Selective corticosteroid and calcineurin-inhibitor withdrawal after pancreas-kidney transplantation utilizing thymoglobulin induction and sirolimus maintenance therapy.

Of 25 simultaneous pancreas-kidney transplant (SPK) recipients treated with thymoglobulin induction, sirolimus and reduced-dose cyclosporine (CsA), 18 low-immune responders (non-African-Americans, PRA < 30%) were withdrawn from prednisone on post-transplant day 5, whereas seven high-immune responders continued on prednisone. Most high- and low-immune responder recipients were converted from CsA to mycophenolic acid (MPA) at six months post-transplantation. At a mean follow-up of 28 +/- 10 months, two pancreas grafts were lost to pancreatitis. There were no patient or kidney graft losses, but one acute rejection episode. At 28 +/- 11 months, all 18 low-responder recipients remain steroid-free. Twenty recipients (14 low and six high-immune responders) were converted from CsA to MPA. During conversion, immune response was monitored by Flow-PRA and T-cell stimulation (Cylex) assays. Nineteen of 20 recipients displayed a post-conversion PRA of 0%, whereas one highly sensitized patient expressed a post-conversion PRA of 67%. Fifty-eight percent of individual T-cell stimulation scores were in the hypo-responsive range. Twelve of 18 low-immune responders are both steroid and CsA-free at a mean follow-up of 17 +/- 13 months, whereas five of seven high-immune responders remain CsA-free at a mean follow-up of 11 +/- 10 months. These data suggest that thymoglobulin induction with combined sirolimus and CsA maintenance therapy permits immunosuppression minimization in selected SPK recipients.

Fibromuscular dysplasia recurrence after kidney transplantation: case report.

We report the extremely rare recurrence of intimal fibroplasia, a rare form of fibromuscular dysplasia, in a kidney recipient at 6 months after transplantation from a living-related donor. The patient was successfully treated and maintains good kidney function, however, the case raises the question of whether kidneys with fibromuscular dysplasia should be included in the expanded criteria for kidney transplantation.

Rabbit antithymocyte globulin: a postoperative risk factor for sirolimus-treated renal transplant patients?

AIMS: Randomized controlled studies suggest an increased incidence of perioperative wound complications among sirolimus-treated renal transplant patients. The present study analyzed the effect of rabbit antithymocyte globulin (rATG) on these postoperative complications. METHODS: Four hundred and twelve renal transplants were performed and managed postoperatively at two University-affiliated hospitals between January 1, 2001, and December 31, 2003. The patients received corticosteroids and Sirolimus, with delayed introduction of cyclosporine when the serum creatinine had decreased below 2.5 mg/dL. Two groups of patients were discriminated: group 1 received Basiliximab 20 mg on day 0 and day 4 (n = 283); group 2 recipients with a high panel of reactive antibody (PRA > 20%) and retransplant patients received rATG for induction (n = 129) for a maximum of 2 weeks postoperatively. The incidence of rejection was 14.5% for group 1 vs. 8.5% for group 2 patients. To avoid confounding variable associated with the rejection treatment, any patient with rejection was excluded for statistical analysis, as were patients with follow- up less than 30 days. The final study group for analysis included 350 patients: 235 with Basiliximab induction (group 1) and 115 rATG induction (group 2). The mean follow-up was 21.8 +/- 11 months. Differences in the incidences of postoperative hernia, wound infections, or lymphoceles requiring any form of drainage were analyzed for statistical significance using the chi-square test. RESULTS: The percentage of patients with wound complications was 26.0% versus 39.1% (P < .025) for group 1 versus group 2, respectively. Incisional hernias occurred in 10.6% versus 18.3% patients (P < .05), wound infections in 11.1% versus 16.5% (P = NS), and lymphoceles in 10.6% versus 15.9% (P = NS) for the two groups, respectively. CONCLUSIONS: rATG-induced renal transplants recipients treated with sirolimus, cyclosporine, and steroids show a significantly increased incidence of postoperative incisional hernias and a trend toward a greater number of lymphocele and wound infection complications.

A pilot study of immunosuppression minimization after pancreas-kidney transplantation utilizing thymoglobulin induction and sirolimus maintenance therapy.

AIMS: To determine outcomes utilizing thymoglobulin and sirolimus immunosuppression, with early steroid withdrawal in low-immune responder pancreas-kidney (SPK) recipients, and conversion from cyclosporine (CsA) to mycophenolic acid (MPA) in all recipients at 6 months posttransplantation. METHODS: SPK recipients received thymoglobulin, sirolimus, and reduced-dose CsA immunosuppression. Low immune responders (non-African-Americans with a pretransplant PRA < 30%) were withdrawn from prednisone on posttransplant day 5 and high immune responders were continued on prednisone. All recipients were converted from CsA to MPA at 6 months posttransplantation. During conversion, recipient immune response was monitored by flow PRA and a T-cell stimulation assay (Cylex). RESULTS: With a mean follow-up of 9 +/- 4 months, one pancreas was lost to pancreatitis, with no patient or kidney losses and no acute rejection episodes. All eight low immune responder patients were steroid-free at 9 +/- 5 months posttransplantation. Seven patients (five low and two high immune responders) with at least 6-month follow-up were converted from CsA to MPA. One high immune responder with a pretransplant PRA of 43% remained with a PRA of 53% +/- 2% postconversion. The second high immune responder had a pretransplant PRA of 34% and a postconversion PRA of 0%. The five low immune responders had a mean pretransplant PRA of 16% +/- 15% and a postconversion PRA of 0% (P < .01). The Cylex assay resulted in 67% low responsiveness for both high and low immune responders. CONCLUSION: Thymoglobulin induction with sirolimus maintenance therapy permitted immunosuppression minimization in selected pancreas transplant recipients. Posttransplant evaluation revealed a diminished (regulated) immune response in six of seven patients.

Transplantation of single pediatric kidneys into adult recipients.

AIM: To evaluate the outcome of single pediatric kidneys transplanted into adult recipients. METHODS: A retrospective single-center review was performed of transplants from donors less than 5 years of age. Outcomes were compared with recipients of grafts from donors 18 to 45 years transplanted during the same time period. RESULTS: Thirty single renal transplants from pediatric donors and 117 transplants from adult donors between 18 and 45 years of age were performed during the study period. The mean age of the pediatric donors was 2.9 +/- 0.8 years versus 31.5 +/- 8.9 years for adult donors (P < .001). The mean age of the recipients of pediatric donors was 41.9 +/- 13 years versus 48 +/- 12.6 years for recipients of adult grafts (P = .020). The mean recipient weight of pediatric donors was 55.9 +/- 7.8 kg versus 78.0 +/- 17.7 kg for recipients of adult donors (P < .001). Sixty-six percent of pediatric donor recipients were of female gender compared to only 36% of adult donor recipients (P = .005). Death-censored actuarial graft survivals at 1 and 4 years for recipients of pediatric donor grafts were 90% and 85% compared to 93% and 85% for recipients of adult donor grafts (P = NS). The mean calculated creatinine clearances of adult donor graft recipients at 1 and 4 years posttransplantation were 70.8 +/- 26.5 and 73.7 +/- 27.2 mL/min, respectively, compared to 50.3 +/- 20.1 and 56.3 +/- 21.4 mL/min for pediatric donor grafts (P < .01 at 1 and 4 years). CONCLUSION: The use of single pediatric donor kidneys provides an excellent opportunity to safely expand the donor pool.

Graft survival and immune regulation of pancreas allograft recipients induced with thymoglobulin, sirolimus, and cyclosporine.

BACKGROUND: Our objective was to determine the impact of thymoglobulin-sirolimus-cyclosporine immunosuppression on the alloimmune response of pancreas-kidney transplant recipients. METHODS: Thirty-six pancreas transplant recipients received an induction protocol of thymoglobulin, sirolimus, reduced-dose cyclosporine, and corticosteroids. A subset of 10 recipients were also enrolled in a study to measure immune responsiveness. Flow PRA-determined HLA antibody, donor-specific flow cytometry crossmatching (FCXM), T-cell subset, and suppressor cell assays were performed at various timepoints during the first posttransplant year. RESULTS: One-year patient, kidney, and pancreas survivals were 97%, 94%, and 92%, respectively. There was 1 death due to sepsis, and 1 kidney and 2 pancreas graft losses. There were no acute rejection episodes. Recipients in the immune-monitoring study displayed depression of CD3, CD4, and CD8 counts (<80%) until 3 months posttransplant. At transplantation, 9 of 10 patients displayed <10% class I HLA antibody. By 3 months, 7 of 10 showed a transient elevation in class I HLA antibodies, with 2 patients expressing >80% flow PRA. At transplant 1 patient was FCXM-positive, whereas, by 3 months posttransplant, 2 of 10 patients demonstrated a positive FCXM. There were no clinical consequences to either the presence of HLA antibody or the positive FCXMs. By 6 months, 7 of 9 patients expressed immunoregulatory suppressor cell activity. CONCLUSIONS: The absence of acute rejection events was likely due to inhibition of donor-specific immunity. Seventy percent of patients demonstrated an early non-donor-directed HLA antibody response that had no adverse effect on graft function and 78% of the patients displayed immunoregulatory suppressor cell function, probably contributing to the successful clinical outcome.

Functional impairment of T-lymphocytes in mouse radiation chimeras by a nucleotide-free diet.

We examined the effect of a nucleotide-free diet on the immune function of mouse syngeneic bone marrow radiation chimeras. The graft-versus-host disease mortality assay revealed that GVH activity of spleen cells from radiation chimeras fed NFD (RCNFD) was reduced at 6-18 weeks after transplantation as compared with the radiation chimeras fed a control diet (RCCD). When tested 11-18 weeks after transplantation, the proliferative response of RCNFD spleen cells to phytohemagglutinin was significantly reduced at 11 and 13 weeks, the response to pokeweed mitogen (PWM) was significantly reduced at 11, 13, and 15 weeks, and the response to bacterial lipopolysaccharide remained virtually unaffected. At both six and eight weeks after transplantation, RCNFD and RCCD showed comparable numbers of CFUc/femur. RCNFD and RCCD did not differ significantly from each other in body weights or in spleen and bone marrow cellularity at 6-18 weeks after transplantation. These results suggest that dietary nucleotides are important for the normal function of mouse T-lymphocytes.

Possible contribution of pretransplant immune responder status to renal allograft survival differences of black versus white recipients.

Black end-stage renal disease patients may present as an immunologically higher-risk group for renal allograft transplantation than white ESRD patients. To test this hypothesis, we correlated graft survivals in 124 black and 241 white cyclosporine-prednisone-treated primary cadaveric renal allograft recipients with pre-Tx nonspecific immune responder status (strong vs. weak immune responders), donor-recipient-specific MLC responsiveness, HLA match, and blood transfusion (BT) history. One-, 2- and 3-year patient survival rates of 95%, 94%, and 94% were identical for both groups. However, the 1-, 2-, 3-year graft survival rates for white recipients of 82%, 79%, and 75% were significantly higher than the 70%, 62%, and 55% rates for black recipients (P less than 0.01 for each, respectively). Pre-Tx nonspecific immune response values for blacks were significantly (P less than 0.01) higher than for whites (38% vs. 28% for active T cell; 1.8 vs. 1.3 for TH:TS ratio; 28,581 c.p.m. vs. 14,870 c.p.m. for spontaneous blastogenesis; and a stimulation index (SI) of 34 vs. 20 for panel mixed lymphocyte culture). Additionally, the specific recipient-donor MLC (SI) for black recipients was significantly greater than the specific recipient-donor MLC for white recipients (MLC SI of 40 vs. 18, P less than 0.01). Blacks present as pre-Tx strong immune responders with a greater frequency than whites (90% vs. 66%, P less than 0.01). Moreover, black strong responders experience a poorer 1-year graft survival than white strong responders (67% vs. 80%, P less than 0.01). Even though the pre-Tx BT histories of white and black ESRD patients studied herein were comparable, the immunoregulatory effect of pre-Tx BT was different in white vs. black patients. A significant reduction in TH:TS ratio was observed when comparing 0 vs. 1-4 pre-Tx white patient BT groups, whereas significant changes in TH:TS ratios were not observed until after comparing 0 vs. greater than or equal to 5 pre-Tx black patient BT groups. HLA matching and pre-Tx BT had no impact on improving the graft survivals of these CsA-Pred-treated white or black recipients. These data, therefore, support the hypothesis that black recipients present as an immunologically higher-risk group than white recipients.

Dietary nucleotides, a requirement for helper/inducer T lymphocytes.

Previous investigations have revealed that dietary nucleotide restriction delays the onset of primary murine cardiac allograft rejection and acute graft-versus-host disease followed H-2-incompatible bone marrow transplantation, suppresses sensitization to intradermally injected antigens and suppresses in vivo and in vitro lymphocyte proliferation to alloantigen or lectin stimulation. To determine the mechanisms responsible for these phenomena, BALB/c mice were placed on chow (F), nucleotide free (NF) diet, or NF diet supplemented with 0.25% RNA (NFR), with 0.6% adenine (NFA), or with 0.06% uracil (NFU). Following four weeks of dietary equilibrium, splenic lymphocytes harvested from naive or immunostimulated mice in the various dietary groups were stained with monoclonal antibodies directed Lyt 1, Lyt 2, 3, or surface mouse immunoglobulin (IgG) surface markers. While naive animals demonstrated no differences in lymphocyte subpopulations between groups, following complete Freund's adjuvant (CFA) stimulation, splenic lymphocytes for NF mice demonstrated 27.3 +/- 1.7% Lyt 1+ cells compared with F (32.6 +/- .04%) and NFR mice (33.2 +/- 1.2%) (P less than 0.02). Restriction of dietary nucleotides affected not only phenotypes of T lymphocytes, but also T cell function. Following conconavalin A stimulation of irradiated splenic lymphocytes, IL-2 production was decreased in NF mice compared with the F control group (P less than 0.01). The RNA-repleted diet maintained normal IL-2 production, while addition of adenine or uracil alone did not. Finally, NF diets adversely affected host resistance to the opportunistic pathogen Candida albicans. Following inoculation with 0.25 X 10(6) organisms NF or NFA-fed hosts succumbed more rapidly than F, NFR, or NFU fed hosts (P less than 0.001). These data suggest that helper/inducer T lymphocytes require exogenous nucleotides to respond normally following immune stimulation. Uracil may be the critical substrate, based upon the studies of Candida resistance. By understanding the metabolic basis of NFD-induced immunosuppression, the role of dietary nucleotides in combatting infection and alloantigen rejection can be more clearly defined.

Successful transplantation of cyclosporine-treated allograft recipients with serologically positive historical, but negative preoperative, donor crossmatches.

Eighteen renal allograft recipients (15 cadaveric and 3 haploidentical living-related donor transplants) with historically (Hx)3 positive, but pretransplant (pre-Tx) negative, donor crossmatches (XM) were treated postoperatively with cyclosporine (CsA) and prednisone (Pred). The one-year allograft survival for the 14 primary allograft recipients was 86% (12/14). This was comparable to, and not significantly different from, the 81% (51/63) graft survival for recipients of primary cadaveric donor allografts transplanted during the same period who displayed a negative donor crossmatch with both Hx and pre-Tx sera. All four retransplant recipients with (+) Hx, but (-) pre-Tx, donor Xms lost their grafts. This result was significantly different (P less than 0.05) from the 75% (27/36) graft survival for retransplant recipients displaying a negative donor crossmatch with both Hx and pre-Tx sera. A significant decrease in PRA of 52 +/- 19% to 19 +/- 16%, P less than 0.05, was displayed by 12/18 CsA patients when comparing (+) Hx to (-) pre-Tx sera, which could have influenced the allograft survival in those patients. However, a graft survival of 44% (4/9) was observed for azathioprine (Aza) and Pred-treated recipients of cadaveric donor renal allografts who also displayed a significant decrease in PRA of 50 +/- 22% to 5 +/- 4%, P less than 0.05 when comparing Hx to pre-Tx sera. The decreasing PRA did not beneficially affect these Aza-Pred patients' graft survival. Therefore, CsA-Pred afforded a beneficial effect when recipients of a primary cadaveric renal allograft displaying a (+) Hx, but (-) pre-Tx, XM were transplanted. Retransplant recipients, however, should receive a cadaveric donor allograft only when they are XM-unreactive, whether testing with pre-Tx or Hx sera.

Immunoregulatory mechanisms in cyclosporine-treated renal allograft recipients.

Cyclosporine (CsA)-treated recipients of a primary cadaveric (CAD) renal allograft were postoperatively evaluated for their donor and nonspecific immune responsiveness. Recipients with posttransplant (Tx) T helper (TH):T suppressor (TS) cell ratios less than 1.0 (averaged for the first 0-30 post-Tx days) had significantly better one-year serum creatinines (SCr) of 1.8 +/- 0.7 vs. 2.3 +/- 0.6 for recipients with TH:TS ratios greater than 1.0, P less than 0.05. Significantly fewer rejection episodes (30 vs. 57) and immune graft losses (10 vs. 19) were experienced by recipients with TH:TS ratios less than 1.0 vs. greater than 1.0, P less than 0.001 and 0.05, respectively. Recipients with TH:TS ratios less than 1.0 vs. greater than 1.0 displayed significantly lower post-Tx panel mixed lymphocyte culture (PMLC) stimulation indices (SI) of 24 +/- 11 vs. 38 +/- 6, P less than 0.05 and donor MLC SI of 15 +/- 6 vs. 31 +/- 8, P less than 0.05, respectively. Moreover, the post-Tx:pre-Tx donor MLC ratio of 0.58 +/- 0.2 vs. 1.1 +/- 0.32 was significantly lower in recipients with TH:TS ratios less than 1.0 vs. greater than 1.0, P less than 0.05. The suggested donor hyporesponsiveness in recipients with post-Tx TH:TS ratios less than 1.0 was further investigated by studying 46 CsA-treated allograft recipients for their ability to display regulatory T cell or adherent monocyte MLC suppressor activity. With a mean follow-up time of 5 +/- 4 months (range 0.5-14 months) we observed that 46% (21/46) of the patients displayed T cell suppressor activity, including 35% (16/46) with T-donor-specific and 46% (21/46) with T non-specific MLC suppressor activity. Additionally, 59% (27/46) of the patients also displayed nonspecific adherent monocyte MLC suppression. Recipients displaying either T cell or adherent monocyte suppression experienced significantly fewer rejection episodes than patients with no suppressor cell activity (P less than 0.05). Moreover, patients with T cell suppressor activity displayed a significantly lower panel and donor MLC vs. patients not displaying T suppressor activity (P less than 0.05. and 0.05, respectively). Finally, there was a significant correlation between the display of T cell suppressor activity in patients who were matched with their donors at the HLA-DR locus vs. no display of T suppressor activity in those patients unmatched with their donors at the HLA-DR locus.

Hepatobiliary and pancreatic complications of cyclosporine therapy in 466 renal transplant recipients.

Two hundred twenty-eight patients from a total of 466 (49%) receiving renal allografts under cyclosporine/prednisone (CsA/Pred) immunosuppression experienced at least one episode of posttransplant hepatotoxicity. All patients were documented to have normal serum bilirubin, serum glutamic oxaloacetic transaminase (SGOT), serum glutamic pyruvate transaminase (SGPT), lactic acid dehydrogenase (LDH), and alkaline phosphatase (AP), as well as negative results of biliary ultrasound and upper gastrointestinal contrast examinations prior to transplantation. Hepatotoxic episodes usually were self-limited (82%), and generally occurred during the very early posttransplant period (76%). Liver function abnormalities included hyperbilirubinemia (48% of patients), elevated SGOT (47%), SGPT (73%), LDH (84%), and AP (59%). The CsA serum trough radioimmunoassay (RIA) was relatively high among hepatotoxic patients with a mean value of 225 +/- 17 ng/ml. Pharmacokinetic parameters, including bioavailability and drug clearance, were significantly altered among this group of patients. The management strategy of CsA dose reduction was effective; however, 11 patients (2.4%) developed biliary calculous disease posttransplant while under CsA/Pred immunosuppression. Seven patients had cholelithiasis, and two patients underwent choledochoduodenostomy because of primary choledocholithiasis. The results contrast with 279 renal transplant recipients from an overlapping nonrandomized group treated with azathioprine (Aza)/Pred in whom cholelithiasis was not identified. Pancreatic abnormalities were relatively common, but clinical pancreatic disease occurred in only six patients. There were two episodes of acute pancreatitis, three patients developed pancreatic abscess, and one patient developed a pancreatic pseudocyst. The apparent proclivity of CsA-treated patients to develop biliary calculous disease, and the occurrence of serious pancreatic complications in a small percentage of patients did not affect the majority of CsA-treated patients. They may, however, represent important problems associated with the use of this immunosuppressive agent.

Improved immunosuppression for heart transplant patients using intravenous doses of cyclosporine.

Inducing immunosuppression in heart transplant patients with intravenous doses of CsA may decrease the incidence of severe rejection in the 1st month after operation. In our initial series, 16 consecutive patients (group A) who had no contraindications to this type of therapy received an i.v. dose of CsA, 1 mg/kg/day, postoperatively, which was then increased by 1 mg/kg every 24 hr until a full maintenance dose of 4 mg/kg/day was achieved (total time, 72 hr). The gradual increase in dosage was designed to prevent nephrotoxicity associated with higher doses of CsA. Intravenous administration was continued for 2 weeks, at which time oral administration of CsA, 14 mg/kg/day, was begun. In a subsequent series, 21 similar patients (group B) received the same amount of CsA, except that doses were increased every 12 hr, so that the full maintenance dose was achieved 36 hr postoperatively. In group B, the i.v. dose of CsA was continued for only 1 week, at which time oral administration of CsA, 14 mg/kg/day, was begun. All patients received the same standard steroid taper (30 mg/day by day 10). Patients from both groups who were greater than or equal to 55 years old and had serum creatinine greater than or equal to 1.5 mg/dl and patients from group B who had creatinine clearance less than or equal to 55 ml/min also received azathioprine, 2 mg/day, which was adjusted to maintain the white blood cell count at a level greater than or equal to 5000/cc. There was a similar number of such patients in both groups. Severe rejection was defined by endomyocardial biopsy with frequent foci of myocyte degeneration. Three (18.7%) patients in group A experienced severe rejection, and 2 (9.4%) in group B did. No patients developed renal failure. All patients survived the 1st month. The overall survival rate for group A at 12.2 +/- 1.5 months was 94%, and for group B it was 86% at 7.5 +/- 1.4 months. Both these groups compared favorably with our historical control group of patients who received oral doses of CsA to induce immunosuppression, in which 59 of 165 (35.8%) had severe rejection in the 1st month, with a 1-year actuarial survival rate of 76%. Based on this experience, we believe that i.v. administration of CsA enhances the induction of immunosuppression, thereby reducing the incidence of severe rejection. This protocol is likely to be effective because it minimizes the problems of oral absorption in the perioperative period.(ABSTRACT TRUNCATED AT 400 WORDS)

Immunohemopoietic effects of dietary nucleotide restriction in mice.

The influence of dietary sources of nucleotides on host in vivo and in vitro immuno-hematologic responses in BALB/c (NCI) mice was studied. Adenosine deaminase (ADA) and purine nucleoside phosphorylase (PNP) were measured in popliteal lymph nodes undergoing proliferative response to syngeneic and allogeneic in vivo stimulation. Supplementation of a nucleotide-free (NF) diet with yeast RNA (NFR) or uracil (NFU) significantly enhanced the host PLN immune response as compared with NF and NF supplemented with adenine (NFA) diets. Levels of ADA and PNP enzymes in the PLNs increased with the alloimmune PLN response of host, and immunosuppression was associated with decreased ADA and PNP activities in lymphocytes following antigenic stimulation. The induction of these enzymes during immune response appears to require dietary sources of certain nucleotides. When bone marrow cells from control chow fed animals were cultured with supernatants (sups) from mitogen activated splenocytes of animals on each dietary group, NF sups significantly decreased (P less than 0.05) the BM proliferative response compared with the response observed with NFR sups, and similar to NFA or NFU sups. When stimulated with purified IL-3, NFR BM cells had higher levels of Thy1.2 or Lyt 1 surface markers as compared with other test groups. In the in vivo splenic colony formation-CFUs assay, spleens from NFR- and NFU-fed animals had a significantly higher number of colonies than spleens from NF- or NFA-fed mice. Thus, NF diet decreases both in vivo lymphoproliferation response to alloantigen and hemopoietic growth factor production, rendering the host splenic environment deficient for stem cell growth. These adverse effects are reversed by RNA supplementation of NF diet. These nutritional studies demonstrate a critical and regulatory role for dietary nucleotides in immunohemopoiesis.

Short-term and long-term function of cadaveric kidneys from pediatric donors in recipients treated with cyclosporine.

Short and long-term renal function of 67 cyclosporine-prednisone (CsA-Pred)-treated recipients of pediatric cadaveric donor kidneys followed for up to 68 months (mean 16 months) were compared with 67 recipients of adult kidneys (group 3), who were demographically matched for recipient age, sex, race, cause of disease, HLA compatibility, ABO blood type, and retransplant status. Thirty-seven of the pediatric kidneys came from donors less than or equal to 10 years old (group 1) and 30 from donors 11-16 years old (group 2). Group 1 displayed impaired short-term graft function: a significantly higher mean value of the nadir serum creatinine (SCr; 2.35 versus 1.63 mg/dl), a lower maximal creatinine clearance during the first 30 days (50.3 versus 65.7 ng/dl/1.73 m2), and a longer time to achieve the nadir creatinine (22.1 versus 17.2 days). Group 1 transplants also had a higher mean nadir creatinine at 3 months and a lower mean creatinine clearance (CCl) at 3 and 6 months. By 12 months the values in the group 1 pediatric kidneys were similar to those using the group 3 adult grafts. Therefore, CsA therapy did not preclude compensatory graft function. Group 2 grafts showed intermediate short-term function relative to groups 1 and 3. Mean SCr and CCl showed progressive improvement over time, significantly better than adult kidneys at two years. Graft loss was significantly greater at two years in pediatric compared with adult grafts, but significantly better than our historical controls using azathioprine-prednisone immunosuppression.

Successful transplantation of 100 untransfused cyclosporine-treated primary recipients of cadaveric renal allografts.

This report examines the effect of pretransplant (pre-Tx) blood transfusions (BT) on the patient and graft survival results of 320 cyclosporine (CsA) and prednisone (Pred)-treated primary (1 degree) recipients of cadaveric (CAD) donor renal allografts. The 320 CsA-Pred treated 1 degree-CAD recipients included 100 pre-Tx untransfused (O-BT) and 220 transfused patients. The overall patient survival at 12, 24, and 36 months post-Tx were 94%, 94%, and 93%, respectively. There were no differences observed in graft survivals at 12, 24, or 36 months post-Tx whether patients received 0, 1-4, greater than or equal to 5-10 or greater than 10 pre-Tx BTs. A mean serum creatinine of 1.9 +/- 0.7 mg/dl was comparable among all BT groups at 12, 24, and 36 months post-Tx. The frequency of rejection episodes--namely, 37% for O-BT and 36% for greater than O-BT were identical. High-risk patients (greater than 45 years of age, diabetics, or blacks) were comparably distributed in O-BT and greater than O-BT groups and did not impact on the data. Similarly, increasing panel-reactive antibodies (PRA), associated with increasing numbers of pre-Tx BTs, did not influence the data. When HLA A, B, and DR matching results were combined with the BT groupings no differences were observed in patient or graft survivals. Poorly matched and untransfused recipients did as well as well-matched, transfused recipients. These findings suggest that CsA-Pred immunosuppressive therapy allows for successful 1 degree-CAD renal allograft transplantation without the need for pretransplant blood transfusion conditioning or matching of donor HLA A, B, and DR antigens to recipients.

The use of cyclosporine in living-related renal transplantation. Donor-specific hyporesponsiveness and steroid withdrawal.

Fourteen HLA-identical (HLA-ID) and 62 haploidentical (HP-ID) living-related donor (LRD) renal allograft recipients were transplanted using cyclosporine (CsA) and prednisone immunosuppression. No patients were preconditioned with pretransplant blood transfusions (third-party or donor-specific)--and, therefore, none were sensitized to their donor. Patient 93% (13/14) and graft 93% (13/14) survival for the HLA-ID patients is not significantly different (P greater than .1) compared with patient 98% (61/62) and graft 91% (56/62) survival in the HP-ID patients, with a mean follow-up of 16.3 (8-30) and 14.7 (2-35) months, respectively. A significant difference was noted in the incidence of treated rejection episodes (0% vs. 31%, P less than .01) and the mean serum (mg/dl) creatinine (1.37 vs. 1.71, P less than .05) at 18 months between the HLA-ID and the HP-ID and HP-ID recipients, respectively. Ten of 22 HP-ID recipients demonstrated donor-specific mixed lymphocyte culture hyporesponsiveness one year posttransplant that may have been due to the emergence of monocytoid suppressor cells. Nine of these HP-ID and seven HLA-ID recipients were subjected to a protocol of steroid withdrawal. Eleven of these patients are currently on CsA monodrug therapy and two are on alternate-day steroids from 9-18 months after discontinuation of prednisone. These findings suggest that CsA is an effective steroid-sparing agent in LRD renal transplantation that diminishes the frequency of treated rejection episodes and may permit monodrug therapy in selected individuals.

The impact of steady-state cyclosporine concentrations on renal allograft outcome.

It has been reported that initial cyclosporine levels over 400 ng/ml posttransplantation result in an increased incidence of delayed graft function (DGF). Several studies have shown early graft function to be a major determinant for long-term graft survival. Continuous intravenous infusion (CIVI) has been employed to induce immunosuppression establishing therapeutic drug levels while minimizing toxicity in renal allograft recipients. This study examines the impact of the achieved serum CsA steady-state concentration (Css) levels upon transplant outcome in 228 patients given CsA by CIVI. In spite of administration of a specific drug dose, interindividual variation in elimination rates yields a broad range of Css levels. Six groups were stratified by CsA Css levels: group A 0-75 ng/ml, group B 76-100 ng/ml, group C 101-150 ng/ml, group D 151-200 ng/ml, group E 201-250 ng/ml, and group F greater than 250 ng/ml. Group A showed a significantly lower age and greater incidence of rejection at 0-10 days. Group F had significantly higher incidences of nephrotoxicity, hepatotoxicity, and delayed graft function. The findings suggest that the antirejection Css threshold for CsA may be at least 75 ng/ml, and the toxicity threshold above 250 ng/ml. Controversy exists about whether CsA influences the incidence of DGF, therefore risk factors for DGF were examined among the groups stratified by CsA Css levels. While cold ischemia time for all 228 patients as a group was highly correlated with DGF (P less than 0.001), neither cold ischemia time nor donor age was significantly different among the groups. There does appear to be a synergistic effect between CsA Css and CIT, since the incidence of DGF was significantly higher when the cold ischemia time was 21-24 hr and CsA Css greater than 200 ng/ml. Long-term graft function did not appear to be affected by early CsA Css levels. The Css of 100-250 ng/ml appears to achieve a satisfactory outcome with a 19.5% incidence of rejection within 10 days, 29.7% DGF, and 5.1% nephrotoxicity. Only 118/228 patients (52%) in this study achieved that range despite a fixed low CIVI of CsA. Thus potential renal allograft recipients may benefit from a pretransplant pharmacokinetic study to predict the proper CIVI dose.

Causes of graft loss beyond two years in the cyclosporine era.

While CsA has improved renal-allograft survival rates in the first 2 years compared with Aza, Terasaki's multicenter study (1) failed to show any difference in long-term graft survival in CsA-Pred versus Aza-Pred-treated recipients. The present study examines the long-term graft-survival rates at a single center using CsA immunosuppression and seeks to discern the causes of 58 graft losses among 343 patients with functioning grafts beyond 2 years posttransplantation. The 6-year primary and cadaveric actuarial graft survival at this institution is 59% with a graft half-life of 10 years, which is better than the 40% and 7.7 years, respectively, reported by Terasaki (1) for primary cadaveric recipients on Aza-Pred. It is also better than the 41%, 6-year survival and 5.5-year half-life for primary cadaveric recipients treated with CsA-Pred as reported in the multicenter study. (1) Less experience with the use of CsA may explain the latter comparison. Primary LRD grafts at this institution (2/3 haploidentical) have a 6-year actuarial survival of 77% and a half-life very closely approximating that of HLA-identical LRD grafts under Aza (23.4 years). These results demonstrate that CsA mitigates the effects of HLA incompatibility to reduce graft survival. The most common cause of graft loss beyond 2 years was chronic rejection (36.2%) followed by noncompliance (27.6%). Patient deaths resulted in 13 of the 58 graft losses; most of the deaths were related to cardiovascular diseases. Only 3 patients died from causes that could be attributed to CsA immunosuppression; 2 from sepsis and 1 from viral hepatitis. Acute rejection caused 8.6% of the graft losses on continuous CsA therapy. When immunologic risk factors were analyzed, the entire graft-loss group had a significantly higher proportion of retransplant patients than the graft-survival group (P less than 0.005), suggesting that prior transplantation imposes a higher risk for graft loss not only acutely but long term as well. However, retransplanted patients were significantly less likely to lose their grafts because of noncompliance (P less than 0.005). Male patients were found to be significantly more noncompliant.

Guillain-Barré syndrome after solid organ transplantation.

BACKGROUND: Neurological complications occur frequently in solid organ transplant recipients. However, the peripheral nerves are usually spared significant toxicity. Guillain Barré syndrome (GBS) is the most common cause of acute neuropathy in adults. Despite numerous reports of GBS in recipients of bone marrow transplants, GBS has rarely been reported in recipients of solid organ transplants. Recent evidence supports the role of the immune system in initiating and perpetuating the ongoing neural damage in this entity. Infectious agents may initiate the immune attack, and the association of GBS with cytomegalovirus (CMV) infection has been studied extensively. METHODS: To alert clinicians to the occurrence of GBS in the latter setting, we report five new cases of GBS after solid organ transplant and summarize five other cases previously reported in the literature. RESULTS: The GBS cases (published and unpublished) have much in common: all the patients were men, most had evidence of active CMV infection at or before the onset of GBS, and all but one developed GBS within 1 year after transplantation (range 1-26 months). CONCLUSION: The association of GBS with cytomegalovirus (CMV) infection in the nontransplant population and evidence of CMV infection in almost all reported cases of GBS in solid organ transplant recipients suggest that CMV may have a role in triggering this illness.