Pilot study of rapid steroid elimination with alemtuzumab induction therapy in kidney and pancreas transplantation.

This study evaluates our initial experience using alemtuzumab induction with rapid corticosteroid elimination in kidney (KTX) and pancreas transplant (PTX) patients. Data were collected retrospectively for all patients who received single-dose alemtuzumab (30 mg IV intraoperatively) with steroid pretreatment and a control group who received alternate day rabbit antithymocyte globulin (rATG) induction with a steroid-based regimen. Patients in both groups received tacrolimus (TAC) and mycophenolate mofetil (MMF). There were 16 patients in each group, including 9 deceased donor KTXs, 5 living donor KTXs, 1 simultaneous K-PTX, and 1 sequential PTX after KTX. Demographic, immunologic, and transplant characteristics were similar between groups. Nine patients (56%) in the alemtuzumab group compared to five (25%) in the control group developed neutropenia requiring MMF or valganciclovir dose reduction (or both). Absolute lymphocyte counts at 3 months were 340 +/- 200/mm3 and 890 +/- 544/ mm3 in the alemtuzumab and control groups, respectively (P = .001). There were two biopsy-proven acute rejection episodes (12.5%) in each group, and no difference in the incidence of infection. Creatinine clearance at 6 months was 58 mL/min in each group. Patient and kidney graft survival rates were both 94% in the alemtuzumab group (one death from cardiac arrest), compared with 100% patient and kidney graft survival rates in the control group (P = NS), with a mean follow-up of 9 and 11 months, respectively. The results of this pilot study suggest that similar short-term outcomes can be achieved using a rapid steroid elimination protocol with alemtuzumab induction therapy compared to rATG with steroids in patients receiving TAC and MMF maintenance therapy.

Successful simultaneous kidney-pancreas transplantation from extreme donors.

UNLABELLED: The purpose of this study was to retrospectively review our experience with "extreme" pancreas donors compared to conventional (CONV) donors. METHODS: "Extreme" (EX) pancreas donors were defined as deceased donors (DDs) age >50 years, <8 years, donation after cardiac death (DCD), and targeted for organ discard. RESULTS: From January 2002 through January 2005, we performed 40 simultaneous kidney-pancreas transplants (SKPT) with Thymoglobulin induction, including 9 (22.5%) from EX and 31 from CONV DDs. Mean DD age was higher in EX DD (41.2 years EX vs 26.0 CONV, P < .05), but mean recipient age and cold ischemia times did not differ between groups. With a mean follow-up of 16.8 months in the EX DD group, patient and kidney graft survival rates are both 100%, and the pancreas graft survival rate is 89%. With a mean follow-up of 21.7 months in the CONV DD group, patient and kidney graft survival rates are both 93.5% and the pancreas graft survival rate is 77.4%. All patients with surviving grafts exhibited good initial (1 case of delayed kidney graft function in a CONV DD) and stable long-term kidney and pancreas graft function. Mean length of initial hospital stay and the incidences of acute rejection, readmissions, operative complications, and infections were similar between groups. CONCLUSIONS: The results of this study suggest that the limits of donor acceptability continue to evolve as excellent outcomes can be achieved in SKPTs from selected EX DDs.

Experience with alternate-day thymoglobulin induction in pancreas transplantation with portal-enteric drainage.

The purpose of this study was to retrospectively review outcomes in patients undergoing pancreas transplantation (PTX) with a novel induction protocol of alternate-day thymoglobulin (rATG) in combination with tacrolimus (TAC), mycophenolate mofetil (MMF), and steroids. From January 2002 through January 2005, we performed 55 PTXs in 53 patients. The first dose of rATG (1.5 mg/kg) was given intraoperatively, and subsequent doses were given on alternate days until therapeutic TAC levels (>8 ng/mL) were achieved. All patients underwent PTX with enteric drainage, including 51 with portal and 4 with systemic venous drainage. Patients received a minimum of 2 and maximum of 6 doses of rATG induction (median 3 doses). The patient group had a mean age of 42.8 years and included 40 simultaneous kidney-PTX, 11 sequential PTX after kidney, and 4 PTX-alone transplant recipients. Patient, kidney, and pancreas graft survival rates are 96%, 96%, and 84%, respectively, with a mean follow-up of 21 months. The incidence of acute rejection was 18%; there were no graft losses due to isolated acute rejection. The incidence of infection was 60%, but there were no cases of polyomavirus or Epstein-Barr virus infection and only 6 cases (11%) of cytomegalovirus infection. The composite endpoint of no rejection, graft loss, or mortality was attained by 71% of patients. At present, 94% of surviving patients are both dialysis and insulin-free, including 5 successful PTX retransplants. These findings suggest that PTX with portal-enteric drainage and alternate day rATG induction may result in excellent intermediate-term outcomes.

A heterophile system in human renal transplantation. VII. The antigen is an intrinsic component of several human tissues.

The presence or absence of the heterophile transplantation antigen was sought in renal tissue from stillborn infants, primary cell cultures, and several organs from adult human cadavers. The heterophile transplantation antigen was found in renal tissue at birth, was retained in human renal cell culture, and was present in human organs other than kidney. The most likely explanation for these results is that the heterophile transplantation antigen is an intrinsic component of many human tissues.

A heterophile system in human renal transplantation. X. HTA sensitivity includes sensitivity to human B lymphocytes.

Antibodies that react with heterophile transplantation antigen (HTA) have been shown previously not to react with HLA-A, B, or C antigens. This paper presents evidence that anti-HTA does react with a subpopulation of human lymphocytes which is comprised primarily of B cells. Anti-HTA reactivity was removed from sera by absorption with each of three different human B lymphocyte cell lines, but it was unaffected by absorption with platelets or thymocytes. Selected high titer anti-HTA sera absorbed with human platelets, human blood group type AB erythrocytes, and sheep erythrocytes caused lysis of a lymphocyte subpopulation principally composed of B lymphocytes. Absorption of these sera with rat erythrocytes removed both lymphocytic activity and anti-HTA activity. Antibody recovered by affinity purification with rat erythrocyte membrane preparations contained both lymphocytic and anti-HTA reactivity. These data, considered with previous studies, seem to establish that B cell sensitization may be acquired by a substantial segment of the population by natural immunization from enteric flora and/or by infections with enteric bacteria.

A heterophile system in human renal transplantation. IX. Comparison of heterophile transplantation antibodies to antivascular endothelial cell antibodies.

Antibodies to heterophile transplant antigen (HTA) were tested for reactivity with antigens on human umbilical cord antigenic specificities on isolated endothelial cells. Furthermore, there are antigens on endothelial cells that are distinct from HLA-A,B, C, and from HTA. It is concluded that the HTA and the VEC antigens are different.

A heterophile system in human renal transplantation. VIII. The morphological distribution of the antigen in rat tissues.

The morphological distribution of heterophile transplant antigen (HTA) was determined in rat tissues using an indirect immunofluorescence technique. Human anti-HTA sera were used to localize HTA in rat kidney, liver, heart, skeletal muscle, spleen, and stomach. HTA was found in basement membrane and supporting stromal elements of all tissues studied. In the kidney, HTA was demonstrated in tubular basement membrane but not glomerular basement membrane. No evidence for cell surface antigen distribution could be ascertained except for erythrocyte membranes. HTA was not found on endothelium of rat blood vessels. We know of no antigens previously implicated in histocompatibility that are stromal in location.

Beneficial effect of cyclosporine on renal transplantation. A multicenter long-term study.

Data were collected prospectively on 8581 cadaveric renal transplants performed by institutions of the South-Eastern Organ Procurement Foundation (SEOPF) during the period November 1, 1983 through December 31, 1987. Cyclosporine was the initial then always used immunosuppressant for 5742 of these patients while 1050 never received cyclosporine. The drug was started late in the course of 481 transplants and stopped early in 378 cases. This allowed for 7651 transplants to be analyzed regarding these four categories of cyclosporine use or non-use. Actuarial graft survival for the cyclosporine "ALWAYS" group was 75% at one year, 68% at two years, 62% at three years, and 59% at four years compared with 55%, 49%, 45%, and 43%, respectively for the cyclosporine "NEVER" group (P less than 0.0001). Inclusion of the 930 cases that could not be categorized regarding cyclosporine use or for which actuarial data was not complete allowed all 8581 transplants to be analyzed by multivariate methods. This analysis disclosed significant effects on graft survival due to delayed graft function, prior transplant, recipient race, HLA match, level of PRA, and cyclosporine use. Organ sharing had no effect on graft outcome. While cyclosporine improves outcome in renal transplantation, the importance of other biologic factors affecting graft survival is not diminished by its use.

Effects of tacrolimus on hyperlipidemia after successful renal transplantation: a Southeastern Organ Procurement Foundation multicenter clinical study.

BACKGROUND: Tacrolimus has been shown to have a less adverse effect on the lipid profiles of transplant patients when the drug is started as induction therapy. In order to determine the effect tacrolimus has on lipid profiles in stable cyclosporine-treated renal transplant patients with established hyperlipidemia, a randomized prospective study was undertaken by the Southeastern Organ Procurement Foundation. METHODS: Patients of the 13 transplant centers, with cholesterol of 240 mg/dl or greater, who were at least 1 year posttransplant with stable renal function, were randomly assigned to remain on cyclosporine (control) or converted to tacrolimus. Patients converted to tacrolimus were maintained at a level of 5-15 ng/ml, and control patients remained at their previous levels of cyclosporine. Concurrent immunosuppressants were not changed. Levels of total cholesterol, triglycerides, total high-density lipoprotein, low-density lipoprotein (LDL), very-low-density lipoprotein, and apoproteins A and B were monitored before conversion and at months 1, 3, and 6. Renal function and glucose control were evaluated at the beginning and end of the study (month 6). RESULTS: A total of 65 patients were enrolled; 12 patients failed to complete the study. None were removed as a result of acute rejection or graft failure. Fifty-three patients were available for analysis (27 in the tacrolimus group and 26 controls). Demographics were not different between groups. In patients converted to tacrolimus treatment, there was a -55 mg/dl (-16%) (P=0.0031) change in cholesterol, a -48 mg/dl (-25%) (P=0.0014) change in LDL cholesterol, and a -36 mg/dl (-23%) (P=0.034) change in apolipoprotein B. There was no change in renal function, glycemic control, or incidence of new onset diabetes mellitus in the tacrolimus group. CONCLUSION: Conversion from cyclosporine to tacrolimus can be safely done after successful transplantation. Introduction of tacrolimus to a stable renal patient does not effect renal function or glycemic control. Tacrolimus can lower cholesterol, LDL, and apolipoprotein B. Conversion to tacrolimus from cyclosporine should be considered in the treatment of posttransplant hyperlipidemia.

Complications from permanent hemodialysis vascular access.

From 1981 to 1986 a total of 499 operations were performed for permanent hemodialysis vascular access in 230 patients. At least 1 year's follow-up was achieved in all cases. This series is divided into 326 primary procedures and 173 secondary procedures. Of the primary procedures, there were 160 autogenous fistulas and 166 expanded polytetrafluoroethylene (PTFE) fistulas. The 156 secondary procedures consisted of 124 thrombectomies, 20 repairs of pseudoaneurysm, 12 fistula ligations, and 17 fistula excisions. The infectious complication rate (29/482) was 6%. Mean length of patency was 3.1 years for autogenous wrist fistula, 2.6 years for elbow fistula, 1.9 years for forearm loop PTFE, 2.1 years for straight forearm PTFE, 1.6 years for femoral popliteal PTFE, and 1.4 years for femoral arteriovenous loop PTFE. A vascular steal syndrome occurred in 8% of patients with autogenous elbow fistulas (4/48), compared with 1.7% (2/112) of patients with wrist fistulas and 1.8% (3/166) of those with PTFE fistulas. All infected fistulas required excision, and all fistulas associated with the steal syndrome required ligation. Use of PTFE to construct permanent hemodialysis vascular access has a significantly higher incidence of thrombosis, infection, pseudoaneurysm formation, and limb loss (p less than 0.01 for all complications) and a significantly lower mean length of patency (p less than 0.0001) when compared with autogenous fistulas. Age, sex, hypertension, diabetes mellitus, and the use of perioperative antibiotics were not found to be related significantly to access complications.

Arteriovenous fistulas for long-term dialysis. Factors that influence fistula survival.

We reviewed our total experience with arteriovenous (AV) fistulas for long-term hemodialysis. We are unable to show any significant difference in the survival of AV fistulas based either on the type of material used to create the fistulas or on their location. Complications encountered early in this experience largely were due to technical or judgmental errors. Thrombosis of radiocephalic fistulas resulted from failure to use a vein of adequate caliber. Failure of bovine artery heterograft AV fistulas resulted either from wound infection or from the use of a diseased artery that was incapable of delivering sufficient blood to keep the fistula open. Infection around a heterograft fistula frequently was associated with a lymphocele. The meticulous division, between clips or ligatures, of all tissues deep to the skin prevented lymphocele formation.

Use of the inferior epigastric artery to revascularize a lower pole renal artery in renal transplant.

The increasing use of living-related donors has increased the incidence wherein the transplant surgeon is required to use special vascular surgical techniques to transplant kidneys with anomalous arterial anatomy. One of the most commonly encountered arterial anomalies is the presence of a lower pole renal artery. In many cases, this artery can be anastomosed to the main renal artery, and the main renal artery can then be anastomosed into the recipient vessel. However, there are cases where the lower pole renal artery is too distant from the main renal artery to allow an anastomosis to be performed. The lower pole renal artery of the graft must be revascularized to avoid ischemic injury to the ureter. Thus, alternate methods for the revascularization of this vessel must be found. We describe the use of the recipient inferior epigastric artery as an arterial supply for the donor lower pole artery. In our case report, this method provided excellent flow to the lower kidney and was documented by later studies.

High-output cardiac failure secondary to a brachiocephalic arteriovenous hemodialysis fistula: two cases.

The use of native arteriovenous fistulas for hemodialysis access is important to the success of this form of treatment for patients with end-stage renal disease. Native fistulas have been shown to provide improved longevity and to have lower complication rates when compared to prosthetic graft fistulas. High-output cardiac failure related to hemodialysis fistulas is an uncommon complication of their usage. Two renal transplant patients who did develop this complication from large well-developed brachiocephalic arteriovenous hemodialysis fistulas are presented. Both patients underwent successful transplantation and have required fistula ligation, with subsequent resolution of their cardiac failure. Native fistulas remain the best choice for hemodialysis access, but the clinician should remain aware of the possible untoward hemodynamic effects of these fistulas.

Assessing family members' motivational readiness and decision making for consenting to cadaveric organ donation.

This study assessed the applicability of two important components of the transtheoretical model of behavior change (TTM) to family consent for cadaveric organ donation. Men and women (N = 169), who consented or refused to donate the organs of a family member, completed a telephone survey reflecting the stage of change and decisional balance constructs. Psychometric analyses resulted in a two-factor decisional balance scale: a seven-item scale representing negative perceptions of consent (cons), and a seven-item scale representing positive perceptions of consent (pros). The pros and cons were significantly associated with stage of readiness for donation consent and with the family consent decision. Research utilizing this measure has the potential to enhance intervention programs to increase donation consent rates.

Renal allograft acute tubular necrosis. II. A light and electron microscopic study of biopsies taken at procurement and after revascularization.

The light and electron microscopic morphology of 57 cadaver renal allografts was assessed at the time of procurement and again after revascularization. Twenty-two kidneys (39%) did not function immediately after transplantation and 19 of these (86%) contained morphologic evidence of acute tubular necrosis (ATN) in the procurement biopsy. The morphology of the post-transplant biopsy was abnormal in all 22 kidneys with delayed function. There was a wide spectrum of morphologic change between the time of procurement and revascularization in all kidneys with normal function. These changes were mild in nature, were usually confined to proximal tubules, and were of unknown clinical significance. The morphology of kidneys that were damaged by the time of procurement was surprisingly different after storage with simple hypothermia (ice) than after storage with hypothermic pulsatile perfusion. The changes attributed to ice storage included endothelial swelling and vacuolation with obliteration and collapse of capillary lumens, fracture and splitting of peritubular basement membrane, and hyalinization of the renal interstitium. It was unknown whether these morphologic abnormalities were associated with delayed recovery of function of the injured kidneys.

Biopsy-proven resolution of immune complex-mediated crescentic glomerulonephritis with mycophenolate mofetil therapy in an allograft.

We report biopsy-proven resolution of immune-complex-mediated crescentic glomerulonephritis (ICMCGn) using mycophenolate mofetil (MMF). Therapy with steroids and cyclophosphamide failed twice in a 39-year-old white man who developed ICMCGn in his native kidneys, and subsequently in a human lymphocyte antigen-identical renal allograft. When he developed ICMCGn in a second, now cadaver, allograft, he was treated with steroids and MMF instead. His serum creatinine (Cr) improved from 4.4 mg/dL to 2.1 mg/dL. A biopsy 21 months later showed him to be free of glomerular disease. MMF is known to be an effective immunosuppressant. In our patient, ICMCGn, a notoriously difficult entity to treat effectively, seemingly resolved with MMF therapy. We suggest that MMF may be effective in the treatment of immunologically mediated pre-end-stage renal disease (ESRD). It should be considered in any posttransplantation setting where the original cause of organ failure is known to be immunologically mediated and likely to recur.

External ureteroneocystostomy and ureteroureterostomy in renal transplantation.

"External" ureteroneocystostomy is a method of reconstructing the urinary tract for renal transplantation. As performed by us, it is a modification of the technique of Witzel, Sampson, and Lich. It has the advantages of requiring a very short length of ureter, avoiding a separate and large cystotomy, and retaining the antireflux mechanism. This technique is described in detail. Ureteroureterostomy has been used as the preferred procedure when the bladder wall is very thin or when the vascular attachments are such that a ureteral length of greater than 6-7 cm would be required for bladder implantation. Since using these techniques we have reduced the early complication rate of ureteral implantation from 11.9% in a consecutive series of 126 transplants to 0% in the last 88 consecutive transplants. A review of the literature which led to the adoption of these techniques is also presented.

Recent experiences with autotransplantation of the kidney, jejunum, and pancreas.

Ten autotransplants are presented. Renal autografts were performed in the correction of renal artery stenosis, renal artery aneurysm, and intrarenal arteriovenous fistula. All were successful. Jejunal autografts were used to replace the cervical esophagus twice and the entire esophagus once. All grafts were successful, although one patient with advanced cancer died. Pancreatic segmental autografts were used to prevent diabetes following three subtotal pancreatectomies for chronic pancreatitis and one total pancreatectomy for carcinoma. Two patients have functioning grafts, require no insulin, and are free of disease at present. One patient is free of pancreatitis but is diabetic, and one patient died of probable pulmonary embolus. These experiences suggest that organ autografts can be used with greater frequency in clinical surgery and may alter standard therapy for several problems.