Mikel Prieto

Complete avoidance of calcineurin inhibitors in renal transplantation : A randomized trial comparing sirolimus and tacrolimus

Calcineurin inhibitors have decreased acute rejection and improved early renal allograft survival, but their use has been implicated in the development of chronic nephrotoxicity. We performed a prospective, randomized trial in kidney transplantation comparing sirolimus‐MMF‐prednisone to tacrolimus‐MMF‐prednisone. Eighty‐one patients in the sirolimus group and 84 patients in the tacrolimus group were enrolled (mean follow‐up = 33 months; range 13–47 months). At 1 year, patient survival was similar in the groups (98% with sirolimus, 96% with tacrolimus; p = 0.42) as was graft survival (94% sirolimus vs. 92% tacrolimus, p = 0.95). The incidence of clinical acute rejection was 10% in the tacrolimus group and 13% in the sirolimus group (p = 0.58). There was no difference in mean GFR measured by iothalamate clearance between the tacrolimus and sirolimus groups at 1 year (61 ± 19 mL/min vs. 63 ± 18 mL/min, p = 0.57) or 2 years (61 ± 17 mL/min vs. 61 ± 19 mL/min, p = 0.84). At 1 year, chronicity using the Banff schema showed no difference in interstitial, tubular or glomerular changes, but fewer chronic vascular changes in the sirolimus group. This study shows that a CNI‐free regimen using sirolimus‐MMF‐prednisone produces similar acute rejection rates, graft survival and renal function 1–2 years after transplantation compared to tacrolimus‐MMF‐prednisone.

Wound-healing complications after kidney transplantation: a prospective, randomized comparison of sirolimus and tacrolimus.

Background. Sirolimus has been associated with an increased risk of wound-healing complications in several retrospective analyses. The authors compared the rates of wound-healing complications in renal allograft recipients in a prospective, randomized trial of sirolimus-mycophenolate mofetil-prednisone versus tacrolimus-mycophenolate mofetil-prednisone. Methods. All patients received antithymocyte globulin induction. In the first phase of the study, patients (n=77) were included regardless of body mass index (BMI). In the second phase (n=46 patients), the authors excluded patients with a BMI greater than 32 kg/m2, and the target trough sirolimus level was lowered to 10 to 15 ng/mL (previously 15–20 ng/mL). Multivariate logistic regression analyses were performed to identify predictors of wound complications. Results. Fifty-nine patients received tacrolimus and 64 received sirolimus and were included in subsequent analyses. The incidence of complications was 8% (5 of 59) in the tacrolimus group and 47% (30 of 64) in the sirolimus group (P <0.0001). Rates of perigraft fluid collections, superficial wound infections, and incisional herniae were significantly higher in the sirolimus group. Multivariate logistic regression showed only sirolimus (P =0.0001) and BMI (P =0.0021) to independently correlate with complications. In the first phase of the study, the wound complication rate in the sirolimus group was 55% (21 of 38 patients). After excluding obese recipients and decreasing the target sirolimus level, the wound complication rate in the sirolimus group was 35% (9 of 26 patients; P =0.1040). Conclusions. The use of sirolimus-based immunosuppressive regimens leads to a higher incidence of wound-healing complications and will require new approaches to patient selection and management to decrease their incidence.

Overcoming a Positive Crossmatch in Living‐Donor Kidney Transplantation

Many patients who have an otherwise acceptable living‐kidney donor do not undergo transplantation because of the presence of antibodies against the donor cells resulting in a positive crossmatch. In the current study, 14 patients with a positive cytotoxic crossmatch (titer ≤ 1 : 16) against their living donor underwent a regimen including pretransplant plasmapheresis, intravenous immunoglobulin, rituximab and splenectomy. Eleven of 14 grafts (79%) are functioning well 30–600 days after transplantation. Two grafts were lost to accelerated vasculopathy and one was lost to death with good function. No hyperacute or cellular rejections occurred. Antibody‐mediated rejection occurred in six patients [two clinical (14%) and four subclinical (29%)] and was reversible with plasmapheresis and steroids. Our results suggest that selected crossmatch‐positive patients can be transplanted successfully with living‐donor kidney allografts, using a protocol of pretransplant plasmapheresis, intravenous immunoglobulin, rituximab and splenectomy. Longer follow‐up will be needed, but the absence of anti‐donor antibody and good early outcomes are encouraging.

ABO-incompatible kidney transplantation using both A2 and non-A2 living donors

Background. Given the scarcity of cadaveric organs, efforts are intensifying to increase the availability of living donors. The current study assessed the feasibility of using ABO-incompatible living-donor kidneys to expand the donor pool. Methods. The authors performed 18 ABO-incompatible living-donor kidney transplants between May 1999 and April 2001. Ten patients received living-donor kidneys from A2 and eight patients received kidneys from non-A2 blood group donors. Immunosuppression consisted of Thymoglobulin antibody induction, tacrolimus, mycophenolate mofetil, and prednisone. Eight non-A2 and two A2 kidney recipients also received a pretransplant conditioning regimen of four plasmapheresis treatments followed by intravenous immunoglobulin and splenectomy at the time of transplantation. Antidonor blood group antibody titer was measured at baseline, pretransplant, at 1- to 3-month and 1-year follow-up, and at the time of diagnosis of antibody-mediated rejection. Results. No hyperacute rejection episodes occurred. One-year graft and patient survival rates in the 18 ABO-incompatible recipients were only slightly lower than those of 81 patients who received ABO-compatible kidney transplants during the same period (89% vs. 96% and 94% vs. 99%, respectively). Glomerular filtration rate and serum creatinine levels did not differ between the groups. Antibody-mediated rejection occurred in 28% of ABO-incompatible recipients, and was reversible with plasmapheresis, intravenous immunoglobulin, and increasing immunosuppression in all patients except one. Conclusions. ABO-incompatible living donor kidney transplants can achieve an acceptable 1-year graft survival rate using an immunosuppressive regimen consisting of Thymoglobulin induction, tacrolimus, mycophenolate mofetil, and prednisone combined with pretransplant plasmapheresis, intravenous immunoglobulin, and splenectomy.

Improved Scoring System to Assess Adult Donors For Cadaver Renal Transplantation

We previously proposed a quantitative approach to assess donor organs for cadaver renal transplantation. To improve on our original scoring system, we studied 34 324 patients who received cadaver renal transplants from adult donors between 1994 and 1999 and were reported to the UNOS Scientific Renal Transplant Registry. A scoring system was developed from five donor variables (age, 0–25 points; history of hypertension, 0–4; creatinine clearance before procurement, 0–4; cause of death, 0–3; HLA mismatch, 0–3) that showed a significant correlation with renal function and long‐term graft survival. Cadaver kidneys were stratified by cumulative donor score: grade A, 0–9 points; grade B, 10–19; grade C, 20–29; and grade D, 30–39. The influence of donor score on renal function and graft survival was most severe above 20 points, designated ‘marginal’ kidneys. In summary, a donor scoring system developed from a large population database was useful in predicting outcome after cadaver renal transplantation. The improved system provides a quantitative approach to evaluation of marginal kidneys and may improve allocation of these organs in cadaver renal transplantation.

Obesity in living kidney donors: clinical characteristics and outcomes in the era of laparoscopic donor nephrectomy.

Acceptance of obese individuals as living kidney donors is controversial related to possible increased risk for surgical complications and concern that obesity may contribute to long‐term renal disease. We retrospectively examined 553 consecutive hand‐assisted laparoscopic living kidney donations between October 1, 1999 and April 1, 2003. We stratified donors into quartiles by baseline body mass index (BMI) assessing perioperative complications and 6–12 months post‐donation metabolic and renal function. Compared to BMI <25 kg/m2, high BMI donors (≥35 kg/m2) had slightly longer operative times (mean increase 19 min), more overall perioperative complications (mostly minor wound complications), yet the same low rate of major surgical complications (conversion to open and re‐operation) and similar length‐of‐stay (2.3 vs. 2.4 days). At 6–12 months after donation (mean 11 months), renal function and microalbuminuria did not differ with BMI. These results suggest that laparoscopic donor nephrectomy is generally safe in selected obese donors and does not result in a high rate of major perioperative complications. Obese donors have higher baseline cardiovascular risk and warrant risk reduction for long‐term health. While early results are encouraging, we advocate careful study of obese donors and do not support their widespread use until longer follow‐up is available.

Experimental and clinical experience with urine amylase monitoring for early diagnosis of rejection in pancreas transplantation

Pancreas allograft rejection in dogs with pancreati-cocystostomy can be predicted in advance of hyperglycemia by monitoring the urinary amylase (UA) concentration (U/L): In initial experiments, UA values declined to <1000 1.3±0.2 days before hyperglycemia in non-immunosuppressed dogs, 3.3±1.0 days in dogs treated with cyclosporine (CsA), and 9.3±0.7 days in dogs treated with CsA, azathioprine (Aza), and prednisone (triple therapy). Autotransplanted control dogs maintained high urine amylase concentrations indefinitely (mean 125,544±36,931). In a subsequent experiment, in 19 dogs with bladder-drained pancreas allografts on CsA only for prophylactic immunosuppression, a five-day course of antirejection treatment with Aza (5.0 mg/ kg) and antilymphocyte globulin ALG (1 mg/kg) was started in group A (n = 10) when a raise in serum glucose was detected, and in group B (n = 9) when a drop of UA below 1000 was observed. The functional allograft survival rate was 9.2±0.5 days in group A (treatment started after hyperglycemia) and 29.0±5.7 days in group B (treatment started after drop in UA) (P = .002). The UA dropped in all dogs before hyperglycemia, at a mean of 2.7 days in group A and 20.8 days in group B. Clinically, 8 patients received a whole cadaver pancreas transplant with urinary drainage of the exocrine secretions. All were followed with UA monitoring. Three recipients lost the grafts for technical reasons. One had a primary nonfunction and UA was below 1000 U/24 hr; two developed abscesses and the grafts were removed while functioning with high UA values. Five grafts are currently functioning; 3 recipients had no rejection episodes and their UA values ranged from 30,000 to 100,000 U/24 hr during their entire postoperative course. The other two had rejection episodes. In both cases UA decreased to baseline levels 1 and 4 days in advance of the hyperglycemia. After antirejection treatment UA rose again to high values and plasma glucose levels declined. Both patients are currently in.

The histology of solitary renal allografts at 1 and 5 years after transplantation

Previous studies suggest that the majority of renal allografts are affected by progressive, severe chronic histologic injury, yet studies using current protocols are lacking. The goal of this study was to examine the prevalence and progression of histologic changes using protocol allograft biopsies at 1 and 5 years after solitary kidney transplantation in patients transplanted between 1998 and 2004. Chronic histologic changes generally were mild at both 1 and 5 years and were similar in deceased and living donor kidneys. The overall prevalence of moderate or severe fibrosis was 13% (60/447) at 1 year and 17% (60/343) at 5 years. In a subgroup of 296 patients who underwent both 1‐ and 5‐year biopsies, mild fibrosis present at 1 year progressed to more severe forms at 5 years in 23% of allografts. The prevalence of moderate or severe arteriolar hyalinosis was similar in tacrolimus and calcineurin inhibitor‐free immunosuppression. These results in the recent era of transplantation demonstrate fewer, less severe and less progressive chronic histologic changes in the first 5 years after transplantation than previously reported.

Histologic findings of antibody-mediated rejection in ABO blood-group-incompatible living-donor kidney transplantation.

The purpose of this study was to characterize the histology of antibody‐mediated rejection (AMR) in ABO blood‐group‐incompatible (ABOI) kidney transplants as well as on protocol biopsies performed at the time of stable allograft function. Between 5/99 and 1/02, we performed 32 ABOI kidney transplants (13 A2, 19 non‐A2 blood‐group living donors). Nineteen biopsies were performed for allograft dysfunction, and 127 protocol biopsies were performed 0, 3, 7, 14, 28 days and 3 and 12 months post transplant. Twenty‐five of 32 patients have functioning allografts (mean 585 days post transplant). Nine of 32 (28%) developed clinical AMR. Biopsy revealed glomerular thrombi (78%), mesangiolysis (78%), peritubular capillary C4d staining (56%) and neutrophil infiltration (67%), interstitial hemorrhage and necrosis (56%) and arteriolar thrombi (33%). Subclinical AMR was diagnosed by protocol biopsies in four patients. Findings consisted of glomerular thrombi (100%), mesangiolysis (25%), and C4d staining (100%). In late protocol biopsies performed 214–420 days post transplant, mild mesangiolysis was seen in 2/17 (11.7%), and C4d immunostaining was detected in 3/12 (25%). AMR is characterized by glomerular thrombi, mesangiolysis, peritubular capillary neutrophil infiltration interstitial hemorrhage, necrosis, and C4d deposition. Glomerular thrombi appear early in AMR and may appear prior to graft dysfunction.

Improving the prediction of donor kidney quality: deceased donor score and resistive indices.

Background. The deceased donor score (DDS), expanded criteria donor (ECD) definition, and resistive index (RI) were developed for pretransplant evaluation of donors. DDS and ECD are determined by a calculation of risk from donor variables, while RI is determined from flow characteristics of kidneys during machine preservation (MP). This study was designed to compare DDS, ECD status, and RI as predictors of outcome after deceased donor transplantation. We were also interested to see if DDS or ECD could identify kidneys most likely to benefit from MP. Methods. We retrospectively reviewed 48,952 deceased donor renal transplants reported to UNOS from 1997–2002. DDS (0-39 pts.), ECD status (+ or −), and preservation technique (MP vs. cold storage [CS]) were determined in all cases. RI during MP was studied in a single-center cohort of 425 transplants. Results. DDS was superior to ECD status and RI in its correlation with early and late renal function after transplantation. DDS identified a subgroup of ECD- kidneys, those with DDS ≥20 pts, that functioned significantly below expectation and similar to ECD+ kidneys. Benefits of MP, which include improved early graft function and a trend towards longer graft survival, were greatest in the group of kidneys with DDS ≥20 pts. Conclusions. DDS was the best predictor of outcome after deceased donor renal transplantation and may be useful in identifying kidneys most likely to benefit from MP.