Reciprocity to Increase Participation of Compatible Living Donor and Recipient Pairs in Kidney Paired Donation.

Inclusion of compatible living donor and recipient pairs (CPs) in kidney paired donation (KPD) programs could increase living donor transplantation. We introduce the concept of a reciprocity-based strategy in which the recipient of a CP who participates in KPD receives priority for a repeat deceased donor transplant in the event their primary living donor KPD transplant fails, and then we review the practical and ethical considerations of this strategy. The strategy limits prioritization to CPs already committed to living donation, minimizing the risk of unduly influencing donor behavior. The provision of a tangible benefit independent of the CP's actual KPD match avoids many of the practical and ethical challenges with strategies that rely on finding the CP recipient a better-matched kidney that might provide the CP recipient a future benefit to increase KPD participation. Specifically, the strategy avoids the potential to misrepresent the degree of future benefit of a better-matched kidney to the CP recipient and minimizes delays in transplantation related to finding a better-matched kidney. Preliminary estimates suggest the strategy has significant potential to increase the number of living donor transplants. Further evaluation of the acceptance of this strategy by CPs and by waitlisted patients is warranted.

Poor seroprotection but allosensitization after adjuvanted pandemic influenza H1N1 vaccine in kidney transplant recipients.

BACKGROUND: Seasonal and pandemic influenza virus infections in renal transplant patients are associated with poor outcomes. During the pandemic of 2009-2010, the AS03-adjuvanted monovalent H1N1 influenza vaccine was recommended for transplant recipients, although its immunogenicity in this population was unknown. We sought to determine the safety and immunogenicity of an adjuvant-containing vaccine against pandemic influenza A H1N1 2009 (pH1N1) administered to kidney transplant recipients. METHODS: We prospectively enrolled 124 adult kidney transplant recipients in the fall of 2009 at two transplant centers. Cohort 1 (n = 42) was assessed before and after pH1N1 immunization, while Cohort 2 (n = 82) was only assessed post immunization. Humoral response was measured by the hemagglutination inhibition assay. Vaccine safety was assessed by adverse event reporting, graft function, and human leukocyte antigen (HLA) alloantibody measurements. RESULTS: Cohort 1 had a low rate of baseline seroprotection to pH1N1 (7%) and a low rate of seroprotection after immunization (31%). No patient <6 months post transplant (n = 5) achieved seroprotection. Seroprotection rate was greater in patients receiving double as compared with triple immunosuppression (80% vs. 24%, P = 0.01). In Cohort 2, post-immunization seroprotection was 35%. In both cohorts, no confirmed cases of pH1N1 infection occurred. No difference was seen in estimated glomerular filtration rate before (54.3 mL/min/1.73 m(2) ) and after (53.8 mL/min/1.73 m(2) ) immunization, and no acute rejections had occurred after immunization at last follow-up. In Cohort 1, 11.9% of patients developed new anti-HLA antibodies. CONCLUSION: An adjuvant-containing vaccine to pH1N1 provided poor seroprotection in renal transplant recipients. Receiving triple immunosuppression was associated with a poor seroresponse. Vaccination appeared safe, but some patients developed new anti-HLA antibodies post vaccination. Alternative strategies to improve vaccine responses are necessary.

The impact of pancreas transplantation on kidney allograft survival.

Whether pancreas after kidney transplantation (PAK) compromises kidney allograft survival, and what pre-PAK glomerular filtration rate (GFR) should be used to select patients for PAK is unclear. We analyzed all (n = 2776) PAK recipients in the United States between 1989 and 2007 and compared their risk of kidney failure to a comparator group of n = 13 635 young adult diabetic kidney only transplant recipients during the same time after accounting for selection bias by the use of a propensity score for PAK in a multivariate time to event analysis. In a secondary analysis, we determined the association of pre-PAK GFR with subsequent kidney allograft survival. Despite an increased risk of death early after pancreas transplantation, PAK recipients had a decreased long-term risk of kidney allograft failure compared to diabetic kidney only transplant recipients HR = 0.89; 95% CI: [0.78-1.00]; p = 0.05. An association of pre-PAK GFR with kidney survival was not evident until 3 years after pancreas transplantation, and patients with a pre-PAK GFR of 30-39 mL/min still attained 10-year post-PAK kidney survival of 69%. We conclude that PAK is associated with improved kidney allograft survival, and pre-PAK GFR 30-39 mL/min should not preclude PAK. Expanded use of PAK is warranted.

Renal function changes over time in adult recipients of small pediatric kidneys. Evidence against hyperperfusion injury.

There has been considerable debate regarding the use of pediatric donor kidneys in adults with end-stage renal disease. These small kidneys may not be able to deal with the metabolic demands of the large adult size, and thus pediatric kidneys may be at higher risk of loss due to hyperperfusion injury. To study the impact of small kidney size on renal outcome, we studied two groups of patients. This retrospective review of patients at a single institution compared recipients of pediatric renal transplants (age < 7 years, n = 37) to a matched group of adult-kidney recipients (1:2 ratio, n = 74). The groups were matched for age, sex, diabetic status, HLA type, and duration of follow-up. Primary outcomes of interest were: calculated creatinine clearance at 6 months, 1 year, 2 years, and 3 years after transplantation and evidence of hyperperfusion damage as determined by proteinuria, graft biopsy, and late graft loss due to chronic rejection. This study demonstrates no significant difference in calculated creatinine clearance between pediatric and adult transplants at 6 months (43.8 vs. 50.7 ml/min, respectively) or at 3 years after transplantation (56.3 vs. 56.2 ml/min), nor was there any evidence of increased proteinuria or late graft loss in the pediatric-kidney recipients compared with adult-kidney recipients. Our data do not demonstrate the detrimental effects of small kidney size relative to recipient on subsequent renal outcomes, and thus support the practice of pediatric donor kidneys being used in adult recipients when pediatric recipients are not available.

Successful renal transplantation with ipsilateral femoral arteriovenous grafts.

BACKGROUND: The choice of location for revascularization of a renal allograft is frequently influenced by the presence of previous pelvic surgery or failed allografts that remain in situ. The presence of polytetrafluoroethylene (PTFE) loop grafts in the femoral vessels may potentially result in iliac venous hypertension, thereby compromising the function of a renal allograft placed nearby. The purpose of this study is to report the hemodynamic changes within the iliac veins as a result of PTFE femoral grafts and report the outcome of renal allografts placed ipsilateral to such grafts. METHODS: THREE patients with a failed renal allograft in the right iliac fossa and functioning left groin PTFE loop grafts underwent left iliac venography and hemodynamic measurements of the iliac venous system. All three patients underwent renal transplantation in the left iliac fossa without ligation or alteration of the loop graft. Standard clinical data were collected after transplantation. RESULTS: All three patients demonstrated widely patent external iliac and common iliac veins ipsilateral to the loop graft. Elevated pressures measured within the venous limb of the loop graft dissipated rapidly within the common femoral and external iliac veins. All three kidneys were well perfused, as documented by posttransplant technetium 99m-diethylenetriaminepentaacetic acid nuclear renography. All three patients have normal renal function past 7 months after transplant, and all three femoral loop grafts are still functioning. CONCLUSIONS: PTFE loop grafts to the femoral vessels are not associated with local venous hypertension in the ipsilateral external iliac veins. Revascularization of a renal allograft may be performed ipsilateral to a femoral loop graft provided other venous diseases, such as strictures, have been excluded.

In vitro immunoglobulin production in long-term renal transplant recipients.

The difference in immunoregulation between stable renal transplant recipients and patients undergoing chronic rejection is unknown. In stable transplant recipients humoral responses to the allograft are controlled, but in patients with chronic rejection this control appears to be lost. In this study we evaluate B cell function in 24 stable transplant recipients and 5 patients with chronic rejection, using pokeweed mitogen (PWM)-stimulated in vitro lymphocyte production of immunoglobulin (Ig). Stable patients and patients with chronic rejection were similar with respect to time posttransplant, age, degree of HLA-A and B matching and immunosuppressive therapy. Unstimulated immunoglobulin production and serum immunoglobulin levels were similar in both groups and within the normal range. PWM stimulated IgG, and IgM production was significantly depressed in stable patients compared with normal controls and patients with chronic rejection. Patients with chronic rejection had normal PWM-stimulated Ig production. Mononuclear cell subsets--as determined by the monoclonal antibodies T4, T8, T11, B1, and M02, as well as the ratio of T4 to T8--were similar in the two patient groups and within the normal range. There was no correlation between decreased Ig production and decreased T4/T8 ratio. We conclude that stable renal transplant recipients have impaired in vitro humoral responses that may be important in maintaining allograft tolerance. In patients with chronic rejection PWM-stimulated responses have escaped control, and this may be important in the pathogenesis of antibody-mediated graft damage. Impaired Ig production in stable patients may be due to a suppressor cell mechanism--however, quantitative measurements of suppressor cells and the T4/T8 ratio do not predict humoral unresponsiveness.

Investigation of a possible interaction between ciprofloxacin and cyclosporine in renal transplant patients.

BACKGROUND: Bacterial infection is a common complication during the first few months after renal transplantation. Ciprofloxacin, a fluoroquinolone broad-spectrum antibiotic, is used frequently in treating infections in the early posttransplant period. Evidence from in vitro studies has suggested that ciprofloxacin can antagonize the cyclosporine (CsA)-dependent inhibition of interleukin-2 production. Such an effect in renal transplant patients could antagonize the immunosuppressive activity of CsA and lead to rejection of the graft. METHODS: To investigate the possibility of a pharmacodynamic interaction between ciprofloxacin and CsA, we conducted a case-control study in 42 patients who had received a kidney transplant and who were prescribed ciprofloxacin in the first 1-6 months after transplantation and in their matched controls (two per case) who did not receive ciprofloxacin during the study period. RESULTS: There was a twofold greater incidence (P=0.008) of ciprofloxacin use at 1-3 months (65%) than was observed at 4-7 months (35%) after transplantation. The proportion of cases experiencing at least one episode of biopsy-proven rejection 1-3 months posttransplant (45%) was significantly greater (P=0.004) than that of controls (19%). Furthermore, there was a marked increase (P<0.001) in the incidence of rejection temporally associated with ciprofloxacin use among cases (29%) compared with that experienced by the controls (2%). CONCLUSIONS: The possibility that ciprofloxacin increases rejection rates in renal transplant patients may be of clinical importance and therefore warrants further investigation.

Racial differences between solid organ transplant donors and recipients in British Columbia: a five-year retrospective analysis.

BACKGROUND: We attempted to determine whether significant racial differences exist between organ donors and transplant recipients in British Columbia, and whether differences exist between individual organ transplant programs (lung, heart, kidney, liver, and pancreas). The design of the study was a retrospective review. METHODS: We used the database of the British Columbia Transplant Society, a provincial agency, for the years 1992 to 1997 inclusive. The outcome measures were a comparison of racial characteristics of organ donors and transplant recipients collectively and by individual organ transplant program. RESULTS: There were 236 organ donors and 766 transplant recipients. Comparing racial groups between donors and recipients, Caucasians contributed the most donors (93.2%) but received proportionately fewer organs (73.4%, P<0.000001). Orientals donated 3.4% of all organs but constituted 14.4% of all recipients (P<0.00001). Non-Oriental, non-Caucasians (predominantly Asian Indians and Native Aboriginals) constituted 3.4% of all donors and 12.2% of all recipients (P=0.0001). Among the individual organ transplant programs, lung, heart, and pancreas recipients were predominantly Caucasian (148 of 156 recipients). Oriental recipients were more likely to be kidney recipients (19.8% of all kidney recipients) compared with all Oriental recipients (P<0.000001). Likewise, Asian Indians were more likely to be kidney recipients (7.2% of all kidney recipients) compared with all Asian Indian recipients (P<0.0001). Native Aboriginals, however, were more likely to be liver allograft recipients (8.3% of all liver transplants) than nonliver allograft recipients (P=0.017). CONCLUSIONS: In British Columbia, disparity exists between Oriental and non-Oriental, non-Caucasian donors and recipients. Orientals and Asian Indians were more likely to be kidney graft recipients than nonkidney graft recipients, whereas Native Aboriginal recipients seemed more likely to have undergone liver transplantation.

A pilot study of steroid-free immunosuppression in the prevention of acute rejection in renal allograft recipients.

BACKGROUND: Corticosteroids have been a mainstay of rejection prophylaxis for several decades, despite the multiple adverse effects of long-term use, including weight gain, hyperlipidemia, diabetes, hypertension, and bone disease. The detrimental effect of steroids on the metabolic profile begins in the early posttransplantation period, and the complete avoidance of steroids in transplantation would therefore be optimal. We hypothesized that the addition of mycophenolate mofetil (MMF) and a humanized monoclonal anti-CD25 antibody (daclizumab) to a cyclosporine (CsA microemulsion)-based immunosuppression protocol would permit transplantation without steroids. METHODS: Steroid-free renal transplantation was attempted in 57 patients treated with daclizumab, MMF, and CsA. Twenty-eight patients received kidneys from living donors; the remaining 29 received cadaveric grafts. RESULTS: At 1 year, patient and graft survival were 95% and 89%, respectively. Fourteen patients (25%) experienced rejections, of which 13 were readily reversed with steroids; 1 patient required OKT3. Mean serum creatinine at 12 months for patients not experiencing rejection was 149+/-58 micromol/L, compared with 158+/-102 micromol/L for those experiencing rejection. Five patients required hospitalization for infection; no patients developed lymphoproliferative disease. At baseline, 17 patients required 3 or more antihypertensive medications, compared with 2 patients at 1 year. Three of 43 nondiabetic patients developed diabetes during the study. There was no significant reduction in lumbar or femoral bone density. CONCLUSIONS: On the basis of these positive results, we believe steroid avoidance with this immunosuppressive regimen merits further study.

Living anonymous kidney donation: what does the public think?

BACKGROUND: Health professionals are increasingly turning to living organ donation to augment cadaveric donation. Although living donation is currently performed with donors who are either genetically or emotionally related to the recipient, a 1997 British Columbia Transplant Society survey indicated that 32% of BC residents would be willing to donate a kidney, while alive, to a stranger (unpublished data). The goal of this study is to tap the public pulse about the living anonymous donor (LAD) by replicating and expanding the 1997 findings. METHODS: Five hundred BC residents completed a telephone survey including demographic information, questions about their organ donation behaviors and attitudes, and their willingness to donate a kidney, while alive, to particular individuals (child, spouse, parent, relative, friend, and stranger). To improve the methodological rigor of the 1997 study, an informed condition was added in the current study where participants learned about living donation before being asked about their willingness to donate. RESULTS: There were no differences among the 1997 results and the two conditions in the 2000 survey. Twenty-eight percent of participants in the uninformed condition and 29% of participants in the informed condition indicated that they would be willing to be LADs. LADs were more likely than self-reported non-donors to have registered as cadaveric donors and to endorse attitudes that were congruent with wanting to donate to a stranger. CONCLUSIONS: This study replicates the 1997 findings and increases confidence that a significant minority of British Columbians support living anonymous donation and that some would consider becoming LADs themselves.

The quality of initial function following renal transplantation determined by creatinine elimination kinetics. Comparison of Minnesota antilymphocyte globulin and cyclosporine induction immunosuppression.

To compare the effect of type of induction immunosuppression on the quality of initial renal allograft function, we identified 35 cadaver donor kidney pairs in which one recipient of a kidney from a given pair received induction immunosuppression with Minnesota antilymphocyte globulin (MALG group) while the recipient of the contra-lateral kidney received cyclosporine from day zero (CsA group). In the absence of an existing quantitative measure to assess and compare the status of those grafts that function primarily, we defined the half-life of creatinine elimination (t1/2SCr) as such an outcome measure based on a review of creatinine elimination kinetics. All organs were procured with in-situ perfusion and en-bloc removal. Total cold storage times, rewarm times, and perioperative management were comparable for the two groups. In the MALG group, the mean t1/2SCr) was not different from that in the CsA group (1.38 +/- 0.96 days vs 1.35 +/- 1.2 days P = NS). Multiple regression analysis performed on the differences in recipient age, number of DR-B locus matches, total cold ischemia time, rewarm time, and central venous pressure at reperfusion of a given donor pair demonstrated no significant impact of any of these differences on the difference in t1/2SCr for the same pair set in this sample. The nadir of serum creatinine achieved in the first five days posttransplant was somewhat higher in the CsA group (234 +/- 131 mumol/L) as compared with the MALG group (200 +/- 132 mumol/L) but the difference was not significant. A similar nonsignificant trend was observed in the comparison of mean serum creatinine values at 30 days posttransplant (MALG group: 158 +/- 62 mumol/L vs. CsA group: 200 +/- 141 mumol/L). Only one of seventy recipients (CsA group) was dialyzed within the first 5 days posttransplant for an overall incidence of ATN of less than 2%. Fourteen of 35 (40%) recipients in both groups received treatment for acute rejection. The mean time to first treatment for acute rejection episode was shorter in the CsA group than the MALG group (10 +/- 8 days vs 23 +/- 24 days, P = 0.055). Graft survival at one year was not different for the two groups (92% vs. 87% for the MALG and CsA groups respectively, P = NS).(ABSTRACT TRUNCATED AT 400 WORDS)

A randomized, prospective multicenter pharmacoepidemiologic study of cyclosporine microemulsion in stable renal graft recipients. Report of the Canadian Neoral Renal Transplantation Study Group.

BACKGROUND: The safety, tolerability, and pharmacokinetics of conventional cyclosporine (ConCsA) and cyclosporine microemulsion (MeCsA) were compared under conditions of normal clinical practice in a prospective, randomized, concentration-controlled, pharmacoepidemiologic study. METHODS: Between September 1994 and March 1995, 1097 stable renal transplant recipients in 14 Canadian centers were randomized 2:1 to treatment with MeCsA or ConCsA. Patients were commenced on each study drug at a dose equal to their previous therapy with ConCsA, and the dose was adjusted to maintain predose whole blood cyclosporine concentrations within the therapeutic range established for each center. Prednisone and azathioprine were continued unless dose adjustment was required for clinical reasons. RESULTS: The mean cyclosporine concentration was comparable in both treatment groups at all time points throughout the 6 months of follow-up. The mean dose of cyclosporine was 3.6 mg/kg/day in both treatment groups at entry to the study, and declined by 0.3% and by 2.8% in patients receiving ConCsA and MeCsA, respectively. The nature and severity of adverse events were similar in both treatment groups, but there was a transient increase in neurological and gastrointestinal complications in the group receiving MeCsA within the first month after conversion (P<0.05). Serum creatinine and creatinine clearance did not change in either treatment group throughout the study. Biopsy-proven acute rejection occurred in three patients (0.8%) receiving ConCsA and in seven patients (0.9%) receiving MeCsA, with non-histologically proven acute rejection in an additional three patients (0.8%) receiving ConCsA and five patients (0.6%) receiving MeCsA (P=NS). Serum creatinine rose transiently in 35 patients (9.8%) receiving ConCsA and 138 patients (18.7%) receiving MeCsA (P<0.05) and resolved either spontaneously or after a reduction in the cyclosporine dose. One graft was lost in the MeCsA group due to irreversible rejection, and seven patients died, three in the group receiving ConCsA and four of those receiving MeCsA (P=NS). Absorption of cyclosporine was more rapid and complete from MeCsA than from ConCsA during the first 4 hr of the dosing interval, resulting in almost 40% greater exposure to the drug (P<0.001). There was close correlation between area under the time-concentration curve (AUC) over the first 4 hr of the 12-hr dosage interval and AUC over the entire 12-hr dosage interval for both formulations, making AUC over the first 4 hr a good predictor of total cyclosporine exposure. Using this parameter, patients with low absorption randomized to receive MeCsA showed a marked increase in drug exposure by months 3 and 6, whereas there was no change in those who continued on ConCsA. A limited sampling strategy utilizing samples at the predose and postdose trough levels provided an excellent correlation with drug exposure, particularly for patients receiving MeCsA (r2=0.94 MeCsA vs. r2=0.89 ConCsA). CONCLUSIONS: MeCsA appears to be a safe and effective therapy in stable renal transplant patients and provides superior and more consistent absorption of cyclosporine when compared with ConCsA. Transient toxicity after conversion to MeCsA occurs in some patients, and may reflect the increased exposure to cyclosporine. Use of a limited sampling approach combining trough and 2-hr postdose concentrations may provide an effective way to monitor this exposure.

Safety and tolerability of cyclosporine and cyclosporine microemulsion during 18 months of follow-up in stable renal transplant recipients: a report of the Canadian Neoral Renal Study Group.

BACKGROUND: There has been concern that the increased drug exposure associated with treatment with cyclosporine microemulsion (CsA-ME) would lead to an increase in adverse events. METHODS: The long-term safety and tolerability of conventional cyclosporine (CsA) and CsA-ME were compared in a randomized, multicenter, pharmacoepidemiologic study involving 1097 stable renal transplant patients after 18 months of follow-up. RESULTS: No significant difference was seen in change in serum creatinine or calculated creatinine clearance between the two groups. Episodes of deterioration in renal function (change in serum creatinine > or = 20%) were categorized with the following results for CsA-ME versus CsA, respectively: acute rejection, 4.5% vs. 4.5%; chronic rejection, 8% vs. 11%; CsA nephrotoxicity, 12% vs. 7% (P=0.008); transient changes, 17% vs. 12%; other causes, 4% vs. 6%. During the first 6 months of the study, a transient increase in the incidence of gastrointestinal and neurological adverse events was seen in the CsA-ME group compared with the CsA group. Up to 18 months, patients in the CsA group reported significantly fewer hearing and vestibular disorders, but more cardiovascular problems than those in the CsA-ME group (P=0.035). CONCLUSIONS: Tolerance to CsA and CsA-ME was similar. Renal function over 18 months was not adversely affected by the increased drug exposure with CsA-ME, although there was a transient increase in nephrotoxicity. The frequency of acute and chronic rejection did not change.

Lack of long-term benefits of steroid withdrawal in renal transplant recipients.

Glucocorticoids used in renal transplantation have been associated with numerous adverse effects. Most studies that showed short-term benefits of steroid withdrawal made comparisons for patients administered prednisone, 10 to 17.5 mg/d, versus no prednisone. Few have studied long-term benefits of steroid withdrawal. We performed a retrospective review and identified 58 patients administered cyclosporine, azathioprine, and prednisone who underwent complete steroid withdrawal. Post-steroid withdrawal follow-up was 7.6 +/- 1.9 years. Nine patients restarted prednisone therapy, 3 patients lost their grafts (2 of those restarted on prednisone therapy), and 2 patients died with functioning grafts. When prednisone dosage was tapered from 10 mg/d to 10 mg every other day, clinically significant improvements were seen in weight, systolic and diastolic blood pressure, blood pressure medications, glycosylated hemoglobin level, and diabetic medications. No further benefits were seen in these parameters and total cholesterol level on complete steroid withdrawal from prednisone, 10 mg every other day. Most of the earlier benefits were not sustained on long-term follow-up, and the increase in these parameters was similar to that of a similar matched control group (that underwent transplantation during the same period) maintained on prednisone, 5 mg/d. Major differences were decreases in creatinine clearances and hemoglobin levels, which were greater in the steroid-withdrawal group (7.4 +/- 1.9 mL/min and 1.2 +/- 0.2 g/dL, respectively) compared with the control group (2.6 +/- 1.5 mL/min and 0.5 +/- 0.2 g/dL, respectively). In conclusion, most of the metabolic benefits were seen with steroid dosage taper from prednisone, 10 mg/d to 10 mg every other day, with no further benefits with steroid withdrawal. Most of these benefits were not sustained on long-term follow-up, questioning the utility of steroid withdrawal.

Prostatic carcinoma following renal transplantation.

A case of prostatic carcinoma diagnosed after renal transplantation is described. Treatment was chosen according to current principles of staging of the disease, and radical prostatectomy proved to be technically feasible after renal transplantation. Immunosuppressive therapy has been continued without apparent consequence to the disease so far. Until there is definite evidence that immunosuppression adversely affects the prognosis of prostatic carcinoma, the decision to terminate immunosuppressive therapy should be based on individual circumstances, such as the response to treatment, the rate of progression of the disease, and the availability of additional treatment for the disease that would be expected to improve prognosis in the absence of immunosuppression.