Alefacept combined with tacrolimus, mycophenolate mofetil and steroids in de novo kidney transplantation: a randomized controlled trial.

Memory T cells play a central role in mediating allograft rejection and are a rational target for immunosuppressive therapy. Alefacept is a recombinant LFA3/IgG1 fusion protein that reduces the number of memory T cells in both psoriatic lesions and the peripheral circulation of psoriasis patients. This study evaluated the efficacy and safety of alefacept compared with placebo when combined with tacrolimus, mycophenolate mofetil and corticosteroids in de novo renal transplant recipients. Between December 2007 and March 2009 patients were randomized in a double-blind fashion to receive alefacept (n = 105) or placebo (n = 107) for 3 months and were then followed for a further 3 months. The primary efficacy endpoint was the incidence of biopsy-confirmed acute T cell mediated rejection (Banff grade ≥ 1) through Month 6. Memory T cell counts were significantly reduced in the alefacept group from Week 3 to study end compared with placebo. However, there was no significant difference between the alefacept and placebo groups for the primary efficacy endpoint (alefacept, 11.0% vs. placebo, 7.0%, p = 0.3). Patient and graft survival as well as renal function was similar between treatment groups. Safety and tolerability were generally similar between the treatment arms. Malignancy was higher in the alefacept treatment arm.

Hepatocyte injury during post-operative sepsis: activated neutrophils as potential mediators.

We evaluated the concept that the vascular entrance of both bacterial and nonbacterial particulate material could lead to hepatic parenchymal cell injury, either due to postphagocytic Kupffer cell activity or the margination of activated leukocytes in the liver. Injection of denatured, collagen-coated particles as well as heat-killed bacteria were used as particulate challenges. Hepatic parenchymal cell injury in vivo during postoperative sepsis was evaluated by plasma aspartate aminotransferase (AST) and ornithine carbamyl transferase (OCT) enzyme levels over 3-72 h. AST and OCT levels elevated following either laparotomy plus cecal ligation (mild sepsis) or laparotomy plus cecal ligation with puncture (severe sepsis), with the peak level at 24 h. In addition, the direct intravenous injection of either nonbacterial foreign particles or heat-killed Pseudomonas aeruginosa into normal rats also produced a dose-dependent elevation of AST and OCT. The plasma level of either AST or OCT actually increased 350-400% after injection of the non-bacterial particles. A similar dose related elevation in enzymes followed the intravenous injection of heat-killed Pseudomonas. To differentiate the potential contribution of activated hepatic Kupffer cells versus activated marginated neutrophils to the in vivo hepatic injury, we determined the release of the hepatic specific enzyme OCT by cultured hepatic parenchymal cells when they were exposed to isolated Kupffer cells or isolated PMNs that were activated by exposure to dead bacteria. Bacteria alone when added to cultured hepatocytes did not induce significant OCT release. In contrast, activated PMNs but not Kupffer cells induced a significant (p less than 0.05) release of OCT from parenchymal cells into the culture media. Thus, in vivo transient hepatic parenchymal cell injury with post-operative sepsis may be mediated by the margination of activated PMNs in the liver.

Reversal of opsonic deficiency in surgical, trauma, and burn patients by infusion of purified human plasma fibronectin. Correlation with experimental observations.

Plasma fibronectin deficiency has been documented in critically ill surgical, trauma, and burn patients. Human plasma fibronectin was isolated by gelatin-Sepharose affinity chromatography and evaluated with respect to its opsonic activity following pasteurization, its in vivo clearance kinetics, and its short-term influence on cardiovascular hemodynamics in postoperative septic sheep. Six patients with low plasma fibronectin levels were also evaluated with respect to temporal changes of immunoreactive fibronectin and opsonic activity following infusion of fibronectin at a dose calculated to elevate the plasma fibronectin level to 400 micrograms/ml. With utilization of three different in vitro radioisotopic phagocytic assays, i.e., liver slice assay, peritoneal macrophage monolayer assay, and Kupffer cell monolayer assay, retention of opsonic activity by fibronectin following pasteurization was documented. The normal biphasic kinetics associated with plasma clearance of fibronectin were also not altered by pasteurization. In postoperative septic sheep with hemodynamic instability, intravenous infusion of 500 mg of purified human fibronectin initiated no abnormal hemodynamic response. Indeed, as compared with placebo, the infusion of fibronectin into the postoperative septic sheep resulted in a more stable systemic vascular resistance and pulmonary vascular resistance with a higher arterial pressure. It also elevated immunoreactive fibronectin levels (p less than 0.05) and increased opsonic activity (p less than 0.05). Surgical, trauma, and burn patients (ages 18 to 80 years) with low plasma fibronectin levels (160 to 236 micrograms/ml) manifested no disturbance in cardiovascular, respiratory, or hematologic parameters following fibronectin infusion (590 to 988 mg per patient), but did display an early increase of opsonic activity. This standardized, pasteurized, and opsonically active preparation of purified human plasma fibronectin (5.0 mg/ml after reconstitution) has utility for future randomized clinical trials in injured patients with sepsis.

The effects of oral pentoxifylline on the cytokine release syndrome during inductive OKT3.

The cytokine release syndrome (CRS) accompanying OKT3 therapy is a major cause of posttransplant morbidity. The pathogenesis of this syndrome has been attributed to the synthesis of tumor necrosis factor, interleukin 2 (IL-2), interleukin 6 (IL-6), and gamma-interferon in response on T lymphocyte stimulation by OKT3. The hemorrheologic agent pentoxifylline (PTX) inhibits the synthesis of TNF alpha in vitro in response to a variety of stimuli, including OKT3. We performed a randomized, double-blinded trial of PTX during OKT3 induction in recipients of cadaveric renal allografts. Patients received either PTX 800 mg or placebo 2 hr before the initial dose of OKT3 and every 8 hr thereafter during the first 3 posttransplant days. Serum TNF alpha and IL-6 concentrations were measured pre-OKT3 and at 2 and 6 hr post-OKT3 on the first 3 posttransplant days. Despite the achievement of apparently adequate plasma levels of PTX and its active metabolites, no difference was observed in the incidence or severity of clinical manifestations of CRS. Serious manifestations of CRS--including acute pulmonary edema, encephalopathy, and aseptic meningitis--were not seen in either group. Serum TNF alpha and IL-6 concentrations were similar in PTX and control patients throughout the course of the study. Plasma levels of PTX and its active metabolites did not correlate with serum TNF alpha levels, serum IL-6 levels, or the incidence and severity of clinical manifestations of CRS.

Fibronectin and the critically ill patient: current status.

In summary, deficiency of plasma fibronectin has now been documented in a variety of clinical entities. Persistently low fibronectin may have prognostic value, and in certain patients may provide a clue to occult sepsis and potential organ failure. The clinical benefit of infusion of fibronectin-rich cryoprecipitate or purified human plasma fibronectin has yet to be determined in well-controlled randomized clinical trials. However, if such results become available then infusion of plasma fibronectin may provide a valuable therapeutic modality in the care of the critically-ill patient.

Type of hemodialysis and preference for behavioral involvement: interactive effects on adherence in end-stage renal disease.

Examined the effects of hemodialysis type (i.e., staff controlled, in center vs. patient controlled, home) and patient preference for behavioral involvement on adherence and emotional adjustment in a sample of 53 patients with end-stage renal disease. Consistent with person x treatment interaction models, higher levels of preference for behavioral involvement were associated with better dietary adherence (i.e., lower serum potassium) for patients receiving dialysis at home but worse dietary adherence for patients receiving treatment in a dialysis center. A similar though weaker patient x treatment type matching pattern was observed for fluid-intake adherence (i.e., interdialytic weight gain). No effects were observed for patients' self-reported depression levels. Possible mechanisms for the interactional effect on adherence are discussed.

Health locus of control and depression in end-stage renal disease.

Research on the association between health locus of control and depression in chronic illness has produced contradictory findings, perhaps because of a failure to consider contextual variables. In this study of 96 hemodialysis patients, the belief that one's health is controllable was associated with less depression among Ss who had not previously experienced a failed renal transplant. This belief was associated with greater depression for Ss who had returned to dialysis following an unsuccessful transplant. This interactive effect occurred among severely ill Ss, but health locus of control was unrelated to depression among Ss with less severe disease. This pattern occurred both when control perceptions reflected a belief in the Ss' own or powerful others' (i.e., health care providers) ability to influence health outcomes. Results underscore the adaptive value of congruence between control beliefs and objective circumstances in chronic illness.

Success of medical and surgical management of acute variceal hemorrhage.

Peripheral intravenous Pitressin infusion, use of the Sengstaken-Blakemore tube, or both effectively controlled variceal hemorrhage in 69 percent of patients, allowing an interval of medical management before elective portasystemic shunt surgery. Prolonged preoperative in-hospital management significantly improved hepatic function in initially poor risk patients. This improvement in hepatic function appeared to result in decreased postoperative morbidity and an operative mortality equal to that of good risk patients.

Sepsis in the management of complicated biliary disorders.

Postoperative sepsis developed in 72 per cent of 25 patients with noncalculous proximal biliary tract obstruction. Six episodes of shock and one death resulted. Twenty-eight per cent of septic events occurred despite the administration of prophylactic antibiotics. The incidence of septic complications was similar regardless of the biliary drainage procedure used. Despite the advent of broad spectrum antibiotics and improved surgical techniques for biliary decompression, sepsis remains a serious and frequent complication in patients with chronic bile duct obstruction.

Calciphylaxis: is there a role for parathyroidectomy?

OBJECTIVE: Calciphylaxis, a rare disorder typically affecting renal failure patients, results in vascular calcification with subsequent skin necrosis, gangrene, and often death from sepsis. Parathyroid hormone is thought to act as a tissue sensitizer leading to these soft tissue changes. As such, parathyroidectomy is often advocated to control this complicated condition. A discussion of calciphylaxis does not exist in the otolaryngology literature, and head and neck surgeons performing parathyroidectomy should be aware of this phenomenon. This study evaluates the success of parathyroidectomy in reversing the ill effects of calciphylaxis in both our patient population and the literature. STUDY DESIGN: Retrospective study and review of the literature. METHODS: Five patients with calciphylaxis treated at our institution were evaluated for mortality, surgical and perioperative complications, wound healing, and predictors of patient outcomes. RESULTS: Two patients died from sepsis and infectious complications of their calciphylaxis shortly after surgery. Of the three survivors, two later died (15 and 18 mo after surgery) from causes not directly related to calciphylaxis. The other long-term survivor required partial amputation of a leg for osteomyelitis. There was one operative complication-- wound infection requiring antibiotic therapy, drainage, and packing. Postoperative hypocalcemia required treatment in two patients. Immediate perioperative survival was more likely in patients with leukocyte counts less than 20,000 cells/mL. CONCLUSIONS: Calciphylaxis is a serious disease and patients often succumb to sepsis and infectious complications. Patients with extremely high leukocyte counts from coexistent infections may have a worse prognosis. Although a conclusive effective therapy does not exist, parathyroidectomy can be safely performed and may benefit some patients with what is often an otherwise fatal disease. The literature to date generally confirms our findings. Key Words: Calciphylaxis, parathyroid hormone, parathyroidectomy, skin necrosis, chronic renal failure.

Laparoscopic treatment of post renal transplant lymphoceles.

BACKGROUND: Traditionally, a post transplant lymphocele (PTL) is drained by widely opening the wall connecting the lymphocele cavity to the intraperitoneal space via laparotomy. We hypothesize that laparoscopic techniques can be effectively used for the treatment of PTL. METHODS: Patients requiring intervention for PTL between 1993 and 2002 were identified via a retrospective review. Results of drainage via laparotomy and laparoscopy were compared. RESULTS: During the study period 685 renal transplants (391 cadaveric, 294 living) were performed. The incidence of lymphocele was 5% [34/685 (36 cases)]. The indications for surgical drainage were local symptoms (69%), graft dysfunction (14%), or both (17%). The mean time to surgical therapy was 4.9 months. Laparoscopic drainage was performed in 25 patients (74%) and open drainage in 9 patients (26%). Open procedures were performed in cases for: previous abdominal surgery (5), undesirable lymphocele characteristics or location (2), or with concomitant open procedures (3). There were no conversions or operative complications in either group. There was no difference in operative time for the laparoscopic group vs the open group (108 +/- 6 vs 123 +/- 18 min, p = 0.8). Hospital stay was significantly shorter for the laparoscopic group (1.7 +/- 0.8 vs 3.8 +/- 1.0, p = 0.0007), with 88% of laparoscopic patients being either overnight admissions or same day surgery. Two patients (5%) developed symptomatic recurrences requiring reoperation [1 laparoscopic (4%), 1 open (10%)]. CONCLUSIONS: Laparoscopic fenestration of a peritransplant lymphocele is a safe and effective treatment. The large majority of patients treated with laparoscopic fenestration were discharged within one day of surgery. Unless contraindications exist, laparoscopy should be considered first-line therapy for the surgical treatment of posttransplant lymphocele.

Effect of bacterial sepsis on gluconeogenic capacity in the rat.

Since sepsis places increased demands on the host for energy and on other substrates for tissue repair and host defense, hepatic gluconeogenesis is critical for the host's adaptation to sepsis. Substrate-stimulated gluconeogenesis (i.e., gluconeogenic capacity) was assessed by the alanine load method in mannoheptulose-pretreated rats made septic by cecal ligation after laparotomy, as well as by cecal ligation and puncture after laparotomy. Fasted rats subjected to laparotomy only (sham-ligated) and fasted, nonoperated rats (controls) were investigated simultaneously. Following an overnight (-18 to 0 hr) fast, nonoperated animals converted 17.9 +/- 1.5% of [14C]alanine to [14C]glucose. Continued fasting in nonoperated animals resulted in enhanced (P less than 0.05) gluconeogenic capacity (6 hr = 27.2 +/- 3.0%; 24 hr = 26.2 +/- 1.9%; and 48 hr = 28.5 +/- 2.6%) relative to Time 0. Laparotomy alone (sham ligation) delayed the fasting-induced increase (P less than 0.05) in gluconeogenesis capacity (6 hr = 21.1 +/- 1.2%; 24 hr = 18.5 +/- 1.3%; 48 hr = 27.8 +/- 1.0%) relative to Time 0. In contrast, postoperative sepsis produced a sustained depression (P less than 0.05) of gluconeogenic capacity relative to nonoperated sham-ligated controls at 48 hr (cecal ligation, 18.4 +/- 1.4%; and cecal ligation and puncture, 18.8 +/- 1.2%). Thus, (1) fasting enhances hepatic gluconeogenic capacity; (2) surgical trauma transiently blunts the gluconeogenic response to fasting; and (3) sepsis undermines the gluconeogenic response to fasting.

Effect of fibronectin-rich human cryoprecipitate on fluid volume requirements in sheep during postoperative sepsis.

Septic surgical patients often require fluid administration to maintain cardiovascular stability due, in part, to the sepsis-induced increase in vascular permeability and associated plasma volume depletion. Plasma fibronectin deficiency exists in such septic patients. We determined if maintenance of fibronectin levels by administration of fibronectin-rich human plasma cryoprecipitate would lower the resuscitative fluid volume needed for support of arterial pressure in septic postoperative sheep which were experimentally depleted of plasma fibronectin. Following a 2-hr postoperative baseline period, denatured collagen (gelatin, 8.7 mg/kg), which has a high affinity for fibronectin, was infused into both control and experimental sheep in order to acutely deplete plasma fibronectin. Sheep were then challenged both intraperitoneally and intravenously with live Pseudomonas (5 x 10(10) bacteria IP; 5 x 10(9) bacteria IV). Experimentals were given fresh plasma cryoprecipitate intravenously at a dose of 4 units bolus, followed by 3 units/hr for 5 hr. Controls received plasma cryoprecipitate selectively depleted of fibronectin by affinity chromatography. Bacterial challenge rapidly resulted in severe systemic hypotension. Ringer's lactate was infused intravenously into both groups at a rate sufficient to maintain a systemic arterial pressure of approximately 50 mm Hg with a maximum pulmonary artery wedge pressure of 15-18 mm Hg. Its rate of infusion was periodically adjusted to maintain this hemodynamic status. Comparison was made of the volume of Ringer's lactate required to maintain an arterial pressure of 50 mm Hg in both groups. Net fluid requirement was significantly (p less than 0.05) less in postoperative septic sheep (47.4 +/- 6.2 mg/kg/hr) treated with fibronectin-rich cryoprecipitate compared to the fluid requirement (71.7 +/- 4.7 mg/kg/hr) for postoperative septic sheep receiving fibronectin-deficient cryoprecipitate. Thus elevation of plasma fibronectin concentration lowers the fluid requirements needed for hemodynamic support in postoperative Gram-negative sepsis.

Perceived family support as a moderator psychological well-being in end-stage renal disease.

End-stage renal disease (ESRD) is associated with an increased incidence of psychological distress. The present research examined the salutary effects of a supportive family environment on the psychological well-being of ESRD patients receiving renal transplants. Patients (N = 57) completed a measure of perceived family support and an assessment of the physical impact of their illness. Psychological well-being was assessed utilizing two measures of depression and two measures of anxiety. One group of patients was classified as experiencing high illness-related physical dysfunction. In this group, patients perceiving a less supportive family environment displayed significantly higher levels of psychological symptoms of depression and anxiety than patients with a more supportive family environment. A second group of patients was classified as experiencing low illness-related physical dysfunction. In this group, the perceived level of family support was not significantly related to their relatively lower reported levels of depression and anxiety.

Gadolinium-enhanced breathhold three-dimensional time-of-flight renal MR angiography in the evaluation of potential renal donors.

PURPOSE: To evaluate the utility of gadolinium-enhanced three-dimensional (3D) time-of-flight (TOF) magnetic resonance angiography (MRA) of the renal arteries in the evaluation of potential renal donors. MATERIALS AND METHODS: Fifty consecutive patients underwent gadolinium-enhanced 3D-TOF MRA of the renal arteries as part of their evaluation as possible renal donors. All imaging was performed on a 1.5-T system with use of a torso phased-array coil. Conventional T1-weighted axial spin-echo and T2-weighted axial fast spin-echo imaging was performed to evaluate the renal parenchyma. Coronal dynamic MRA was performed during bolus injection of 40 mL of gadolinium with use of a 3D-TOF sequence requiring a breathhold of approximately 30 seconds. Maximum-intensity-projection reconstructions were obtained of the renal arterial and venous anatomy. All studies were prospectively evaluated by a single radiologist experienced with body MRA. Intraoperative findings were used as the reference standard in 35 patients. To evaluate interobserver variability, each examination was evaluated for image quality, renal artery number, and anatomy by two radiologists experienced with MRA and blinded to the other's interpretations and surgical results. RESULTS: Ninety-eight percent of all MRAs were graded as diagnostic quality (Kappa value = 0.38; P < .05). Multiple renal arteries were identified in 29 (29%) of 100 kidneys. Four of 50 patients studied (8%) had renal parenchymal abnormalities identified with MR imaging. Sensitivity and specificity for accessory renal artery detection was 71% and 95%, respectively. Overall, accuracy for MRA in determining renal artery number was 90%. CONCLUSION: Gadolinium-enhanced breathhold 3D-TOF renal MRA is sufficient to assess the renal arteries in potential donors.

Lung fluid and protein flux during postoperative sepsis.

Pulmonary microvascular injury during sepsis after injury appears to be amplified with plasma fibronectin deficiency, but the degree of injury relative to the extent of sepsis has not been defined. We evaluated pulmonary vascular permeability in sheep as influenced by various levels of postoperative Pseudomonas sepsis during a period of plasma fibronectin deficiency. The hemodynamic response to Pseudomonas was very similar regardless of the intensity of septic challenge and characterized by systemic arterial hypotension, decreased cardiac output, and pulmonary arterial hypertension. In contrast, increased pulmonary microvascular permeability was observed with increments in the bacterial challenge. Thus, lung protein clearance (LPC) or so called pulmonary transvascular protein clearance (TPC) used as an index of lung vascular permeability was 9.1 +/- 1.9 ml/hr, 15.1 +/- 1.7 ml/hr, and 19.3 +/- 3.0 ml/hr 2 hr after low (3 X 10(9) i.v.; 1 X 10(10) i.p.), medium (3 X 10(9) i.v.; 3 X 10(10) i.p.), and high (5 X 10(9) i.v.; 5 X 10(10) i.p.) dose Pseudomonas challenges, respectively. Thus, the extent of the altered pulmonary microvascular integrity in sheep during sepsis after surgery in the presence of fibronectin deficiency is dependent on the degree of bacterial sepsis. In addition, infusion of cryoprecipitate was an effective means of reversing the plasma fibronectin deficiency. Accordingly, this may be used as a model to investigate the mechanism of altered lung fluid balance during postoperative septic shock and the effect of fibronectin on this response.