per g kidney wt; P < 0.001). Heart rate and RVR (71 versus 47 mmHg/ml per min; P < 0.05) increased. The decreases in RBF and GFR after LPS were attenuated in TP-KO mice versus WT mice (both P < 0.05). In both TP-KO and TP antagonist-treated mice, RVR remained stable in response to LPS versus WT mice that did not receive LPS. Delayed TP-antagonist treatment (12 h after LPS injection) ameliorated RBF and RVR but did not restore GFR. In other WT animals, TP-antagonist treatment for 2 h before intravenous LPS abolished the early renal vasoconstriction and alleviated the decrease in GFR. These results demonstrate that renal vasoconstriction during endotoxemic shock induced by LPS is mediated by TP receptors as indicated by pharmacologic blockade and genetic disruption of TP receptors.
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PMID:Thromboxane receptor mediates renal vasoconstriction and contributes to acute renal failure in endotoxemic mice. 1533 84

Septic shock is characterized by hypotension and decreased systemic vascular resistance and impaired vascular reactivity. Renal vasoconstriction markedly contrasts with sepsis-induced generalized systemic vasodilation, which is strongly dependent on nitric oxide. Whether maintained renal vascular reactivity to vasoconstrictors contributes to the decrease in renal blood flow (RBF) and GFR observed during LPS-induced sepsis was tested by assessment of the acute effects of pressor agents on mean arterial pressure (MAP) and renal hemodynamics in endotoxemic and control mice. LPS-injected mice displayed lower MAP, RBF, and GFR than controls (P < 0.001). Despite a lower MAP, basal renal vascular resistance (RVR) was higher during endotoxemia (P < 0.02). Angiotensin II infusion produced a weaker MAP response in septic mice (24 versus 37%; P < 0.005), suggesting impaired vasoconstriction and hyporeactivity. A similar MAP increase was observed between groups during norepinephrine (NE) infusion. The MAP increase to nitric oxide synthase inhibition by N(G)-nitro-L-arginine methyl ester (L-NAME) was much greater in LPS-treated mice (41 versus 15%, P = 0.01), indicating a strong influence of nitric oxide in sepsis. In contrast, the RBF and RVR responses to angiotensin II, NE, or L-NAME were similar in both groups. Moreover, vasopressin produced greater changes in MAP, RBF, and RVR in septic mice than in controls. Among the vasoconstrictor challenges, only NE ameliorated the decrease in GFR 14 h after LPS injection. The in vivo results demonstrate that the renal microvasculature displays a normal or enhanced reactivity to constrictor agents as compared with nonrenal circulatory beds. Such responsiveness may contribute to reduced RBF and GFR during endotoxemia.
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PMID:Maintenance of renal vascular reactivity contributes to acute renal failure during endotoxemic shock. 1556 66

Acute renal failure (ARF) in septic patients drastically increases the mortality to 50-80%. Sepsis induces several proinflammatory cytokines including tumor necrosis factor-alpha (TNF-alpha), a major pathogenetic factor in septic ARF. Pentoxifylline has several functions including downregulation of TNF-alpha and endothelia-dependent vascular relaxation. We hypothesized that pentoxifylline may afford renal protection during endotoxemia either by downregulating TNF-alpha and/or by improving endothelial function. In wild-type mice, pentoxifylline protected against the fall in glomerular filtration rate (GFR; 105.2 +/- 6.6 vs. 50.2 +/- 6.6 microl/min, P < 0.01) at 16 h of LPS administration (2.5 mg/kg ip). This renal protective effect of pentoxifylline was associated with an inhibition of the rise in serum TNF-alpha (1.00 +/- 0.55 vs. 7.02 +/- 2.40 pg/ml, P < 0.05) and serum IL-1beta (31.3 +/- 3.6 vs. 53.3 +/- 5.9 pg/ml, P < 0.01) induced by LPS. Pentoxifylline also reversed the LPS-related increase in renal iNOS and ICAM-1 and rise in serum nitric oxide (NO). Enhanced red blood cell deformability by pentoxifylline may have increased shear rate and upregulated eNOS. Studies were therefore performed in eNOS knockout mice. The renal protection against endotoxemia with pentoxifylline was again observed as assessed by GFR (119.8 +/- 18.0 vs. 44.5 +/- 16.2 microl/min, P < 0.05) and renal blood flow (0.86 +/- 0.08 vs. 0.59 +/- 0.05 ml/min, P < 0.05). Renal vascular resistance significantly decreased with the pentoxifylline (91.0 +/- 5.8 vs. 178.0 +/- 7.6 mmHg.ml(-1).min(-1), P < 0.01). Thus pentoxifylline, an FDA-approved drug, protects against endotoxemia-related ARF and involves a decrease in serum TNF-alpha, IL-1beta, and NO as well as a decrease in renal iNOS and ICAM-1.
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PMID:Pentoxifylline protects against endotoxin-induced acute renal failure in mice. 1698 10


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