Gene Expression in Biopsies of Acute Rejection and Interstitial Fibrosis/Tubular Atrophy Reveals Highly Shared Mechanisms That Correlate With Worse Long-Term Outcomes.

Interstitial fibrosis and tubular atrophy (IFTA) is found in approximately 25% of 1-year biopsies posttransplant. It is known that IFTA correlates with decreased graft survival when histological evidence of inflammation is present. Identifying the mechanistic etiology of IFTA is important to understanding why long-term graft survival has not changed as expected despite improved immunosuppression and dramatically reduced rates of clinical acute rejection (AR) (Services UDoHaH. http://www.ustransplant.org/annual_reports/current/509a_ki.htm). Gene expression profiles of 234 graft biopsy samples were obtained with matching clinical and outcome data. Eighty-one IFTA biopsies were divided into subphenotypes by degree of histological inflammation: IFTA with AR, IFTA with inflammation, and IFTA without inflammation. Samples with AR (n = 54) and normally functioning transplants (TX; n = 99) were used in comparisons. A novel analysis using gene coexpression networks revealed that all IFTA phenotypes were strongly enriched for dysregulated gene pathways and these were shared with the biopsy profiles of AR, including IFTA samples without histological evidence of inflammation. Thus, by molecular profiling we demonstrate that most IFTA samples have ongoing immune-mediated injury or chronic rejection that is more sensitively detected by gene expression profiling. These molecular biopsy profiles correlated with future graft loss in IFTA samples without inflammation.

Observations on the use of cidofovir for BK virus infection in renal transplantation.

BACKGROUND: In renal transplantation, BK virus infection can result in significant graft nephropathy and loss. While reduction in immunosuppression (IS) is considered standard therapy, adjunct agents may be warranted. Data are suggestive of a possible role of cidofovir for the management of BK. This study aims to describe the course of BK viremia (BKV) in a large cohort of renal transplant patients receiving adjunct cidofovir. METHODS: We evaluated kidney and kidney-pancreas recipients who received cidofovir combined with reduced IS for management of high-level BKV or BK virus nephropathy (BKVN). We examined the rate and timing of BKV clearance, and performed a multivariate analysis to identify risk factors associated with long-term (>6 months) viremia. RESULTS: In total, 75 patients received a median of 13 doses of cidofovir in conjunction with reduced IS; 32 patients (43%) had short-term BKV (≤6 months), and 43 (57%) had long-term BKV. Overall, 53 of 75 patients (71%) eventually cleared BKV at a median of 4.2 months (interquartile range 2.1-9.3 months). Independent factors associated with long-term BKV included older age (odds ratio [OR] 1.1, P = 0.02), delayed graft function (OR 31.4, P = 0.01), and higher peak BKV (OR 12.8, P = 0.02), while BKV reduction by at least 1 log(10) copies/mL at 1 month of treatment was associated with clearance within 6 months (OR 49.3, P < 0.01). Patients with earlier clearance maintained stable graft function and no graft losses, while long-term BKV was associated with a 15% decline in estimated glomerular filtration rate. CONCLUSIONS: Adjunct cidofovir resulted in preservation of renal function when viral clearance occurred within 6 months of initiation. This retrospective review defines factors predicting response to cidofovir in conjunction with reduced IS for BKVN or high-level BKV. Still, considering cost, frequency of administration, and treatment duration, a randomized trial is necessary to define the exact utility of cidofovir in the setting of BK virus infection.

Analgesic nephropathy selectively affecting a unilateral non-functioning hypoplastic kidney.

Analgesic nephropathy results from chronic abuse of non-narcotic analgesics, most frequently with the use of phenacetin and mixed analgesic preparations. Renal papillary necrosis and chronic interstitial nephritis with progressive scarring are characteristic of the histopathology of analgesic nephropathy. Typically, papillary necrosis in these patients is bilateral and affects almost all renal papillae. This report describes a case of severe analgesic nephropathy that discriminantly affected a unilateral non-functioning kidney and spared the contralateral normally developed kidney. The patient herein consumed therapeutic doses of acetaminophen and naproxen daily and for several years. We estimated the cumulative doses of acetaminophen and naproxen used by the patient during that period to be approximately 1.0 and 0.4 kg, respectively. The cumulative dose of acetaminophen is at the threshold of doses that were traditionally associated with an increased risk for end-stage kidney failure. Simultaneous intake of both analgesics could have had a synergetic adverse effect on renal function. This case also demonstrates that preexisting renal insufficiency is prerequisite to the development of analgesic nephropathy. Conversely, kidneys with normal function are resistant to the chronic nephrotoxicity associated with habitual analgesic use.

Serial peripheral blood cytotoxic lymphocyte gene expression measurements for prediction of pancreas transplant rejection.

Acute rejection after pancreas transplantation remains a significant problem and contributes to immunological graft loss. No clinical markers of pancreas rejection have been universally accepted. The purpose of this study was to investigate the use of genetic markers; granzyme B, perforin, and HLA-DRA in the peripheral blood of pancreas transplant recipients. These genes have been identified in renal and islet cell transplant recipients as noninvasive tools to predict acute rejection. Blood samples were collected weekly for up to 1 year posttransplant. Surveillance biopsies of the pancreas were scheduled at weeks 2, 4, 8, and 12 as part of the typical posttransplant protocol for patients with pancreas alone or pancreas after kidney transplantation. Exclusion criteria included a diagnosis of biopsy-proven chronic rejection alone, pancreatitis, or kidney rejection within 2 months after pancreas biopsy. Gene expression levels of granzyme B, perforin, and HLA-DRA were compared in patients with (n = 7) and without biopsy proven acute rejection (n = 7). Recipients with acute rejection showed increased expression of granzyme B, HLA-DRA, as well as perforin genes compared to patients without biopsy-proven rejection. In addition, we observed that elevation of these genes occurred as early as 4 weeks before the traditional biopsy diagnosis, while the recipients with no rejection showed no change in gene expression. Our data indicated that serial measurements of peripheral blood granzyme B, perforin, and HLA-DRA gene expression can be a useful tool to predict pancreas rejection in its earliest stage.

Changes in abdominal wounds following treatment with sirolimus and steroids in a rat model.

Wound healing complications have been observed in patients receiving sirolimus (SLR). This study examined the degree and duration of delayed healing in various protocols using SLR. Sprague-Dawley rats underwent a standard midline abdominal incision and wound closure. Groups of 6 rats each were randomized to receive different doses of SLR (2 and 5 mg/kg) with or without loading dose (10 mg/kg x3 days), and with or without steroids (20 mg/kg x3 days followed by 5 mg/kg for 2 weeks). Rats were humanely killed on postoperative days 5, 10, or 15. Wound breaking force was measured using the EHMI BIAX-II instrument and tensile strength was calculated. Wounds in control animals had gradual increase in tensile strength during the 15-day observation. In contrast, high and loading doses of SLR caused reduction in wound strength until day 10, but the wounds' tensile strength became equivalent to control by day 15. The addition of steroids prolonged wound recovery with low doses of SLR until day 15 and had very profound effects on healing in high-dose SLR-treated animals (>50% reduction) that continued beyond the 2 weeks of observation. Low doses of SLR in non-steroid-treated animals had a short-term (5-day) impact on wound healing; high dose and loading doses delayed healing for 10 to 15 days. The addition of steroids had a synergistic effect on delayed wound healing, particularly in animals receiving high-dose SLR, which demonstrated prolonged wound weakness. These results may provide practical guidelines for postoperative introduction of SLR in the context of various clinical protocols.

Prediction by postrevascularization biopsies of cadaveric kidney allografts of rejection, graft loss, and preservation nephropathy.

This prospective study of postrevascularization biopsies was undertaken to determine if pathological changes might be correlated with subsequent allograft rejection and loss. Such a relationship, if identified, could be used to predict graft outcome, thus permitting earlier intervention for individuals at an increased risk for rejection or graft loss. Fifty-seven biopsies were obtained, and the number of polymorphonuclear leukocytes marginating in the glomerular loops and peritubular capillaries was documented along with risk factors associated with the recipients' immunological status and with risk factors associated with ischemic preservation injury. The presence of seven PMN leukocytes in the peritubular capillaries is related to the subsequent occurrence of cellular rejection and accurately predicted in 82% of the patients studied whether or not rejection would occur. Mean glomerular PMN leukocyte count was related to cold ischemia time and subsequent graft loss, while an elevated mean glomerular PMN leukocyte count in conjunction with an elevated peritubular PMN leukocyte count was always associated with hyperacute rejection. Focal glomerular thrombosis (less than 50%) and tubular cast formation are manifestations of preservation nephropathy and had no effect on graft outcome. These findings suggest that the peritubular capillaries are a more sensitive target for immune changes and that minor donor/recipient disparities can be detected in the peritubular capillaries while preexisting sensitization to the donor is reflected by concurrent changes in the glomerular and peritubular capillaries.

The correlation of Banff scoring with reversibility of first and recurrent rejection episodes.

Recurrent acute rejection remains a significant problem for recipients of renal allografts, with a large proportion of patients progressing to graft loss. The newly introduced Banff schema was used to determine whether the histologic pattern of acute rejection (severity and renal compartment scoring) could discriminate recurring from nonrecurring rejections and to examine whether objective rejection scoring had predictive value for rejection reversal and outcome. A total of 67 biopsies obtained from 50 patients with acute rejection were examined for the occurrence of recurrent allograft rejection. All patients were maintained on a cyclosporine-based triple immunosuppressive protocol and had biopsy-proven acute rejection without chronic changes. Rejection recurred in 13 patients (26%), of whom 4 further developed a third rejection. The majority of the patients developed this first rejection within 2 months posttransplantation. Demographics, prebiopsy renal function, immunosuppression, and peak serum creatinine level at the time of biopsy were similar in patients with multiple and single rejection. Peak levels of reactivity to panel of lymphocytes seemed higher in the group of patients with recurrent rejection, whereas HLA matching was similar for all patients. Banff scores for acute rejection did not discriminate patients at risk of rejection recurrence who had lower vascular (0.6 vs. 1.2), tubular (0.6 vs. 1.1), and lower cumulative SUM (3.0 vs. 4.5) scores on their first rejection when compared with patients with one rejection. Histological scoring was, however, significantly different when first and third episodes were compared in the same patient, indicating increased rejection severity with recurrence. Moreover, the rate of reversal of recurrent rejection by anti-lymphocyte therapy was significantly less than that of first rejection (P<0.05). In conclusion, these data demonstrate that Banff scoring correlated with rejection reversal and steroid responsiveness, yet rejection recurrence was independent of histological score of the first rejection. Furthermore, Banff schema provided an objective histological correlation to the poor clinical outcome seen with recurrent rejection. The data also suggest that patients with early mild rejection continue to be at risk for recurrence and graft loss.

An analysis of renal function in pancreas-kidney and diabetic kidney-alone recipients at two years following transplantation.

Pancreas-kidney recipients (SPK) are at higher risk for rejection than diabetic kidney-alone recipients (KA), and thus generally receive higher doses of maintenance immunosuppression. This has lead to concern that the potential benefits to renal function, brought about by posttransplant euglycemia, may be negated by the nephrotoxicity of immunosuppression. We therefore sought to compare patterns of renal function in diabetic patients following SPK and KA transplantation. Serum creatinine levels, corrected glomerular filtration rates (cGFR), and whole blood TDX cyclosporine levels were recorded on 25 SPK and 17 KA at 3, 6, 12, and 24 months posttransplant when patients were free of acute renal dysfunction. The SPK recipients had significantly higher cyclosporine levels at each of the measurement points as compared with the KA recipients (P < or = .01). In spite of these higher cyclosporine levels, the SPK recipients showed stable creatinine and cGFR levels throughout the study, as did the KA group until 24 months. At 24 months, the KA group experienced a rise in creatinine from 1.3 +/- .09 ng/dl at 3 months to 1.6 +/- .07 ng/dl at 24 months (P < or = 0.006). Urine albumin excretion was examined at 24 months, and 6 of 8 KA patients found to have abnormally elevated levels compared with only 3 of 9 SPK patients. These findings indicate that SPK recipients experience stable renal function despite significantly higher cyclosporine levels, while KA recipients demonstrate early signs of deteriorating function at the 2-year follow-up.

Glomerulosclerosis as a determinant of posttransplant function of older donor renal allografts.

Transplantation of kidneys from older donors is being advocated to expand the organ donor pool. However, the prevalence of atherosclerosis and age-induced renal structural alterations account for the variable function of allografts procured from these older donors. Pretransplant biopsies are sometimes used to evaluate kidneys from older donors, but to date there are no defined criteria correlating the extent of structural alterations in these kidneys to subsequent function. We investigated the effect of glomerulosclerosis, a marker for nephrosclerosis, on graft outcome. Sixty-five baseline biopsies of kidney allografts were retrospectively analyzed to identify a referent point of glomerulosclerosis that correlated with inferior graft outcome. Age and death from nontraumatic cerebrovascular injuries were the main correlates for donor glomerulosclerosis (P < 0.001). Allografts with poor function at 6 months defined as serum creatinine > 2.5 mg/dl (n = 13) or nephrectomy (n = 4) had a mean of 20% glomerulosclerosis at the time of implantation compared with only 2% sclerosis in allografts with good function (P < 0.05). Delayed graft function occurred in 22% and 33% of recipients with no glomerulosclerosis and those with less than 20% glomerulosclerosis, respectively. In contrast, patients receiving kidneys with > 20% sclerosis had an 87% incidence of delayed function (P < 0.05). Moreover, graft loss occurred in 7% of recipients of kidneys with less than 20% sclerosis and in 38% of recipients with > 20% sclerosis (P < 0.04). Measurements of serum creatinine in the donors did not distinguish the different degrees of glomerulosclerosis found on biopsy. Our data indicate that donor glomerulosclerosis greater than 20% increases the risk of delayed graft function and poor outcome of transplanted kidneys. Therefore, we advocate the use of routine biopsies of kidneys from older (> 50 yrs) donors and those donors with nontraumatic cerebrovascular accidents, despite seemingly normal preprocurement serum creatinine.

Utility of standardized histological classification in the management of acute rejection. 1995 Efficacy Endpoints Conference.

BACKGROUND: Standardized histological grading of transplant kidney biopsies has become a primary criterion for diagnosis of rejection in immunosuppression clinical trials. METHODS: A consortium of 19 transplant centers from North America, Europe, and Australia convened in 1995 to examine kidney transplant rejection. Data from the 1995 Efficacy Endpoints Conference were examined for frequency of adoption of Banff schema. Biopsy grading was correlated with clinical parameters of rejection and therapy response. RESULTS: Histological confirmation of rejection episodes occurred in 73% of 953 cases, with Banff criteria adoption increasing in frequency between 1992 and 1995. Banff grading significantly correlated with clinical rejection severity (rejection creatinine: grade I, 2.8+/-0.2 mg/dl; grade II, 3.5+/-0.2 mg/dl; grade III, 4.1+/-0.3 mg/dl; P < 0.001), although nadir creatinines were similar. Response rates of Banff grades I and II to steroid therapy were not different, but only 42% of grade III rejections responded to steroids (P < 0.003. Banff grading also correlated with postrejection creatinine, day 15: grade I, 2.2+/-0.2 mg/dl; grade II, 3.0+/-0.2 mg/dl; grade III, 3.8+/-0.4 mg/dl (P < 0.001), and day 30: grade I, 2.1+/-0.1 mg/dl; grade II, 2.2+/-0.2 mg/dl; grade III, 2.7+/-0.2 mg/dl (P < 0.06). Banff grade III correlated with reduced graft survival at 1 year: grade I, 86%; grade II, 88%; grade III, 70% (P < 0.01). CONCLUSIONS: This multicenter review of rejection severity confirms that standardized histologic classifications such as the Banff schema provide a reliable means for stratifying patient risk of treatment success or failure. These data support the use of Banff criteria in clinical trial design.

Simultaneous kidney-pancreas transplantation without antilymphocyte induction.

BACKGROUND: The introduction of potent new immunosuppressive agents may allow simultaneous kidney-pancreas transplantation to be performed without antilymphocyte induction. METHODS: We analyzed 30 simultaneous kidney-pancreas transplantations receiving tacrolimus, mycophenolate mofetil, and steroids without without antilymphocyte induction. Eighteen patients underwent pancreas transplantation with portal-enteric (P-E) drainage and the remaining 12 had systemic bladder (S-B) drainage. Target 12 hr trough tacrolimus levels for the first 3 months after simultaneous kidney-pancreas transplantation were 15-20 ng/ml. The oral mycophenolate mofetil dose was 2-3 g/day begun immediately posttransplant in two to four divided doses. Steroids were tapered according to protocol. RESULTS: All patients experienced immediate function of both kidney and pancreas grafts. One-year actuarial patient, kidney, and pancreas graft survival rates are 93, 93, and 90%, respectively. Nine patients (30%) had a total of 13 rejection episodes (12 biopsy proven) including 4 within 2 weeks, 6 between 2 weeks and 3 months, and 3 beyond 3 months after simultaneous kidney-pancreas transplantation. Three rejection episodes were treated with steroids alone and 10 were treated with antilymphocyte therapy (5 OKT3 and 5 ATGAM). A total of seven patients (23%) received antilymphocyte therapy. Three patients (10%) had more than one rejection episode. Two pancreas grafts (7%) and one kidney graft (3%) were lost from rejection. Four patients (13%) developed cytomegalovirus infection, but none had tissue-invasive cytomegalovirus. At present, 22 surviving patients (81%) remain on triple immunosuppression with tacrolimus, mycophenolate mofetil, and prednisone with excellent dual graft function. CONCLUSION: Tacrolimus, mycophenolate mofetil, and prednisone immunosuppression without without antilymphocyte induction is safe and effective after simultaneous kidney-pancreas transplantation.

Results of the double-blind, randomized, multicenter, phase III clinical trial of Thymoglobulin versus Atgam in the treatment of acute graft rejection episodes after renal transplantation.

BACKGROUND: Thymoglobulin, a rabbit anti-human thymocyte globulin, was compared with Atgam, a horse anti-human thymocyte globulin for the treatment of acute rejection after renal transplantation. METHODS: A multicenter, double-blind, randomized trial with enrollment stratification based on standardized histology (Banff grading) was conducted. Subjects received 7-14 days of Thymoglobulin (1.5 mg/kg/ day) or Atgam (15 mg/kg/day). The primary end point was rejection reversal (return of serum creatinine level to or below the day 0 baseline value). RESULTS: A total of 163 patients were enrolled at 25 transplant centers in the United States. No differences in demographics or transplant characteristics were noted. Intent-to-treat analysis demonstrated that Thymoglobulin had a higher rejection reversal rate than Atgam (88% versus 76%, P=0.027, primary end point). Day 30 graft survival rates (Thymoglobulin 94% and Atgam 90%, P=0.17), day 30 serum creatinine levels as a percentage of baseline (Thymoglobulin 72% and Atgam 80%; P=0.43), and improvement in posttreatment biopsy results (Thymoglobulin 65% and Atgam 50%; P=0.15) were not statistically different. T-cell depletion was maintained more effectively with Thymoglobulin than Atgam both at the end of therapy (P=0.001) and at day 30 (P=0.016). Recurrent rejection, at 90 days after therapy, occurred less frequently with Thymoglobulin (17%) versus Atgam (36%) (P=0.011). A similar incidence of adverse events, post-therapy infections, and 1-year patient and graft survival rates were observed with both treatments. CONCLUSIONS: Thymoglobulin was found to be superior to Atgam in reversing acute rejection and preventing recurrent rejection after therapy in renal transplant recipients.

Coexistence of anti-neutrophil cytoplasmic antibody-associated glomerulonephritis and membranous glomerulopathy.

The association of renal Wegener's granulomatosis with other glomerular diseases is very rare. A case of anti-neutrophil cytoplasmic antibody-associated necrotizing glomerulonephritis superimposed on a membranous glomerulopathy in a patient with systemic Wegener's granulomatosis is reported. Renal failure was corrected by immunosuppressive therapy treatment, but a non-nephrotic-range proteinuria persisted for several months. The association of membranous glomerulopathy with anti-glomerular basement membrane disease and other autoimmune diseases is well described; however, anti-neutrophil cytoplasmic antibody-associated vasculitis superimposed on membranous glomerulopathy has not been reported previously.

Invasive partial mole.

A case of invasive partial hydatidiform mole requiring chemotherapy and hysterectomy in a 30-year-old white woman is presented. This is the first histologically and cytogenetically documented partial mole with persistent elevation of human chorionic gonadotropin (hCG) level and invasion of myometrium. There was no evidence of distant spread.

Induction of acute pancreatitis in germ-free rats: evidence of a primary role for tumor necrosis factor-alpha.

BACKGROUND: Tumor necrosis factor-alpha (TNF-alpha) has been implicated as a mediator of the systemic manifestations associated with acute pancreatitis. The purpose of this study was to show that TNF-alpha expression in pancreatitis is a primary response and is not the result of endotoxemia. METHODS: Severe acute pancreatitis was induced in germ-free rats, which have no source of endogenous endotoxin, by ductal infusion of artificial bile. Control animals underwent sham operation and ductal infusion of saline solution. TNF-alpha levels were measured by the WEHI bioassay. Endotoxin was measured by the Limulus assay. RESULTS: TNF-alpha levels remained low in the sham group (mean, 24.6 +/- 8.0 pg/ml) but were significantly elevated in normal rats with pancreatitis (181 +/- 26.8 pg/ml; p < 0.001 versus sham group) and in germ-free rats with pancreatitis (213 +/- 90 pg/ml; p < 0.002 versus sham group). No endotoxin was detected in any of the experimental rats. CONCLUSIONS: Our results indicate that TNF-alpha levels are elevated in acute pancreatitis despite the absence of endotoxin, indicating a primary role of TNF-alpha in this disease.

A prospective comparison of systemic-bladder versus portal-enteric drainage in vascularized pancreas transplantation.

BACKGROUND: Most pancreas transplants are performed with systemic venous delivery of insulin and bladder drainage of the exocrine secretions (systemic-bladder [S-B]). To develop a more physiologic procedure, we performed pancreas transplantations with portal venous delivery of insulin and enteric drainage of the exocrine secretions (portal-enteric [P-E]). METHODS: During an 11-month period, we prospectively alternated 32 consecutive pancreas transplant recipients to either S-B (n = 16) or P-E (n = 16) drainage with standardized immunosuppression. RESULTS: Patient, kidney, and pancreas graft survival rates after simultaneous kidney-pancreas transplantation were 91% S-B versus 92% P-E, 91% S-B versus 92% P-E, and 82% S-B versus 92% P-E, respectively. Pancreas graft survival rates after solitary pancreas transplantation were 80% S-B versus 75% P-E. There were no graft losses either to immunologic or infectious complications in either group, but the incidence of acute rejection was slightly higher in the S-B group (44% S-B vs 31% P-E, P = NS). The cost and length of the initial hospital stay were similar between groups. The incidence of operative complications, major infections, and cytomegalovirus infections were likewise comparable. However, the S-B group was characterized by a slight increase in the number of readmissions, urinary tract infections, and urologic complications. Furthermore, metabolic acidosis and dehydration were more common in the S-B group. CONCLUSIONS: Pancreas transplantation with P-E drainage can be performed with short-term results comparable to those of transplantation with S-B drainage.

Renal allograft outcomes in African American versus Caucasian transplant recipients in the tacrolimus era.

METHODS: Between January 1995 and December 1999, 185 kidney transplants were performed with tacrolimus (TAC)-based immunosuppression including 120 African American (AA, 65%) and 65 Caucasian recipients (C, 35%). Mean follow-up was 34 months. The AA group was characterized by a higher incidence of renal disease due to hypertension (72% AA vs 37% C, P <.001), pretransplant dialysis (95% AA vs 82% C, P =.003), waiting time (1.9 years AA vs 1.1 years C, P =.02), cadaveric donation (88% AA vs 68% C, P =.01), HLA mismatching (mean 3.5 AA vs 2.4 C, P <.001), and delayed graft function (DGF; 50% AA vs 22% C, P =.001). RESULTS: The 5-year actuarial patient and graft survival rates were 96% AA versus 83% C (P = NS) and 83% AA versus 75% C, (P = NS), respectively. The incidence of acute rejection (21% AA vs 12% C, P = NS) and mean time to acute rejection (12 months AA vs 11 months C) were similar. Although the incidence of chronic allograft nephropathy (CAN) was comparable (7% AA vs 5% C), the mean time to CAN was shorter in AA recipients (18 months AA vs 37 months C, P =.03). CONCLUSIONS: These results suggest marked improvement in post-transplant outcomes in the TAC era in patients with multiple immunologic risk factors including AA ethnicity, cadaveric donor source, DGF, and HLA mismatching.

A 9-year experience with 126 pancreas transplants with portal enteric drainage.

HYPOTHESIS: A novel technique of pancreas transplantation (PTX) with portal venous delivery of insulin and enteric exocrine drainage (portal enteric) was developed at our center to improve the PTX procedure. DESIGN: Case series. SETTING: Single-center experience at a university hospital. PATIENTS AND INTERVENTION: From October 1990 through December 1999, we performed 126 PTXs with portal enteric drainage, including 90 simultaneous kidney PTXs (SKPT) and 36 solitary PTXs (18 sequential PTXs after kidney transplantation and 18 PTXs alone). MAIN OUTCOME MEASURES: Patient and graft survival rates; medical and surgical morbidity. Three groups, representing 3 eras of immunosuppression, were compared. Thirty patients underwent SKPT with muromonab-CD3 induction and cyclosporine-based therapy in era 1 (October 1990 through June 1995); 42 SKPTs received tacrolimus and mycophenolate mofetil-based immunosuppression without antibody induction in era 2 (July 1995 through May 1998); and 18 SKPTs were performed in era 3 (June 1998 through December 1999) with either basiliximab or daclizumab induction. RESULTS: One-year patient survival rates after SKPT were 77% in era 1, 93% in era 2, and 100% in era 3 (P =.03). The 1-year kidney graft survival rates were 77% in era 1, 93% in era 2, and 94% in era 3 (P =.08). The 1-year pancreas graft survival rates after SKPT were 60% in era 1, 83% in era 2, and 83% in era 3 (P =.06). The incidences of rejection (63% vs. 33% vs. 39%; P<.001) and thrombosis (20% vs. 7% vs. 6%; P<.001) were decreased in eras 2 and 3. CONCLUSION: Simultaneous kidney PTXs with portal enteric drainage can be performed with improved outcomes.

Calcium channel blockade inhibits release of TNF alpha and improves survival in a rat model of acute pancreatitis.

Tumor necrosis factor-alpha (TNF alpha) has been implicated as one of the numerous likely mediators of the systemic complications of acute pancreatitis. Recent suggestions that calcium (Ca2+) acts as a signal not only for TNF alpha release but also for TNF alpha action at distant sites led us to hypothesize that the calcium channel blocker diltiazem could inhibit TNF alpha release in acute pancreatitis, ameliorating the severity of the disease and improving overall survival. A rat model of acute pancreatitis induced by retrograde ductal infusion of bile was used for two experiments (n = 120). Experiment 1 was designed to determine the effects of calcium channel blockade using diltiazem on the severity of pancreatitis as measured by changes in biochemistry, pathology, and serum TNF alpha levels. In experiment 2, effects of calcium channel blockade on animal survival were measured over 72 h. Calcium channel blockade was associated with a significant reduction in serum TNF alpha levels as well as amelioration of pancreatitis by biochemical and pathological criteria. Overall survival from bile-induced pancreatitis was dramatically improved in rats pretreated with diltiazem (80%) compared to untreated animals (40%). Our data suggest that calcium channel blockade is associated with TNF alpha inhibition and improved outcome in a rat model of acute pancreatitis.

Temporal correlation of tumor necrosis factor-alpha release, upregulation of pulmonary ICAM-1 and VCAM-1, neutrophil sequestration, and lung injury in diet-induced pancreatitis.

Lung injury is a major cause of patient morbidity in acute pancreatitis. The purpose of this study was to examine the mechanism of pulmonary infiltration and lung injury in acute pancreatitis. Mice were fed a choline-deficient/ethionine-supplemented (CDE) diet for 144 hours to induce severe acute pancreatitis. Serum samples were collected for measurement of biochemical markers of disease and for the detection of tumor necrosis factor-alpha (TNF-alpha). Cell surface adhesion molecule expression was quantified by the sensitive radiolabeled dual monoclonal antibody technique. Neutrophil sequestration in lung tissue was measured by the myeloperoxidase assay. Lung injury was determined histologically and lung edema was assessed by wet/dry ratios. Pancreatic injury was demonstrated to occur in all CDE-fed mice, which developed significant hyperamylasemia and hypoglycemia by 48 hours (P <0.0001). Serum TNF-alpha levels increased significantly by 48 hours over baseline values (P <0.02). Expression of intracellular adhesion molecule (ICAM-1) in pulmonary endothelia was significantly increased above baseline by 30% at 48 hours (P <0.02) and peaked at 120 hours by 100% (P <0.0001). Vascular cellular adhesion molecule (VCAM-1) was constitutively expressed at baseline and was upregulated threefold by 48 hours (P <0.0001). Neutrophil infiltration increased gradually 24 hours after ICAM-1 and VCAM-1 were upregulated with significant elevation of myeloperoxidase activity over baseline at 72 hours (7.2 +/- 1.2 vs. 18.1 +/- 2.2 activity units/gram tissue; P <0.05). Neutrophil infiltration peaked at 144 hours (26.24 +/- 10.49 activity units/gram tissue P <0.0001), and its kinetics correlated with the onset and progression of morphologic injury as well as increased lung edema. These results show that acute pancreatitis is associated with a systemic release of inflammatory cytokines, followed by increased expression of pulmonary ICAM-1 and VCAM-1, neutrophil infiltration, and histologic lung injury. The adhesion molecule axis may be a potential target for practical intervention to ameliorate lung injury and morbidity in acute pancreatitis.