Cadaveric Renal Transplant Recipients Research Articles

Cyclosporin Maintenance Monotherapy After Renal Transplantation

The use of cyclosporin monotherapy as maintenance immunosuppression in primary cadaveric renal transplant recipients is not popular except in a few European centres. Corticosteroid withdrawal is becoming more popular, and is usually attempted with the newer immunosuppressants which have a more corticosteroid-sparing effect than cyclosporin. The adverse effects and morbidity associated with maintenance regimens consisting of 2 or 3 immunosuppressive drugs are well known, but the potential benefits of cyclosporin monotherapy must be balanced against an increased risk of graft loss by rejection. We selected patients for a trial of corticosteroid withdrawal and subsequent cyclosporin monotherapy. These patients received an individually designed immunosuppressive regimen with careful control of cyclosporin trough concentrations. The cyclosporin formulations used were its original oil-based solution or gelatin capsule (Sandimmun, Sandimmune )until mid-1996 and then the microemulsion formulation (Neoral). Corticosteroid withdrawal was attempted in 89% of patients with a graft functioning at 3 months after transplantation and was effective in 88% of them. At a mean follow-up time of 98 +/- 23 months, 69% of grafts were functioning and 92% of patients were alive. 50% of patients with a functioning graft were receiving long term cyclosporin monotherapy. Mild rejection episodes occurred in 6% of patients receiving cyclosporin monotherapy per year of treatment, and chronic rejection caused graft loss in 1.4% of patients per year of treatment. Comparison of successful and unsuccessful outcomes allows us to define favourable predictive factors. For corticosteroid withdrawal these are: older recipient age, lower creatininaemia at months 6 and 8 and higher trough cyclosporin concentrations at month 6. For cyclosporin monotherapy these are: later timing of azathioprine withdrawal, recipient age >25 years, donor age <or=40 years, creatininaemia <or=125 micromol/L at initiation of monotherapy and no rejection episode before initiation of monotherapy. We have observed a low incidence of nonmelanoma skin cancers and of squamous-cell carcinoma in our series. This is perhaps the result of the azathioprine-sparing effects of the regimen (7 azathioprine-free years per patient with successful cyclosporin monotherapy, and 4 azathioprine-free years per patient with unsuccessful monotherapy). This important point will need further studies but is encouraging. Maintenance cyclosporin monotherapy is feasible and probably useful in selected primary graft recipients without deleterious effects on overall results in terms of graft and patient survival. Careful patient selection using the predictive factors we have defined should make cyclosporin monotherapy more effective, allowing the present 57% success rate at 5 years post-transplantation to be increased by 15 or 20%.

A prospective randomised study of CSA monotherapy versus CSA plus mycophenolate mofetil in cadaveric renal transplant recipients

A prospective randomised study of CSA monotherapy versus CSA plus mycophenolate mofetil in cadaveric renal transplant recipients

Rebound effect of the allogenic T-cell response to donor and third-party lymphocytes after cyclosporine withdrawal in renal transplant recipients

Mixed lymphocyte reaction (MLR) assays were performed serially over 24 months in 19 first cadaver renal transplant recipients. Immunosuppression consisted of cyclosporine, methylprednisolone and azathioprine. Cyclosporine was withdrawn at 6 months postoperatively. The MLR reactivity gradually decreased over the first 3 months following transplantation. However, there was a significant increase in MLR reactivity at 12 months postoperatively after the cyclosporine withdrawal. This rebound effect in MLR reactivity following cyclosporine withdrawal could account for the increased incidence of acute rejection episodes.

Persistent secondary hyperparathyroidism after renal transplantation

The persistence of secondary hyperparathyroidism after renal transplantation is frequent and often complicated by overt hypercalcemia. Recent investigations have shown an effect of the different vitamin D receptor (VDR) genotypes on parathyroid hormone (PTH) secretion in both primary and secondary hyperparathyroidism. The aims of this study were (i) to assess whether persistent secondary hyperparathyroidism after renal transplantation is characterized by any change in calcium-controlled PTH secretion, and (ii) whether different VDR allelic distributions might play any role on this setting. Eighty-one cadaveric renal transplantation recipients, followed-up for at least 12 months, were checked for PTH, other primary metabolic and clinical variables, and VDR B/b alleles (BsmI). In 22 of these the following parameters were evaluated: (a) kinetics parameters of the Ca-PTH relation curve; (b) vertebral mineral density; (c) calcitriol serum levels; (d) PTH-related peptide serum levels; and (e) urinary hydroxyproline. According to the stabilised PTH levels (reached by the third month), the patients were divided in two groups: group A (N = 40, PTH < 80 pg/ml) and group B (N = 41, PTH > 80 pg/ml). Group B differed from group A in that patients had higher PTH levels at the time of transplantation, were older in age, and spent more time on dialysis. Group B had increased maximal and minimal PTH levels, and higher set-point levels than Group A. The patients with the BB pattern of VDR genotype were characterized by the lowest PTH levels both at time of transplantation and after stabilization, and lower set point values than patients with Bb and bb patterns. Our study suggests that (i) the severity of pre-existing secondary hyperparathyroidism is the main factor determining its persistence after renal transplantation, (ii) persistent secondary hyperparathyroidism is characterized by an autonomous pattern of PTH secretion, (iii) the VDR BB genotype seems to be related to lower PTH levels.

DONOR BONE MARROW, CHIMERISM, HISTOCOMPATIBILITY AND RENAL ALLOGRAFT REJECTION

18 Does donor bone marrow infusion have immunological effects on renal allograft recipients? From September 1994 through December 1997 63 cadaver renal transplant recipients of either 1 (n=21) or 2 (n=42) post-operative donor bone marrow cell (DBMC)-infusions have been followed, compared with 220 non-infused controls given equivalent immunosuppression (Tacrolimus, mycophenolate mofetil, methylprednisolone, and OKT3 induction). Additionally, 16 kidney recipients of DBMC-infusion from living-related donors (LRD) (1-infusion) were followed from November 1996 through December 1997, and given the same immunosuppression. With both CAD and LRD DBMC infusions, the DBMC was similarly processed, frozen under liquid nitrogen, and thawed for administration at the bedside, with similar cell viability in each group. Chimeric analyses were performed by the PCR-Flow technique. There were 8/63 biopsy-proven acute rejection episodes (AR) in the CAD DBMC-infused group, and 33/220 AR in the controls (p=N.S.). However, only 2/63 DBMC recipients had biopsy-proven chronic rejection (CR), while 35/220 showed CR in the controls (p=<.02). Actuarial patient and graft survival (1-40 months) were 93% and 92% in the CAD DBMC-infused group and 96% and 91% in the controls, respectively. If two infusions of CAD DBMC were used, the AR rate was 5% (2/42); while, if one infusion was given, it was 24% (6/21) (p=<0.02). In both groups mortality was not associated with rejection. AR was associated with at least a 5-fold decrease in peripheral blood PCR-Flow chimerism of Total, CD3+, and CD34+ DBMC mononuclear cells (monocyte-lymphocyte gate), i.e., a useful indicator of rejection-not seen with infections of any type. In the LRD DBMC-infused recipients, patient and graft survival were 100% and 100%, respectively (3-15 months), with PCR-Flow DBMC chimerism in peripheral blood being 2× higher than CAD DBMC-infused recipients at serial monthly intervals up to 15 months post-operatively (p=<0.01). However, only 25% of the total average DBMC were initially infused in the LRD group (i.e., 7 × 1010 cells CAD, vs. 1.5 × 1010 cells LRD). These results indicate 1) an effect of histocompatibility on DBMC chimerism, 2) a modulatory effect of DBMC on allograft rejection, 3) the utility of peripheral blood "real time" PCR-Flow as a serial monitoring tool for AR in DBMC-infused patients. We conclude that DBMC infusions have a positive clinical long-term immunoregulatory effect on renal allograft recipients using a heavy induction and early maintenance immunosuppressive regimen.

Optimization of cyclosporine therapy in renal transplantation

It is well recognized that CsA is a potentially nephrotixic drug. CsA can induce a dose-dependent intrarenal vasoconstriction with reduced renal plasma flow and glomerular filtration rate. These functional abnormalities are reversible, even after months of CsA. However, CsA can also be responsible of morphologic lesions that are usually dosedependent. The tubular lesions, such as megamythocondria, isometric vacuolization, and calcification, are reversible. More severe is the so-called CsA-arteriolopathy, which affects the afferent arterioles and is characterized by mucinoid thickening of the arteriolar wall or by a nodular hialynosis of the intima. This arteriolopathy may be reversible if CsA is stopped, but in many cases it heralds the appearance of interstitial fibrosis with irreversible progression to renal failure. The nephrotoxicity of CsA has been considered as a main limit for a prolonged renal allograft survival. The retrospective data of the United Network for Organ Sharing seem to support this concern, since the half-life of cadaveric renal transplants was reported to range around 7 years both in the years between 1975 and 1979 when CsA was not available and between 1985 and 1990 when most transplant units used CsA. On the other hand, a number of studies reported that the most common cause of late graft failure in CsA-treated renal transplants was not represented by chronic toxicity but by chronic rejection, which was often triggered by the use of insufficient doses of CsA. To evaluate the long-term impact of CsA on graft survival we retrospectively examined our own series of renal transplants treated with CsA and functioning for at least 6 months. In 632 CsA-treated primary renal allografts followed for 68 6 40.6 months, the graft half-life was 19.9 years (standard error [SE] 22.5), and the pure graft half-life was 24.8 years (SE 30.99). Chronic rejection (83%), recurrence of glomerulonephritis (10%), and vascular thrombosis (5%) accounted for graft losses that occurred after the sixth month. Only one case of well documented CsA nephropathy was responsible for late graft failure. To assess the impact of long-term CsA on renal function, we studied 121 cadaveric renal transplant recipients with their allograft still functioning after 10 years of uninterrupted CsA administration. The mean creatinine clearance was 59 6 14.9 mL/min at 1 year after transplantation and was 57 6 25.3 mL/min at 10 years. Only 11 patients doubled their plasma creatinine from the first to the tenth year. The mean systolic (136 6 20 mmHg) and diastolic (87 6 11 mmHg) blood pressure values were within normal values at the tenth year. At 10 years, 104 patients (86%) versus 96 (80%) at 1 year received antihypertensive therapy. Proteinuria more than 1 g per day was found in 23 patients. All of them received a renal biopsy that showed chronic rejection in 15 cases, de novo membranous glomerulonephritis in 3, and recurrence of primary glomerulonephritis in 5. In conclusion, the prolonged use of CsA does not impede but rather favors a long-term allograft survival. At least in expert hands, the prolonged administration of CsA does not produce progressive attrition of renal function. The main cause of late graft failure remains chronic rejection that can be favored by the use of doses of CsA too low for maintenance.

Co-administration of Tacrolimus and Mycophenolate Mofetil in Cadaveric Renal Transplant Recipients

Co-administration of tacrolimus and mycophenolate mofetil in cadaveric renal transplant recipients.

IMPROVED OUTCOME AND STEROID WITHDRAWAL IN MYCOPHENOLATE MOFETIL TREATED PRIMARY CADAVERIC RENAL TRANSPLANT RECIPIENTS

232 The long term of corticosteroids in renal transplant recipients continues to be associated with significant morbidity even in the Cyclosporine (CSA) era. Although steroid withdrawal (STW) utilizing maintenance therapy with CSA/azathioprine (AZA) results in a reduction in steroid complications, an increased risk of acute rejection in the early withdrawal period and a gradual but significant increase in the serum creatinine during long term followup was noted. The substitution of Mycophenolate Mofetil (MMF) for AZA has lead to an overall reduction in the number and severity of acute rejection episodes. We report the short term outcome of STW in 2 groups: 18 CSA/MMF treated primary cadaveric renal transplant recipients and 95 CSA/AZA treated patients. STW was initiated in both groups as 9 months posttransplant when the maintenance methylprednisolone dose was 10 mg/day. A decrease of 2 mg/month was started until complete STW. Inclusion criteria for STW required a serum creatinine < 2.5 mg/dl and no prior steroid resistant rejections requiring antibody therapy. MMF was dosed at 1 g twice daily and AZA was provided at 1.5 mg/kg/day. Mean followup was 13 ± 8 months in the CSA/MMF group and 64 ± 32 months in the CSA/AZA group (p < 0.05). STW was accomplished at the same time posttransplant in both groups (CSA/MMF - 14± 2 months vs. 14 ± 3 months for CSA/AZA, p=ns). The incidence of prior steroid sensitive rejection episodes was lower in the CSA/MMF group - 12% vs. CSA/AZA group - 25% (p < 0.05). The 1 and 2 year success of maintaining complete STW was significantly higher and the incidence of acute rejection after STW and recurrent glomerulonephritis (RCR GN) was lower in the CSA/MMF group. TableThe serum creatinine was slightly but not significantly lower in the CSA/MMF group at 1 year (1.5 ± 0.2 mg/dl vs. 1.7 ± 0.2 mg/dl-CSA/AZA) and 2 years (1.5 ± 0.2 mg/dl vs. 1.8 ± 0.3 mg/dl- CSA/AZA). In conclusion, the combined use of CSA/MMF after STW resulted in improved 1 and 2 year success rates with a reduction in the risk of acute rejection after STW compared to a CSA/AZA based protocol. A reduction in early posttransplant rejection episodes may play a role in this improved outcome. MMF appears to add more potent short and long term immunosuppression which may increase the opportunity to achieve successful STW.

Outcome in Cadaveric Renal Transplant Recipients Treated with Cyclosporine A and Mycophenolate Mofetil versus Cyclosporine A and Azathioprine

Background.Recent multicenter reports have demonstrated improved outcome in recipients of cadaveric renal transplants treated with mycophenolate mofetil (MMF) versus azathioprine (AZA) in combination with cyclosporine A (CSA) and prednisone. We compared the outcome at our center in patients treated with MMF versus AZA, CSA, and prednisone.Methods.We retrospectively reviewed 242 adult cadaveric renal transplant recipients treated between 11/91 and 5/97. We compared 25 donor variables and 27 recipient variables and outcome parameters between patients treated with MMF versus AZA. There were 117 patients treated with CSA+AZA, 84 with CSA+MMF, and 42 who received other immunosuppressive strategies.Results.There were no significant differences in any clinically important donor variables. Patients treated with MMF versus AZA and CSA had significantly fewer rejections and readmissions. There was no significant difference in 1- or 2-year patient survival. Recipients treated with MMF had a 5% higher graft survival at 2 years, although the difference did not reach statistical significance.Conclusions.Outcome is improved in adult recipients of cadaveric renal transplants treated with MMF versus AZA in combination with CSA and prednisone.

Continuing observations on the regulatory effects of donor-specific bone marrow cell infusions and chimerism in kidney transplant recipients.

Continued follow-up of a series of donor bone marrow cell (DBMC)-infused first cadaver renal transplant recipients is described (n=58), now at a 36-month actuarial time point postoperatively. Serial polymerase chain reaction-flow cytometry (PCR-Flow) and cellular immune assays of iliac crest bone marrow aspirates and peripheral blood have begun to be compared with concomitantly transplanted recipients of living-related donor (LRD) kidneys and donor marrow infusions given the same immunosuppressive regimen (n=16). There have also been comparisons (36 months) with 188 controls transplanted concomitantly, i.e., recipients of first cadaver kidney transplants, who did not receive bone marrow. Each group was given equivalent immunosuppressive regimens of OKT3 anti-T cell induction and maintenance tacrolimus, mycophenolate mofetil, and methylprednisolone. Actuarial patient and graft survival have been 96% and 93%, respectively, in the controls and 91% and 91%, respectively, in the DBMC-infused recipients. Trough levels of tacrolimus were significantly lower in the DBMC-infused group. In PCR-Flow measurements, in peripheral blood up to 6 months postoperatively, there were higher levels of chimerism, i.e., in the total number of donor cells, as well as the donor CD3+ and CD34+ subsets in the LRD recipients administered DBMC infusions, compared with cadaver DBMC recipients, supporting the notion of a positive effect of histocompatibility on chimerism levels. In PCR-Flow measurements of recipient iliac crest bone marrow aspirates as in previous studies on peripheral blood, early acute rejection episodes (<1 month) were found to be associated with a later (6-14 months) decrease in donor cell lineage chimerism. However, a trend toward recovery of chimeric levels occurred by 21-28 months in a second iliac crest marrow aspirate 1 year after the first aspirate in the DBMC-infused recipients who experienced such early rejection episodes. This was in contrast to the controls in whom there were sustained low levels of iliac crest bone marrow chimerism at both the earlier and later intervals (i.e., no chimeric recovery), with 17/183 surviving controls progressing into chronic rejection. This has not yet been seen in the DBMC-infused group (0/54). In in vitro observations on cellular immune reactivity at 1 year postoperatively, decreased peripheral blood lymphocyte proliferative reactions were seen in response to phytohemagglutinin and Staph-A mitogens, as well as to cytomegalovirus and Epstein-Barr viral protein antigens in the DBMC-infused group versus the controls. Chronic immunosuppression did not seem to effect a vigorous in vitro inhibitory (regulatory) activity of bone marrow taken from these transplant recipients 2 years postoperatively in mixed lymphocyte culture and cell-mediated lympholysis reactions, using allogeneic responding cells from "normal" laboratory volunteers. Autologous peripheral blood lymphoproliferative responses to phytohemagglutinin and Staph-A mitogens, as well as to cytomegalovirus and Epstein-Barr virus protein antigens, were also regulated by either organ donor (non-immunosuppressed) bone marrow cells or by transplant recipient (immunosuppressed) bone marrow cells. What appeared to be disparate between the DBMC-infused and control groups (both immunosuppressed) was the trend for the (autologous) bone marrow suppressive effect on antiviral lymphoproliferative responses, to be stronger in the DBMC-infused group, who also had significantly (>one order of magnitude) higher levels of chimerism (P=0.01). It is concluded that the establishment of a chimeric state in DBMC-infused recipients, albeit of relatively low magnitude (approximately 1% at 2 years in recipient iliac crest bone marrow), has had a definite regulatory effect on immune responses. These results, therefore, add weight to the "causal" horn of the dilemma as to whether donor cell chimerism is a cause or an effect of

EFFICACY AND SAFETY OF LAMIVUDINE ON REPLICATION OF RECURRENT HEPATITIS B AFTER CADAVERIC RENAL TRANSPLANTATION

The aim of this pilot study was to evaluate the efficacy and the safety of lamivudine therapy in hepatitis B virus (HBV)-positive/DNA-positive renal transplant recipients. Six HBV DNA-positive cadaveric renal transplant recipients ranging in age from 49+/-6 years were administered lamivudine, at 100 mg/day for a period of at least 6 months, on a compassionate-use basis. Lamivudine is the (-) enantiomer of 3'-thiacytidine, which is known to be a potent inhibitor of HBV replication. All of the patients but one were on cyclosporine-based immunosuppression. The mean serum creatinine was 134+/-44 micromol/L. The mean duration of HBV infection was 230+/-54 months (156-288). All of the patients but one had high serum alanine aminotransferase levels (122+/-52 IU/L; range, 45-243). Histological evaluation showed the presence of either chronic active hepatitis (n=4) or cirrhosis (n=2). All of the patients but one were hepatitis B e antigen negative/hepatitis B e antibody positive, but none were coinfected with either hepatitis C virus or hepatitis D virus. Lamivudine therapy was associated with (i) a normalization of alanine aminotransferase levels in four of five patients when these levels were increased at the beginning (n=5); (ii) a rapid disappearance of HBV DNA from the serum (detected by hybridization) in all of the patients; (iii) the negativity of HBV DNA by polymerase chain reaction in four patients; and (iv) no change in renal function and in proteinuria when present (one patient). Finally, no adverse effects were noted. When lamivudine therapy was stopped for four patients after 6 months, it was associated with a biochemical and virological relapse within the weeks that followed. Lamivudine therapy was therefore resumed for these patients.

Risk factors for renal allograft survival from older cadaver donors.

The shortage of cadaver donors for kidney transplantation has prompted many centers to use kidneys from older donors. The use of older donor kidneys has been associated with lower graft survival. United Network for Organ Sharing data of all adult cadaveric renal transplant recipients receiving kidneys from adult donors between 1988 and 1994 (transplants, n=35,621) were analyzed to further study this issue. All patients were followed for a minimum of 1 year after transplantation. The recipients were classified according to donor age: group 1, 19-50 years; group 2, 51-60 years; and group 3, >60 years. The actuarial kidney survival estimates for group 1: (n=27,999) at 1, 3, and 5 years were 82.7%, 72.2%, and 61.4%. The corresponding values for group 2 (n=5,367) and group 3 (n=2,255) were 77.3%, 63.3%, and 51.3%; and 71.7%, 55.3%, and 42.7%, respectively (P<0.0001). Logistic regression analysis for 1-year graft survival was performed, and odds ratios (ORs) were computed for various risk factors. Increased odds of graft failure were seen with increasing donor age, previous transplantation, and elevated panel-reactive antibody. In the older donor group, lower ORs were observed if the recipients were Hispanic or Asian. In addition, kidneys from African-American or Asian donors had a poorer graft outcome. A similar analysis for 3-year graft survival for those grafts functioning at 1 year revealed poorer survival with older African-American donors (OR=1.78, P<0.02), whereas improved survival rates were seen when older kidneys were used for older (OR=0.635, P<0.01) and female (OR=0.733, P < 0.01) recipients. Statistically significant factors such as HLA mismatch, cold ischemia time, and African-American or diabetic recipients differ in their impact on graft survival across the donor age groups. In conclusion, kidneys from older donors are associated with poorer graft survival rates with African-American and Asian donors and African-American recipients, and no detrimental effects when used for older, Hispanic, Asian, or female recipients.

The effects of cytomegalovirus serology on graft and recipient survival in cadaveric renal transplantation: Implications for organ allocation

The potential benefits from allocating donated cadaveric kidneys based on donor and recipient cytomegalovirus (CMV) serology remain controversial. We estimated graft survival and recipient survival using bivariate KaplanMeier models and multivariate Cox proportional hazards models for 24,543 first cadaveric renal transplantations performed in the United States between 1989, coinciding with the introduction of ganciclovir, and 1994. The effects of donor and recipient CMV serology were estimated, and the implications of these estimates for CMV-based allocation of cadaveric kidneys were considered. From Kaplan-Meier estimates, the 3-year impact of CMV-seropositive donor kidneys was a 3.6% reduction in graft survival and a 2.4% reduction in recipient survival for CMVseronegative recipients, and a 3.9% reduction in graft survival and a 3.0% reduction in recipient survival for CMVseropositive recipients. Multivariate Cox analysis demonstrated an adverse impact of donor CMV seropositivity regardless of recipient CMV status. D-/R- CMV serologic pairs had the best 3-year outcomes, with 73.4% graft survival and 87.7% recipient survival. D+/R+ CMV serologic pairs were found to have the worst 3-year outcomes, with 68.4% graft survival and 83.1% recipient survival, and were significantly worse than D+/R− pairs in terms of recipient survival. The maximum estimated impact of a program allocating donor kidneys to maximize the number of D-/R-CMV serologic pairs, assuming no impact on HLA mismatches, was a 0.1% reduction in aggregate 3-year graft survival and a 0.2% reduction in aggregate recipient survival. An alternative program allocating donor kidneys to minimize the number of D+/R+ pairs had no estimated effect on either graft or recipient survival. We conclude that during the ganciclovir era, CMV continues to have an important impact on first cadaveric renal transplantation. However, even under ideal conditions, CMV-based kidney allocation to either maximize the number of D−/R− pairs or minimize the number of D+/R+ pairs is likely to provide little benefit to the population of cadaveric renal transplant recipients.

HLA-DR and DQ typing by polymerase chain reaction using sequence-specific primer mixes reduces the incidence of phenotypic homozygosity (blanks) over serology.

Because of the inherent difficulties in allele assignment with HLA-DR serological typing, in 1993 our organ procurement organization-based HLA laboratory replaced serology with the molecular method of polymerase chain reaction using sequence-specific primer mixes (PCR-SSP) to type for DR and DQ at a resolution level equivalent to that of serologically defined antigens. In this study, we compared the incidence of DR blanks, where allocative homozygosity occurred, and graft outcome during our serology epoch (1987-1993) with that of our molecular epoch (1993-1996). The incidence of DR blanks by PCR-SSP (17.0%; 138/1101) was significantly lower (P<0.005) than in the serology epoch (21.5%; 569/2647). Although DQ is not a component of the allocation algorithm, the incidence of blanks in the molecular era (21.9%; 196/895) was 46% lower (P<0.001) than in the serology epoch (40.8%; 931/2277). Graft survival in 163 cadaveric renal transplant recipients for whom molecular DR allocation occurred (patient and donor were molecularly typed) showed that PCR-SSP typing had no significant effect on 2.5-year graft survival for patients mismatched for 0 (97%), 1 (90%), or 2 (94%) HLA-DR antigens (P=0.4; log-rank). In conclusion, molecular typing lowered the rate of DR and DQ blanks, but molecular matching for HLA DR and DQ did not influence graft outcome at 2.5 years.

De novo light-chain deposition disease in a cadaver renal allograft

The deposition of immunoglobulin (Ig) light chains after renal transplantation most commonly occurs as a manifestation of recurrent multiple myeloma or recurrent light chain nephropathy. We report the development of de novo light chain deposition disease (LCDD) in a cadaveric renal transplant recipient 16 years after transplantation with no evidence of prior multiple myeloma or LCDD and no current evidence of myeloma or lymphoproliferative malignancy.

A logistic-regression model provides novel guidelines to maximize the anti-acute rejection properties of cyclosporine with a minimum of toxicity.

Although cyclosporine has become the mainstay of immunosuppression in organ transplantation, there is still no consensus on the criteria to optimize its anti-rejection activity with minimum toxicity. A clear and objective definition of target cyclosporine trough levels at different times from renal transplantation is still lacking, primarily because of the lack of a model correlating cyclosporine levels with probability of rejection or toxicity. In this study, logistic-regression model was developed that was applied to data collected retrospectively from two postoperative periods, i.e., Days 0 to 9 and 10 to 30, in 135 consecutive cadaveric renal transplant recipients, for a total of 1851 determinations. Only minimum and maximum trough levels were considered for each period. Concentration-response curves were estimated for Days 0 to 9 (P = 0.0001 for efficacy and P = 0.028 for toxicity) and for Days 10 to 30 (P = 0.015 for efficacy and P = 0.037 for toxicity). Therapeutic intervals of 330 to 430 ng/mL (parent compound in whole blood) for Days 0 to 9 and 260 to 390 ng/mL for Days 10 to 30 predicted an incidence of acute rejection of 22% and 12%, respectively, with a reasonably low toxicity that primarily consisted of elevation of serum aminotransferases.

Early steroid withdrawal after kidney transplantation

The side effects of steroid are serious problems in renal transplant patients. However, withdrawal of steroid has been controversial. We evaluated the benefits and risk of early steroid withdrawal after renal transplantation. The outcomes of early steroid withdrawal from triple immunosuppressive drug therapy were analyzed in four living related and one cadaveric renal transplant recipients. The dosage of steroid was gradually reduced and the time of steroid withdrawal after transplantation was 5 to 7.5 months. Four Patients have been able to be free from steroid and maintained stable graft functions and normal urinary findings for 14 to 33 months after withdrawal. The findings of rejection were not observed in the graft specimens obtained by serial biopsies. One patient who received a living related graft developed an increase in serum creatinine level and proteinuria two weeks after discontinuation of steroid. The serum creatinine level returned to that before withdrawal and proteinuria disappeared by steroid readministration. Long term side effects of steroid were not observed in 4 patients with successful steroid withdrawal. These results suggest that steroid withdrawal about 6 months after transplantation can be accomplished without jeopardizing graft function in selected renal transplant recipient and the withdrawal in the early stage is preferred for reducing the side effects. Careful and long-term follow up are required to assess the further risk and benefit of steroid withdrawal on immunosuppressive morbidity.

Delayed hypersensitivity skin tests and subsequent renal transplant outcome.

Some studies in the literature have supported, while others have denied, the relationship between results of delayed hypersensitivity skin tests (DHST), renal allograft and patient survival rates. Several factors contribute to the unreliability of these studies. For example, most of these studies were performed in the precyclosporine era, furthermore, other variables which influence renal allografts and patient survival rates were not controlled in those studies. The purpose of this study was to investigate the relationship between results of DHST performed in the pretransplant period with the subsequent renal transplant outcome in the cyclosporine era. The study included 103 first cadaveric renal transplant recipients. DHST were performed during pretransplant evaluation by intradermal injections of a battery of recall antigens. Based on skin-test results, the patients were assigned to two groups--those with a positive skin test (STP+) and those with a negative (anergic) skin test. These two groups were compared with each other regarding allograft survival, patient survival, and other variables known to influence survival rates. The mean age, sex and racial distribution, degree of HLA matches between recipients and donors, number of acute rejection episodes, and number of patients with acute tubular necrosis were similar between the two groups. Renal allograft survival rates in the anergic group at 6 months, 1 year, 2 years, and 3 years were 97%, 90%, 84%, and 57%, respectively. The survival rate for renal allografts in the STP+ group for the same time points was 90%, 86%, 80%, and 72%, respectively. Patient survival rates for the anergic group at 6 months, 1 year, 2 years, and 3 years were 95%, 94%, 89%, and 85%, respectively, while those for the STP+ group were 98%, 98%, 98%, and 97% respectively. Differences between the STP+ and anergic groups, with regard to patient and allograft survival rates, were not significant. We conclude that DHST is not helpful in predicting outcome of patient or renal allograft survival rates over a 3-year time period.

Risk factors and outcome of hypertension in living related renal transplant recipients

Summary: Impaired allograft function is an important cause of hypertension in cadaveric renal transplant recipients. the risk factors for post‐tranplant hypertension in living related transplant recipients with inherent good graft functions are likely to be different and have not been studied. In addition, controversy surrounds any independent effect hypertension might have on renal allograft functions. Four hundred and seventy three living related renal allograft recipients were retrospectively analysed to study the risk factors for development of post‐transplant hypertension and its effect on graft outcome. Prevalence of hypertension was 76.1%. the presence of pre‐transplantation hypertension was the most important independent risk factor for development of hypertension after transplantation. This suggests an important role of retained native diseased kidneys as a cause of hypertension. Other risk factors included: cyclosporin A immunosuppression, patient age less than 40 years and the presence of renal insufficiency at last follow up. Hypertension did not have any effect on patient or graft survival during the mean follow‐up period of 20.1 ± 13.7 months; however, it was associated with an independent risk for the presence of renal insufficiency in the post‐transplant period.

Apophysomyces elegans infection in a renal transplant recipient

A 50-year-old cadaveric renal transplant recipient on immunosuppressive therapy is described with post-traumatic cutaneous infection caused by Apophysomyces elegans. He showed no evidence of hematogenous dissemination and recovered fully after therapy with extensive local debridement and amphotericin B lipid complex. An apparent drug-drug interaction between amphotericin B lipid complex and cyclosporine was encountered. The course of A elegans infection in transplant recipients may be similar to that described in immunocompetent hosts. A elegans infection should be considered in evaluation of post-traumatic cutaneous infection not readily responsive to antibacterial therapy. This is a US government work. There are no restrictions on its use.