Acute intracranial complications of temporal bone trauma

BACKGROUND: A total of 110 patients, in whom kidneys from 95 living related and 15 cadaver donor, had experienced renal transplantation between February 1985 and October 1996 in our clinic. This study was conducted to evaluate the influence of the various pre-operative factors to the graft survivals and clinical course of patients in living related renal transplantation. METHODS: In 95 recipients, 17 adult patients had long term graft survivals over 5 years including 6 recurrent or denovo nephritis without chronic allografts nephropathy. Eight failed to graft loss attributed to chronic allografts nephropathy diagnosed within 5 years. Retrospective analysis were performed to elucidate the differences of these recipients. RESULTS: Donors of long graft survival recipients were younger (49.1 +/- 12.1 v.s. 58.9 +/- 10. 2) and had a better renal function evaluated by preoperative creatinine clearance in living related donors (115.5 +/- 37.0 v.s. 79.7 +/- 22.0 1/day). Graft long survival recipients had experienced less frequencies of acute rejection within 6 months (0.53 +/- 0.62: 8 patients, 9 times) compared with chronic allografts nephropathy recipients (1.00 +/- 0.53: 7 patients, 8 times). Long graft survival recipients had better responses to the antirejection therapy. Additionally acute rejection over 6 months were experienced only in chronic allografts nephropathy recipients. Higher serum creatinine level was revealed in recipients with chronic allografts nephropathy at 1 year after transplantation (1.27 +/- 0.27 v.s. 1.88 +/- 0.42 mg/dl). CONCLUSIONS: We concluded that donor age and renal function are related to the graft long survival as background factors. Long graft survival recipients had less frequency of acute rejection and good response to the antirejection therapy. In recipients with of acute rejection and good response to the antirejection therapy. In recipients with chronic allografts nephropathy, serum cretine level had already increased gradually within 1 year.     

Transplantation of pediatric en bloc cadaver kidneys into adult recipients

BACKGROUND: To maximize the renal donor pool, cadaveric pediatric en bloc kidneys have been transplanted as a dual unit by some transplant centers. We compared the short- and long-term outcomes of adult recipients of cadaveric pediatric en bloc renal transplants versus those of matched recipients of cadaveric adult kidneys. METHODS: Thirty-three adults who received pediatric en bloc kidney transplants between April 1990 and September 1997 were retrospectively identified and were compared with 33 matched adults who received adult cadaveric kidney transplants. The groups were identical for transplantation era, immunosuppression, recipient sex, race, cause of renal failure, mean weight, and follow-up duration (37.8 vs. 37.5 months). The mean recipient age study versus control was lower (36.3 vs. 48.9 years, P=0.0003). Results. There was no difference between the en bloc and adult donor groups in the 3-year patient survival rates (95% vs. 87%, P=0.16) or the 3-year graft survival rates (87.3% vs. 84.2%, P=0.35). Further, there was no difference in en bloc patient or en bloc graft survival time stratified by recipient age (14-44 vs. >45 years, P=0.11), en bloc donor age (<24 vs. >24 months, P=0.39), or recipient weight (<60, 61-75, >75 kg; P=0.60). Differences in serum creatinine (mg/dl) for the en bloc versus the control group at the time of discharge (3.0 vs. 7.8 mg/dl, P=0.06), at 1 year (1.4 vs. 2.0 mg/dl, P=0.06), and at 2 years (1.1 vs. 1.6 mg/dl, P=0.14) had dissipated by the time of the 5-year follow-up examination (1.1 vs. 1.6 mg/dl, P=0.14). Vascular complications were more prevalent in the en bloc group: renal vein thrombosis (one case), thrombosis of donor aorta (two cases), arterial thrombosis of one renal moiety (two cases), and renal artery stenosis (two cases). There were no differences between groups in delayed graft function, acute or chronic rejection, posttransplant hypertension, posttransplant protein-uria, or long-term graft function. CONCLUSIONS: Collectively, these data indicate that transplanting pediatric en bloc kidneys into adult recipients results in equivalent patient and graft survival compared with adult cadaveric kidneys. Further, the data also suggest that pediatric en bloc kidneys need not be strictly allocated based on recipient weight or age criteria.     

Deleterious effects of delayed graft function in cadaveric renal transplant recipients independent of acute rejection

BACKGROUND: In cadaveric renal transplantation, delayed graft function (DGF) correlates with poor long-term graft survival; however, whether its effects are independent of acute rejection is controversial. We wished to study the effect of DGF on graft survival, controlling for acute rejection, discharge creatinine, and human leukocyte antigen match. METHODS: We analyzed 27,096 first cadaveric donor renal transplants reported to the UNOS Scientific Renal Transplant Registry between January 1994 and November 1997. DGF was defined as dialysis need in the first week. Acute rejection was recorded for initial hospitalization and within 6 months. Kaplan Meier survival curves were analyzed with the log rank test. RESULTS: DGF increased the incidence of acute rejection before discharge (8% without DGF; 25% with DGF, P<0.01) and any acute rejections by 6 months (25% without DGF, 42% with DGF, P<0.01). Without early rejection, DGF reduced 1-year graft survival from 91 to 75% (P<0.0001) and graft half-life from 12.9 to 8.0 years. In kidneys with acute rejection within 6 months, DGF decreased 3-year graft survival from 77 to 60% and graft half-life from 9.4 to 6.2 years (P<0.001). With a discharge creatinine of less than 2.5 mg/dl, the difference in graft half-life between no DGF and no rejection (13.4 years) and DGF with rejection (9.8 years) was significant (P<0.001). Increased donor age and cold ischemia time additionally decreased graft survival, whereas a good human leukocyte antigen match could not overcome the deleterious effects of DGF or acute rejection. CONCLUSIONS: DGF is an important independent predictor of poor graft survival. Newer immunosuppressive strategies must minimize nonimmune and immune renal injury if long-term graft survival is to improve.     

Determinants of graft survival after renal transplantation

We studied multiple determinants of graft survival at a single center and the effects of nonimmunologic graft loss on transplant survival. This retrospective study examined the results of 589 cadaver donor transplants performed between 1986 and 1992. Graft survival rates were calculated using Kaplan-Meier estimates for both overall graft survival (all causes of graft loss) and immunologic graft survival (function lost due to acute or chronic rejection and noncompliance). Cadaver graft survival was significantly poorer with an increasing degree of DR mismatch (P=0.02). An analysis of pretransplant variables showed graft loss risk was highest with greater DR mismatches, two B-antigen mismatch, higher donor serum creatinine, and younger recipient age. After transplantation, acute rejection was the most significant factor associated with long-term graft survival. Our data demonstrate a significant advantage for zero DR and one DR mismatch cadaver donor transplants, with excellent immunologic graft survival. This study suggests that a combination of immediate graft function, prevention of acute rejection by appropriate early immunosuppressive therapy, and acceptable DR match enhances cadaveric graft survival.     

HLA-identity--long-term renal graft survival, acute vascular, chronic vascular, and acute interstitial rejection

The object is analysis of the impact of acute and chronic rejection on long-term function in HLA-identical renal transplants performed from 1967 to 1995 by the Saskatchewan Renal Transplant Unit. Forty-eight grafts in 46 patients were studied, of which 39 were first and nine second grafts. Forty-two were for primary and six for secondary renal disease. Thirty-five received azathioprine/prednisone prophylaxis, and 13 received cyclosporine/prednisone with/without azathioprine. Ten-year all graft actuarial survival was 84%, 10-year actuarial graft survival in patients with primary renal disease 90%, and with subsequent graft after first HLA graft failed 97.5%, for age-matched population 98.5% (P=NS). Overall death rate was 8.7% (4/46); in secondary renal disease patients 50% (3/6); in primary renal disease patients 2.5% (1/40, P=0.004). All (9/9) HLA-identical second grafts functioned. Acute rejection with azathioprine/prednisone prophylaxis occurred in 55% (9/17) of grafts treated with <6 pre-graft blood transfusions, with the same prophylaxis but >5 units in 12% (2/16, P=0.015), and with cyclosporine prophylaxis in 13% (2/15, P=0.021). Pulse steroids alone reversed all acute rejection. Grafts failed in 6.2% (3/48), all in primary renal disease patients and one from technical one noncompliance, and one chronic rejection. Graft cost/patient/year amortized over 9 years is $3,855 and comparable dialysis cost would be $35,650; cost for all patients on dialysis for 9 years would be $11,293,320 while comparable graft cost was 1,221,418, a savings of 89.2%. Our conclusions are that HLA-identity associates with the following: (1) a 10-year actuarial survival in primary renal disease that equals that of the age-matched population, (2) uniform success in repeat grafts, (3) virtual absence of chronic rejection despite a high incidence of acute rejection in azathioprine/prednisone grafts that (4) always reversed on pulse steroids, and (5) a cost reduction for grafting of 93.2% compared with dialysis therapy.     

Effect of race on outcome after kidney and kidney-pancreas transplantation in type 1 diabetic patients

OBJECTIVE: The racial impact on graft outcome is not well defined in diabetic recipients. The purpose of this study is to analyze our experience with kidney-alone (A) and kidney-pancreas (KP) transplantation in type 1 diabetic recipients and evaluate the impact of racial disparity on outcome. RESEARCH DESIGN AND METHODS: The records of 217 kidney transplants (118 KA, 99 KP) performed on type 1 diabetic patients between 1985 and 1995 at the Medical University of South Carolina and the University of Texas Medical Branch were reviewed. RESULTS: A total of 53 (31%) white patients and 15 (33%) black patients experienced at least one episode of biopsy-proven acute rejection of the renal graft (NS). Patient survival at 1, 2, and 5 years was similar in white (92, 87, 69%) and black (91, 91, 69%) patients (NS). Kidney graft survival at 1, 2, and 5 years in the KA group was 72, 62, and 42% in blacks, compared with 79, 76, and 53% in whites (NS). Kidney graft survival at 1, 2, and 5 years in the KP group was 92, 92, and 74% in blacks, compared with 83, 77, and 58% in whites (NS). Pancreas graft survival at 1, 2, and 5 years was 81, 81, and 81% in blacks, compared with 81, 75, and 62% in whites (NS). Cox regression analysis revealed that donor age > or = 40 years increased the risk of renal graft failure 6.2-fold (P = 0.0001), whereas the addition of a pancreas transplant to a kidney and a living-related transplant decreased the risk of failure of the kidney graft 0.2 (P = 0.005) and 0.1 times (P = 0.005). CONCLUSIONS: Our results suggest that when compared with whites, there may be a trend toward an improved kidney and pancreas graft outcome in blacks undergoing KP transplants. These findings suggest that diabetes may override the risk factors that account for the pronounced disparity in outcome observed between nondiabetic white and black recipients.     

Long-term improvement in renal function after cyclosporine reduction in renal transplant recipients with histologically proven chronic cyclosporine nephropathy

BACKGROUND: Chronic cyclosporine (CsA) nephropathy, which has been unequivocally documented in recipients of heart, heart-lung, liver, or bone marrow transplants, as well as in nontransplant situations, usually results in a progressive deterioration of renal function. In this study, we assessed the potential reversibility of chronic CsA nephropathy in renal transplant recipients. PATIENTS AND METHODS: Twenty-three renal transplant patients with biopsy-proven CsA nephropathy associated with long-term CsA administration (27+/-4 months) were followed up for more than 2 years after CsA reduction (18/23 patients) or withdrawal (5/23 patients) and addition of azathioprine. Changes in effective renal plasma flow and glomerular filtration rate were assessed before and 2 years after CsA reduction, whereas serum creatinine, proteinuria, blood pressure, and CsA concentrations were monitored up to 5 years. RESULTS: At 2-year follow-up, glomerular filtration rate increased from 40+/-3 to 47+/-4 (P<0.05) and effective renal plasma flow from 217+/-23 to 244+/-24 ml/min/1.73 m2 (NS). Mean arterial pressure significantly decreased from 98.7+/-2.9 to 93.1+/-2.7 mmHg (P<0.05). There was no significant change in renal vascular resistance, filtration fraction, or albumin excretion. A significant decrease in serum creatinine was also observed during the whole follow-up (73+/-6.5 months). CsA reduction was followed by only one episode of acute reversible rejection; chronic rejection developed in three patients 2 years or later after CsA reduction. CONCLUSIONS: These data suggest that CsA nephropathy participates in graft dysfunction in a small group of renal transplant recipients. In addition, graft dysfunction may be reversible when CsA dosage is reduced early after diagnosis of chronic CsA nephropathy.     

Steroid-free immunosuppression after kidney transplantation with antithymocyte globulin induction and cyclosporine and mycophenolate mofetil maintenance therapy

BACKGROUND: Our goal in clinical renal transplantation is to find immunosuppressive procedures that not only promote long-term patient and graft survival but also improve the overall well-being of the patients. METHODS: In a retrospective consecutive clinical study with historical controls, 68 patients were discharged from our center with functioning grafts between September 1995 and December 1997. Patients received steroid-free immunosuppression using an initial 10-day antithymocyte globulin induction and maintenance therapy with cyclosporine and mycophenolate mofetil (MMF). No steroids were given. RESULTS: After an observation for up to 2.5 years (median 488 days, range 127 to 945 days), 66 patients (one died from sepsis after 6 months, and one died of peritonitis after returning to dialysis) were alive and well. Sixty-four grafts were functioning well, hemolytic uremic syndrome recurred in one graft, one graft had to be removed for noncompliance, and two patients returned to dialysis after chronic rejection-one after 8 months (the patient who died in peritoneal dialysis) and one (a third graft in an antibody-positive patient) 16 months after transplantation. We observed only 10 acute rejections (15%), a rate significantly lower (P=0.0006) than the 71 acute rejections observed in 190 previous consecutive transplants (37.4%) treated without MMF but otherwise after exactly the same protocol. In further comparison, the MMF-treated group also showed an equivalent (P=NS) rate of cytomegalovirus infections and a lower rate (P<0.00005) of Epstein-Barr virus infections. Graft function was excellent (median serum creatinine below 200 micromol/L at 1 year), and no malignancies were observed in the MMF-treated patients. Side effects were mainly leukopenia and two gastrointestinal disturbances. CONCLUSIONS: Our first-line, steroid-free immunosuppressive protocol allows initial graft function, provides a safe level of long-term graft survival and function with a very low rejection rate, gives an acceptable rate of side effects, and possesses the potential for lowering the incidence of chronic rejection over the long-term. Compared with protocols that discontinue steroids after the initial posttransplant period, a steroid-free protocol avoids the increased risk of infection and body disfigurement in the early posttransplant period. It also avoids the long-term risks of steroid use and the increased risks of rejection when the steroids are withdrawn.     

Metabolic factors have a major impact on kidney allograft survival

BACKGROUND: At the present time, late graft loss is the major cause of kidney failure after transplantation. However, the influence of metabolic factors on this process is ill-defined. METHODS: To identify the impact of lipid metabolism, glucose metabolism, and blood pressure and their prognostic value for graft survival, data for all recipients of a kidney allograft with a potential graft survival of >15 years and a minimum graft survival of 1 month were analyzed retrospectively. Recipients of kidney grafts functioning more than 15 years (n=32) were compared with those with a graft function of less than 10 years (n=152, controls) and evaluated in a multivariate analysis. RESULTS: Low levels of serum cholesterol, triglycerides, and glucose, before and after transplantation, were accompanied by a prolonged graft survival. Prognostic factors for early graft failure included serum triglycerides >300 mg/dl, cholesterol >250 mg/dl before transplantation, serum creatinine >4.0 mg/dl 1 month after transplantation, and donor age above 45 or less than 10 years. Additionally, systolic and, particularly, diastolic blood pressure was lower in the group with a prolonged graft function as compared with controls immediately before and after transplantation. In addition, the incidence of primary graft function was lower and the incidence of acute rejection episodes higher in controls. Cold and warm ischemic time, body mass index, recipient age, and gender did not differ significantly. CONCLUSIONS: Our data suggest that metabolic parameters play an important role in the process of late graft loss after kidney transplantation.     

Results of allogeneic bone marrow transplants for leukemia using donors other than HLA-identical siblings

PURPOSE: To compare outcomes of bone marrow transplants for leukemia from HLA-identical siblings, haploidentical HLA-mismatched relatives, and HLA-matched and mismatched unrelated donors. PATIENTS: A total of 2,055 recipients of allogeneic bone marrow transplants for chronic myelogenous leukemia (CML), acute myelogenous leukemia (AML), and acute lymphoblastic leukemia (ALL) were entered onto the study. Transplants were performed between 1985 and 1991 and reported to the International Bone Marrow Transplant Registry (IBMTR). Donors were HLA-identical siblings (n = 1,224); haploidentical relatives mismatched for one (n = 238) or two (n = 102) HLA-A, -B, or -DR antigens; or unrelated persons who were HLA-matched (n = 383) or mismatched for one HLA-A, -B, or -DR antigen (n = 108). HLA typing was performed using serologic techniques. RESULTS: Transplant-related mortality was significantly higher after alternative donor transplants than after HLA-identical sibling transplants. Among patients with early leukemia (CML in chronic phase or acute leukemia in first remission), 3-year transplant-related mortality (+/-SE) was 21% +/- 2% after HLA-identical sibling transplants and greater than 50% after all types of alternative donor transplants studied. Among patients with early leukemia, relative risks of treatment failure (inverse of leukemia-free survival), using HLA-identical sibling transplants as the reference group, were 2.43 (P < .0001) with 1-HLA-antigen-mismatched related donors, 3.79 (P < .0001) with 2-HLA-antigen-mismatched related donors, 2.11 (P < .0001) with HLA-matched unrelated donors, and 3.33 (P < .0001) with 1-HLA-antigen-mismatched unrelated donors. For patients with more advanced leukemia, differences in treatment failure were less striking: 1-HLA-antigen-mismatched relatives, 1.22 (P = not significant [NS]); 2-HLA-antigen-mismatched relatives, 1.81 (P < .0001); HLA-matched unrelated donors, 1.39 (P = .002); and 1-HLA-antigen-mismatched unrelated donors, 1.63 (P = .002). CONCLUSION: Although transplants from alternative donors are effective in some patients with leukemia, treatment failure is higher than after HLA-identical sibling transplants. Outcome depends on leukemia state, donor-recipient relationship, and degree of HLA matching. In early leukemia, alternative donor transplants have a more than twofold increased risk of treatment failure compared with HLA-identical sibling transplants. This difference is less in advanced leukemia.     

Experience of 28 deliveries in 21 kidney transplant recipients

BACKGROUND: Risk factors to induce graft dysfunction during pregnancy in kidney transplant recipients were studied. METHODS: A total of 28 deliveries from 21 female kidney transplant recipients were analyzed. RESULTS: All recipients were maintained on either azathioprine-based (n = 17) or cyclosporine-based (n = 11) immunosuppressive regimens. Graft dysfunction (creatinine clearance < 40 ml/min) occurred in 8 cases (8 patients) during pregnancy. No acute rejection, however, could be observed. In a case-controlled study comparing a group with graft dysfunction vs. a group with good graft function, there were significantly differences in the incidence of the cases with pre-existing hypertension (62.5% vs. 10.0%), the age of the grafted kidney (58.1 vs 47.6 year), the maternal anemia (Hb: 10.3 vs. 11.8 g/dl) and the creatinine level (1.4 vs. 1.0 mg/dl) at the first trimester. These findings suggested that poorer graft function had been underlying before pregnancy and that additional loading of the pregnancy reduced further graft function, while the deterioration would be recovered after delivery in all cases except one case. CONCLUSION: Risk factors to induce graft dysfunction during pregnancy are as follows. 1) high age of the grafted kidney (> 50 year), 2) pre-existing hypertension, 3) maternal anemia (Hb: < 11 g/dl) and 4) high creatinine level (> 1.3 mg/dl) at the first trimester.     

CsA levels in the early posttransplant period--predictive of chronic rejection in liver transplantation?

The increasing success of clinical liver transplantation has brought rejection to the forefront as a cause of morbidity and graft loss. The relationship of immunosuppressive drug doses and levels to acute and chronic rejection remains a matter of debate. The effect of blood CsA levels and drug doses on the incidence of acute and chronic rejection and the impact of acute rejection episodes on the occurrence of chronic rejection were studied in 146 grafts in 132 patients. These patients were transplanted in the 4-year period from June 1989 using CsA-based immunosuppression (CsA, azathioprine, prednisolone). Liver grafts in patients maintained on median CsA levels (whole blood, trough level) of > or = 175 micrograms/L in the first 28 days posttransplant had a significantly lower incidence of chronic rejection (2 out of 49 vs. 22 out of 97; P = 0.002). There was no significant difference in incidence of graft loss due to fatal sepsis (6% vs. 5%) or nephrotoxicity between the high and low CsA level groups. The overall graft loss rate was lower in the higher CsA level group (22% vs. 37%). The total doses of the individual drugs did not correlate with the incidence of acute or chronic rejection. Although the occurrence of acute rejection itself did not determine later chronic rejection, late occurrence (P < 0.00001) and multiple episodes (two or more; P = 0.0002) of acute rejection were significant risk factors for the occurrence of chronic rejection. We conclude that to minimize graft loss to rejection, CsA levels should be maintained at greater than 175 micrograms/L in the early posttransplant period, and late and recurrent episodes of acute rejection should be prevented.     

Identification of regulatory elements of human alpha 6 integrin subunit gene

BACKGROUND: A study was performed by 17 different U.S. liver transplantation centers to determine the safety and efficacy of conversion from cyclosporine to tacrolimus for chronic allograft rejection. METHODS: Ninety-one patients were converted to tacrolimus a mean of 319 days after liver transplantation. The indication for conversion was ongoing chronic rejection confirmed by biochemical and histologic criteria. Patients were followed for a mean of 251 days until the end of the study. RESULTS: Sixty-four patients (70.3%) were alive with their initial hepatic allograft at the conclusion of the study period and were defined as the responder group. Twenty-seven patients (29.7%) failed to respond to treatment, and 20 of them required a second liver graft. The actuarial graft survival for the total patient group was 69.9% and 48.5% at 1 and 2 years, respectively. The actuarial patient survival at 1 and 2 years was 84.4% and 81.2%, respectively. Two significant positive prognostic factors were identified. Patients with a total bilirubin of < or = 10 mg/dl at the time of conversion had a significantly better graft and patient survival than patients converted with a total bilirubin > 10 mg/dl (P=0.00002 and P=0.00125, respectively). The time between liver transplantation and conversion also affected graft and patient survival. Patients converted to tacrolimus < or = 90 days after transplantation had a 1-year actuarial graft and patient survival of 51.9% and 65.9%, respectively, compared with 73.2% and 87.7% for those converted > 90 days after transplantation. The mean total bilirubin level for the responder group was 7.1 mg/dl at the time of conversion and decreased significantly to a mean of 3.4 mg/dl at the end of the study (P=0.0018). Thirteen patients (14.3%) died during the study. Sepsis was the major contributing cause of death in most of these patients. CONCLUSIONS: Our results suggest that conversion to tacrolimus for chronic rejection after orthotopic liver transplantation represents an effective therapeutic option. Conversion to tacrolimus before development of elevated total bilirubin levels showed a significant impact on long-term outcome.     

Pancreatitis-associated protein: a putative marker for pancreas graft rejection

BACKGROUND: Graft rejection is one of the major causes of graft loss after pancreas transplantation. Pancreatitis-associated protein (PAP) is synthesized by the pancreas due to pancreatic inflammation and has shown to be a good serum marker for injury of the pancreas. It may also be potentially useful in the early recognition of rejection and may thus improve pancreas survival. METHODS: We retrospectively evaluated PAP as an early serum marker of pancreas graft rejection in a cross-sectional study in which immunohistochemical analysis of pancreas biopsies was undertaken using antibodies against PAP. PAP concentrations were also measured in sera of blood donors and in patients with renal failure, renal replacement therapy, kidney transplantation alone, and simultaneous pancreas-kidney transplantation. RESULTS: All patients had elevated PAP serum levels compared with blood donors (median PAP: 22 ng/ml, range: 5-75 ng/ml; P<0.0001). Patients on renal replacement therapy had higher values than patients with renal failure (median: 420 ng/ml and 150 ng/ml, respectively). There was a strong inverse correlation between PAP levels and creatinine clearance (P<0.001). PAP values in simultaneous pancreas-kidney transplantation patients with histological rejection were significantly higher than values in those who were clinically stable (median: 925 ng/ml and 322 ng/ml, respectively; P=0.006). Rejection was significantly associated with PAP staining of acinar cell surface. There was also a significant correlation between surface positivity of staining and serum PAP levels (P=0.008). No positive PAP staining was observed in concurrently collected biopsies of renal allografts undergoing rejection. CONCLUSIONS: Serum PAP levels appear to strongly correlate with creatinine clearance measurements. In patients with a pancreas-kidney transplantation, PAP may prove to be a useful biological and histological marker of pancreatic graft rejection.     

Primary immunosuppression with mycophenolate mofetil and antithymocyte globulin for kidney transplant recipients of a suboptimal graft

BACKGROUND: In renal transplantation the beneficial immunosuppressive effects of cyclosporin (CsA) may be curtailed by its nephrotoxicity, specially in patients receiving a cadaveric allograft from suboptimal donors or at risk of delayed graft function. Mycophenolate mofetil (MMF) and antithymocyte globulin (ATG) have each demonstrated to be potent immunosuppressants in renal transplantation. In a prospective analysis we have studied the results at 6 months of the combination of MMF, ATG and low-dose steroids in patients with low immunological risk receiving a first cadaveric renal allograft from a suboptimal donor or at risk of delayed graft function. METHODS: Patients with preformed reactive antibodies < 500% receiving a first graft from a suboptimal donor (age > or = 40 years, non-heart-beating, acute renal failure, arterial hypertension) or at risk of delayed graft function (cold ischaemia time > or = 24 h) were eligible for this open single-arm pilot trial. From September 1996 to March 1997 we recruited 17 patients. They were treated with MMF 2 g p.o. preoperatively, and after transplantation at 3 g/day; rabbit ATG i.v. at 2 mg/kg preoperatively, and 1.5 mg/kg/day the first day after transplantation, followed by four doses of 1 mg/kg on alternate days; prednisone was given at 0.25 mg/kg/day and reduced progressively to 0.1 mg/kg/day at 3 months. Primary outcomes were incidence of biopsy-proven acute rejection, delayed graft function, opportunistic infections, graft and patient survival, and the need for introduction of CsA treatment. RESULTS: delayed graft function occurred in two cases (12%). Four of 17 patients (24%) had a biopsy-proven acute rejection (2 grade I and 2 grade II) within the first 3 months after transplantation. CsA was added in two cases with grade II biopsy-proven acute rejection, and in one with grade I biopsy-proven acute rejection. In one patient MMF was replaced by CsA because of gastrointestinal intolerance. Mean serum creatinine 6 months after transplantation was 159+/-59 micromol/1. Cytomegalovirus tissue invasive disease occurred in one patient (6%). At 6 months follow-up all patients are alive with functioning allografts. CONCLUSIONS: These preliminary results suggest that in low-immunological-risk patients who receive a suboptimal renal allograft or at risk of delayed graft function, the combination of MMF, ATG, and steroids is an efficient immunosuppressive regime that may avoid the use of CsA in 70% of the recipients.     

Histopathologic findings from 2-year protocol biopsies from a U.S. multicenter kidney transplant trial comparing tarolimus versus cyclosporine: a report of the FK506 Kidney Transplant Study Group

BACKGROUND: This paper reports the histopathologic results of 2-year protocol biopsies from patients who were enrolled in the U.S. FK506 kidney transplant study . METHODS: Recipients of cadaveric kidney transplants were randomized to tacrolimus or cyclosporine therapy. Patients active in the trial at 2 years after transplantation were approached for a protocol biopsy. Biopsies were scored by the Banff classification in a blinded fashion by one pathologist. RESULTS: A total of 144 patients (41.3% of those active at 2 years) had a 2-year protocol biopsy performed; 79 patients were treated with tacrolimus and 65 patients were treated with cyclosporine. Evidence of acute rejection was found in seven (8.9%) of the 2-year biopsies in tacrolimus-treated patients and six (9.2%) cyclosporine-treated patients. Chronic allograft nephropathy was found in 49 (62.0%) tacrolimus biopsies and 47 (72.3%) cyclosporine biopsies (P=0.155). There were no apparent histopathologic differences between the tacrolimus and cyclosporine biopsies. The occurrence of chronic allograft nephropathy was significantly higher in patients who received a graft from an older donor (P<0.01), who experienced presumed cyclosporine or tacrolimus nephrotoxicity (P<0.001), who developed a cytomegalovirus infection (P=0.038), or who experienced acute rejection in the first year after transplantation (P=0.045). A multivariate analysis showed that nephrotoxicity and acute rejection were the most significant predictors for chronic allograft nephropathy. CONCLUSIONS: The occurrence of histologic acute rejection was rare at 2 years, confirming the absence of subclinical acute rejection in these late biopsies. A majority of the biopsies showed features consistent with chronic allograft nephropathy that was associated with acute rejection (particularly in cyclosporine-treated patients), nephrotoxicity, and cytomegalovirus infection in the first year. This suggests that nonimmunologic factors, such as drug-induced toxicity, may play an important role in chronic allograft nephropathy.     

1,5-anhydroglucitol as a marker for the differential diagnosis of acute and chronic renal failure

Serum creatinine and 1,5-anhydroglucitol (1,5-AG) were measured in 21 non-dialysis acute renal failure (ARF) and 32 chronic renal failure (CRF) patients. Fasting blood glucose was under 100 mg/dl and no patient had a history of diabetes mellitus. Serum 1,5-AG decreased with increase in serum creatinine in CRF, but not in ARF patients. A significant negative correlation was found between serum 1,5-AG and creatinine in CRF patients (r = -0.592, p < 0.001). Serum 1,5-AG in patients with serum creatinine of 4 mg/dl or more was less than the lowest limit of the normal range in 14 of 15 CRF patients, but only 2 of 12 ARF patients. In these 27 patients, serum 1,5-AG was significantly higher in ARF than CRF (19.0 +/- 5.9 vs. 7.2 +/- 4.1 micrograms/ml, p < 0.01). From these results, it would follow that serum 1,5-AG should serve effectively as a marker for the differential diagnosis of nondiabetic ARF and CRF.     

The dipsogen angiotensin II does not stimulate ethanol intake in mice

The Banff classification of acute rejection is based on histologic grades and scores for borderline changes, glomerular, vascular, interstitial and tubular lesions. We reviewed 56 episodes of acute rejection occurring in 44 kidney allograft recipients (30 cadaveric and 14 living donor transplants), comparing Banff classification to degree of reversibility of rejection. Rejection reversal was defined as complete if serum creatinine returned < or = 25% of baseline, partial if creatinine was > 25% to < 75% of baseline, and irreversible if creatinine was > or = 75% of baseline or graft loss occurred. Eight biopsies were classified as borderline (SUM score 1.6 +/- 0.5), 14 grade I (SUM score 3.3 +/- 0.4), 19 grade II (SUM score 4.2 +/- 0.3), and 15 grade III (SUM score 8.5 +/- 0.4). SUM distinguished borderline and grade III rejections, but not grades I and II. Clinically, grade and SUM score correlated with rejection reversal. Complete reversal of rejection occurred in 93% of patients with grade I rejection, while 47% of patients with grade III had irreversible rejection. The mean SUM for complete reversal was 3.9 +/- 0.34 and was different from SUM of partial (6.0 +/- 0.86) and irreversible (8.5 +/- 0.93), P < 0.006. Meanwhile, vascular scores were similar for rejections with complete (0.9 +/- 0.2) or partial (1.0 +/- 0.4) reversal, but significantly higher in those with irreversible rejection (3.0 +/- 0.4, P < 0.000). Likewise, mean scores for tubulitis and interstitial inflammation were significantly higher for irreversible rejection. Resolution of rejection by steroids was correlated to low vascular score (steroid sensitive 0.65 +/- 0.25 vs. steroid resistant 1.42 +/- 0.18, P < 0.01), and low SUM score (steroid sensitive 3.7 +/- 0.5 vs. steroid resistant 5.22 +/- 0.43, P < 0.04). Neither scores for tubulitis nor interstitial cellular inflammation were predictive of steroid sensitivity. These data demonstrate that Banff scoring has clinical relevance in predicting rejection reversal and has implications to first-line therapy of rejection episodes.     

A comparison of tacrolimus (FK506) and cyclosporine for immunosuppression after cadaveric renal transplantation. FK506 Kidney Transplant Study Group

BACKGROUND: Tacrolimus (FK506), a macrolide molecule that potently inhibits the expression of interleukin 2 by T lymphocytes, represents a potential major advance in the management of rejection following solid-organ transplantation. This randomized, open-label study compared the efficacy and safety of tacrolimus-based versus cyclosporine-based immunosuppression in patients receiving cadaveric kidney transplants. METHODS: A total of 412 patients were randomized to tacrolimus (n=205) or cyclosporine (n=207) after cadaveric renal transplantation and were followed for 1 year for patient and graft survival and the incidence of acute rejection. RESULTS: One-year patient survival rates were 95.6% for tacrolimus and 96.6% for cyclosporine (P=0.576). Corresponding 1-year graft survival rates were 91.2% and 87.9% (P=0.289). There was a significant reduction in the incidence of biopsy-confirmed acute rejection in the tacrolimus group (30.7%) compared with the cyclosporine group (46.4%, P=0.001), which was confirmed by blinded review, and in the use of antilymphocyte therapy for rejection (10.7% and 25.1%, respectively; P<0.001). Impaired renal function, gastrointestinal disorders, and neurological complications were commonly reported in both treatment groups, but tremor and paresthesia were more frequent in the tacrolimus group. The incidence of posttransplant diabetes mellitus was 19.9% in the tacrolimus group and 4.0% in the cyclosporine group (P<0.001), and was reversible in some patients. CONCLUSIONS: Tacrolimus is more effective than cyclosporine in preventing acute rejection in cadaveric renal allograft recipients, and significantly reduces the use of antilymphocyte antibody preparations. Tacrolimus was associated with a higher incidence of neurologic events, which were rarely treatment limiting, and with posttransplant diabetes mellitus, which was reversible in some patients.     

Evolution of glomerular basement membrane changes in chronic rejection

We have investigated the evolution of chronic glomerular changes in the absence of the recurrence of original disease in an experimental rat model of chronic renal allograft rejection. Using serial graft needle biopsies and serum creatinine levels, we were able to focus on early glomerular changes that are associated with good graft function. The recipient rats were divided into 5 groups, 2 with allogeneic (DA to WF) transplants and 3 with syngeneic (DA to DA) transplants. In the first 2 allogeneic groups, one group received cyclosporine (CsA) for 2 weeks (n = 7) and the other received CsA for 12 weeks (n = 5). In the 2-week treatment group, all allografts developed chronic rejection, compared with none in the 12-week group. Syngeneic controls received CsA for 2 (n = 3) and 12 weeks (n = 3), or no immunosuppression (n = 2) in order to exclude the effects of CsA. The first detectable ultrastructural event was slight deposition of electron lucent material in the glomerular basement membrane. Contrary to previous morphological studies, the initial deposition was not subendothelial, but was within the lamina densa itself. Examination of allogeneic grafts with good graft function and syngeneic grafts showed glomerular alterations that were similar to the early changes preceding chronic rejection. The intensity of changes in optimally immunosuppressed allografts was mild, and they were arrested early in the evolving stage of glomerular basement membrane changes. In the suboptimally immunosuppressed allografts with chronic rejection, the glomerular basement membrane changes became more pronounced and extensive in subsequent biopsies. Thus, all recipients in different groups showed similar glomerular alterations, but to different intensities. These results suggest a common pathogenetic mechanism which might be endothelial damage. In chronic rejection, the endothelial damage might be immunologically mediated by rejection episodes and progressive, whereas in syngeneic grafts and in allografts without chronic rejection, perioperative trauma, ischemia, and graft reperfusion may be responsible for the self-limiting glomerular changes.