Carl J. Cardella

Outcome of kidney transplantation from high-risk donors is determined by both structure and function.

METHOD Despite the need to expand the donor pool, it is unclear what parameters should be used. The value of donor renal pathology and calculated creatinine clearance (CrCl) in determining recipient outcome was assessed in 57 kidney transplants from 34 donors in whom pretransplant renal biopsies were performed because of age > or =60, hypertension, and/or vascular disease. We retrospectively compared clinical outcomes in these recipients and 57 control recipients selected to have the same baseline demographics but receiving transplants from low risk donors who were significantly younger (32+/-13.9 vs. 61+/-7.3 years) and lighter weight (71+/-18.1 vs. 84+/-20.2 kg) than the high-risk donors (P<.001 for both). RESULTS Recipients of high-risk kidneys had a higher incidence of delayed graft function, defined by a <10% fall in serum creatinine (Cr) in the first 24 hr, (56% vs. 30%, P<.01), a higher incidence of rejection (60% vs. 37%, P = .02) and a higher Cr level (197+/-64 vs. 144+/-54 micromol/L at 18 months, P<.005). Graft and patient survival were similar; 12% and 5% vs. 91% and 9% in high-risk vs. control groups, respectively (P = NS). Donor renal pathology was scored 0-3 (none to severe disease) in four areas: glomerulosclerosis, interstitial fibrosis, tubular atrophy, and vascular disease. A donor vessel score of 3/3 was associated with a 100% incidence of delayed graft function and a mean 1-year Cr level of 275+106 micromol/L (compared with 43% and 192+54 micromol/L in those with lower vessel scores, P<.05). Calculated donor CrCl <100 ml/min was associated with higher recipient Cr levels at 1 year, 240+/-95 micromol/L vs. 180+/-54 micromol/L in recipients of kidneys from donors with CrCl levels >100 ml/min (P<.05). The mean 1-year Cr level was 320+/-102 micromol/L in recipients with both a vascular score of 3/3 and a donor CrCl <100 ml/min and 184+/-63 micromol/L in those with neither factor (P = .001). CONCLUSION Calculated donor CrCl and donor vascular pathology predict recipient graft function and may be helpful in selecting high-risk donors for single kidney transplantation.

Clinical benefits of neoral C2 monitoring in the long-term management of renal transplant recipients.

Background. Cyclosporine monitoring using the 2-hr postdose sample, C2, has been shown to have advantages in monitoring de novo renal transplant recipients. The purpose of this study was to assess cyclosporine exposure, using C2, in stable renal transplant patients previously monitored by C0 to determine the effect of dose reduction on patients with C2 more than 10% above target and the course of those with C2 at and more than 10% below target, whose dose was not modified. Methods. One hundred and seventy-five patients, three or more months after transplantation, had C2 assessed. The relationship of C2 to C0 and of both to renal function was analyzed by linear regression. Blood pressure, serum creatinine level, and lipids were followed for a mean of 15±2.6 months. Results. Eighty-five patients had values more than 10% above target, 42 were within 10% of target, and 48 were more than 10% below target. Cyclosporine dose was reduced in all patients above target. In this group, serum creatinine level was stable overall, but fell significantly in 46 (54%) of 85 from 153±55 to 132±49 &mgr;M. Blood pressure also fell in that group from 135/82 to 131/77. Serum creatinine level was stable in the remaining two groups of patients. Conclusions. These data suggest that dose reduction in many overexposed patients leads to improvements in renal function and blood pressure. Further study is required to confirm the long-term benefits of this strategy.

Ten Years of Experience with Vascular Complications in Renal Transplantation

From 1970 to 1980, 341 consecutive renal transplants were performed in 307 patients at our hospital. Operative technique was uniform and performed by a single surgeon. Acute arterial thrombosis occurred in 12 kidneys (3.5 per cent) and venous thrombosis occurred in 3 (0.9 per cent). All of these kidneys were lost. Renal artery stenosis, diagnosed in 17 kidneys (4.9 per cent), resulted from surgical technique or rejection and was associated with hypertension in all cases. Of these kidneys 5 responded to drug therapy alone, 4 to transluminal angioplasty and 5 to surgical reconstruction. Three grafts were lost. Vascular complications occurred in 9 per cent of our patients. The results suggest that factors other than surgical technique alone can contribute to the incidence of vascular complications.

Delayed Graft Function and the Risk for Death with a Functioning Graft

Delayed graft function (DGF) associates with an increased risk for graft failure, but its link with death with graft function (DWGF) is unknown. We used the US Renal Data System to assemble a cohort of all first, adult, deceased-donor kidney transplant recipients from January 1, 1998, through December 31, 2004. In total, 11,542 (23%) of 50,246 recipients required at least one dialysis session in the first week after transplantation. Compared with patients without DGF, patients with DGF were significantly more likely to die with a functioning graft (relative hazard 1.83 [95% confidence interval 1.73 to 1.93] and 1.53 [95% CI 1.45 to 1.63] for unadjusted and fully adjusted models, respectively). The risk for DWGF was slightly higher among women with DGF than among men. There was no significant heterogeneity among other subgroups, and the results were robust to sensitivity analyses. Acute rejection within the first year attenuated the DGF-DWGF association. Cardiovascular and infectious deaths were slightly more prevalent in the DGF group, but the relative hazards of cause-specific death were similar between DWGF and deaths during total follow-up. In summary, DGF associates with an increased risk for DWGF; the mechanisms underlying the negative impact of DGF require further study.

SUCCESSFUL RENAL TRANSPLANTATION IN PATIENTS WITH T-CELL REACTIVITY TO DONOR

A positive crossmatch due to T-cell reactivity against donor cells is considered a strong contraindication to renal transplantation because of the risk of graft loss from rejection. However, the significance of T-cell reactivity before but not at the time of transplantation is unknown. To determine whether transplantation can be successful under these circumstances, graft survival was observed in 15 highly sensitised patients whose T cells were reactive to donor sera before but not at the time of transplantation. All patients have been followed up for at least 1 year post transplant. Immunosuppression was by azathioprine, prednisone, and rabbit antithymocyte sera. 9 (60%) have functioning grafts and a mean serum creatinine of 1.6 mg/dl. Early non-function occurred in 12 patients. One graft was lost to early acute humoral rejection and two other to chronic rejection. 14 of the 15 had a fall in reactivity to a panel of normal lymphocytes before transplant. 4 of the 15 had donor-specific B-cell antibodies at the time of transplantation and 3 of these lost their grafts because of rejection.

The role of anti-non-Gal antibodies in the development of acute humoral xenograft rejection of hDAF transgenic porcine kidneys in baboons receiving anti-Gal antibody neutralization therapy.

Background. The present study was undertaken to determine the role of preformed and induced anti-non-Gal antibodies in the rejection of hDAF pig-to-baboon kidney xenotransplants after anti-Gal antibody neutralization therapy. Methods. Seven baboons received life-supporting kidney transplants from hDAF transgenic pigs. Anti-Gal antibodies were neutralized by GAS914 or TPC (a Gal PEG glycoconjugate polymer). Group 1 (n=5) underwent a conventional immunosuppressive therapy with FK506, rabbit anti-thymocyte serum/immunoglobulin, mycophenolate mofetil, and steroids. Group 2 (n=2) received an anti-humoral immunity regimen with LF15-0195, Rituxan and cobra venom factor in addition to ATG, FK506 and steroids. Levels of anti-non-Gal antibodies and their mediated complement-dependent cytotoxic activities (CDC) were detected by flow cytometry using Gal knockout (k/o) pig lymphocytes (LC) or endothelial cells (EC) as targets. Results. Continuous infusion of GAS914/TPC significantly reduced anti-Gal antibodies. In Group 1, four of five baboons developed severe acute humoral xenograft rejection (AHXR) and the rejection was associated with either a high level of preformed anti-non-Gal IgG or a marked elevation in induced anti-non-Gal IgG and IgM. Sera collected at the time of AHXR had a high level of CDC to porcine LC/EC from Gal k/o animals. The intensive anti-humoral therapy in Group 2 completely inhibited both anti-Gal and non-Gal antibody production and prevented AHXR. However, this therapy was not well tolerated by the baboons. Conclusion. In a pig-to-baboon kidney transplant model, both preformed and induced anti-non-Gal antibodies are strongly associated with the pathogenesis of AHXR when anti-Gal antibodies are neutralized.

A comparison of rabbit antithymocyte serum and OKT3 as prophylaxis against renal allograft rejection

A total 166 first cadaveric renal allograft recipients were randomly assigned to receive either rabbit antithymocyte serum (RATS) (n = 83) or OKT3 (n = 83) for 10 to 14 days after transplant as prophylaxis against rejection. Both groups were similar with respect to age, sex, donor age, diabetes, time on dialysis, panel-reactive antibody, HLA matching, and transfusion before transplantation. All patients were followed for 1 year after transplantation. A comparison of the rejection rates between the 2 groups of patients showed that patients receiving OKT3 had a rate of first rejection 1.87 times higher than those receiving RATS (95% confidence interval 1.18-2.8, P = 0.007). Twenty-five steroid-resistant rejections occurred in OKT3-treated patients as compared with 12 in the RATS-treated group (P < 0.05). There was no significant difference in early or late renal function between the 2 groups of patients. Actuarial 1-year graft survival for the RATS group was 78% and for the OKT3 group, 80.7% (P = NS). Actuarial 1-year patient survival was similar: 89.5% in the RATS group and 94.6% in the OKT3 group (P = NS). Total hospitalization time was 29.8 +/- 19.9 days for RATS vs. 39.5 +/- 22.1 days for those treated with OKT3 (P < 0.006). A number of infections were observed but there were no significant differences between the groups. We conclude that RATS provides better prophylaxis than OKT3 in first cadaveric renal transplants because it is associated with fewer rejection episodes, less hospitalization, and no additional morbidity or mortality.

A randomized controlled trial of verapamil on cyclosporine nephrotoxicity in heart and lung transplant recipients.

BACKGROUND Cyclosporine (CsA) is a potent immunosuppressive drug widely used in organ transplantation and in the treatment of autoimmune diseases (1, 2). However, its common nephrotoxic effect is a major limiting factor. Short-term CsA treatment has been shown to cause reversible renal vasoconstriction, whereas long-term treatment can lead to an afferent arteriolopathy and chronic renal failure. METHODS We performed a randomized controlled trial to examine the short-term renal effects of verapamil in 32 CsA-treated heart or lung transplant recipients. Sixteen patients each were randomized to receive a 6-week course of verapamil or control treatment (atenolol in hypertensive patients and placebo in normotensive patients) 1-2 months after transplantation. An 8-hr sequential clearance study of inulin and p-aminohippuric acid for estimating glomerular filtration rate and renal plasma flow, respectively, was performed at baseline and at completion of study. The integral area under the curve of the clearance parameter over 8 hr was then calculated to generate a clearance-time index. RESULTS There was no difference in the clearance-time indices for inulin and p-aminohippuric acid between the two groups at baseline. However, at the completion of study, the within-group change in the glomerular filtration rate clearance-time index was different between the verapamil and control groups (48+/-20 vs. -35+/-17 ml/min/1.73 m2 x hr, respectively; P=0.0038). A similar trend was seen for renal plasma flow, but did not reach statistical significance. Mean arterial blood pressure and whole-blood CsA levels did not differ between the two groups during the study. Verapamil treatment was also associated with a decrease in CsA dose requirement (7.6+/-0.58 mg/kg/day at baseline vs. 4.6+/-0.40 mg/kg/day at completion; P<0.001) without any significant change in trough whole blood CsA levels. Rejection episodes did not differ between the two groups. CONCLUSIONS The use of verapamil in the heart or lung transplant recipients may therefore provide both renal protective effects and cost savings.

Percutaneous Needle Biopsy of the Transplanted Kidney: Technique and Complications

Over 11 1/2 years, 420 percutaneous needle biopsies were obtained from the transplanted kidneys of 205 patients at one institution. The procedure was performed by one nephrologist and 55 nephrology trainees. No limit was placed on the number of biopsies performed on one kidney, and the highest number was seven. The complications were macroscopic hematuria in 28 biopsies, prolonged hematuria (greater than 24 hours) in eight, transient anuria in five, and prolonged anuria requiring surgical intervention in one. Perinephric hematoma occurred in three patients; retroperitoneal hematoma led to compression of the iliac vein in one. None of these complications led to loss of the transplant. It is suggested that the freedom from serious complication is related to the safety of the technique and the precautions applied to preparation of the patient. These are described in detail.

Improvement in rejection of human decay accelerating factor transgenic pig-to-primate renal xenografts with administration of rabbit antithymocyte serum.

Background. Survival in pig-to-baboon kidney xenotransplantation is currently limited by acute humoral xenograft rejection (AHXR). We hypothesized that the administration of rabbit antithymocyte serum (RATS) would delay or prevent AHXR as compared with a cyclophosphamide (CyP)-based immunosuppressive regimen. Methods. Nine baboons received life-supporting heterotopic single-kidney transplants from human decay accelerating factor transgenic pigs. Immunosuppression consisted of GAS (a galactosyl &agr;-1,3-galactose analog), cyclosporine, and steroids. Group 1 (n=2) was also treated with CyP and a rapamycin derivative (RAD), group 2 (n=4) received RATS and RAD, and group 3 (n=3) received only RATS. Animals were maintained until death or sacrifice because of uncontrollable rejection or other complications. Graft histopathology was assessed at the study endpoint. Results. Mean survival was 28±11.3 days, 23±2.5 days, and 20±2.5 days for groups 1, 2, and 3 (not significant). Graft rejection was the cause of death in both CyP-treated animals. One RATS-treated animal died of rejection; the others died of infections or bleeding. Two RATS-treated animals developed posttransplant lymphoproliferative disorder, and one died of cytomegalovirus pneumonitis. Histopathology revealed severe AHXR in group 1 kidneys, involving 100±0% of the tissue examined. In contrast, AHXR was reduced in groups 2 and 3, involving 21±14% and 18±28%, respectively, of the tissue examined (P <0.01). Conclusions. Substitution of RATS for CyP was well tolerated and resulted in reduced severity of AHXR in this model. Complications seen in RATS-treated animals may be preventable through the use of standard prophylaxis for infections. Our data suggest that further studies are warranted to explore the use of antilymphocyte agents in xenotransplantation.