Ana Sánchez-Fructuoso

Victims of Cardiac Arrest Occurring Outside the Hospital: A Source of Transplantable Kidneys

Context Waiting lists for kidney transplants are long. Contribution This study from Madrid, Spain, compared transplantation outcomes of 584 recipients of kidneys from heart-beating donors and 320 recipients of kidneys from nonheart-beating donors who died of cardiac arrest that occurred outside the hospital. One-year (about 90%) and 5-year (about 85%) graft survival rates were similar for transplantations from nonheart-beating donors and those from heart-beating donors who were younger than 60 years of age. Cautions This retrospective study is from a center with a well-developed nonheart-beating donor transplantation program. Implications People who die of cardiac arrest that occurs outside the hospital can be a viable source for kidney transplantations. The Editors The waiting list and waiting time for transplantations will inevitably become longer as the demand for kidneys continues to exceed the supply. The kidney waiting list of the United Network for Organ Sharing currently increases at a rate of 20% per year, and the list will be 100000 to 150000 patients long by the year 2010 (1). The overall annual mortality rate for wait-listed patients for kidney transplants is estimated to be 6.3% (2). While obtaining more organs from brain-dead donors with heartbeats is necessary, additional sources of organs are also needed, which has prompted the use of the nonheart-beating donor. Nonheart-beating donors are categorized into 5 types (Appendix Table) (3). Type I and type II are considered uncontrolled donors because cardiac arrest events in these patients occur outside the hospital and, thus, the transplant team is unaware of them. In type III and type IV nonheart-beating donors, cardiac arrest is managed, or controlled, in the hospital, and the transplant team can prepare for the procurement process. In type V nonheart-beating donors, this aspect can vary. Several reports have discussed the use of nonheart-beating donors (424), and the incidence of this type of donation is increasing. However, most patients described in these studies have in-hospital cardiac arrest, and few references have been made to donors whose deaths occur outside the hospital. Appendix Table. Description of the NonHeart-Beating Donor Types (Maastricht System) In 1989, our institution (Hospital Clnico San Carlos, Madrid, Spain) began a nonheart-beating donor procurement and transplant program. Our hospital is currently the largest procurement center for this type of transplantation in Spain, supplying 46% of the nonheart-beating donor kidneys transplanted in Spain in 1997 (3, 25). Most of our donors are adults who die suddenly outside the hospital and are transferred to the hospital for the sole purpose of donation (Maastricht type I donors) (26). We aimed to compare the graft survival of kidneys from uncontrolled nonheart-beating donors (Maastricht donors type I and II) and kidneys from heart-beating donors. Methods Donor Program In 1989, our hospital started a program to obtain organs from nonheart-beating donors (3). In 1996, we signed a formal agreement with the Madrid emergency facilities (SAMUR, 061, SERCAM) and established a standard protocol for obtaining organs from persons who die suddenly outside the hospital of irreversible cardiac arrest (type I Maastricht donor category) and are transported to our center for organ donation. Before 1996, most of these persons were directly transported to the morgue, but after 1996, patients were transferred to our hospital after unsuccessful cardiovascular pulmonary resuscitation (CPR). This protocol does not affect any CPR maneuver. All measures and times specified in the established CPR procedures are undertaken, and we evaluate the patient as a potential donor only when the cardiac arrest is considered irreversible (when an effective heartbeat cannot be recovered after a stipulated period [usually 30 minutes] or when the lesions provoking the cardiac arrest are incompatible with life). The following conditions should also be met when considering a potential donor: known cause of death, ruling out violence; known time of cardiac arrest; no bleeding injuries to the thorax or abdomen to avoid blood leaks in subsequent cardiopulmonary bypass during procurement; external cardiac massage and mechanical ventilation performed within 15 minutes of the cardiac arrest; no external signs of possible intravenous drug abuse suggesting a risk for HIV, hepatitis C, or hepatitis B infection; and donor age less than 60 years. When an individual has been classified as a potential donor, the emergency team continues with cardiac massage, mechanical ventilation, and intravenous fluid perfusion to maintain adequate hemodynamic conditions during transport to our hospital. Upon arrival, the transplant coordination team checks for the conventional prerequisites for donation (for example, no infections; negative results on serologic tests for HIV and hepatitis B and C; and no tumors) and then transfers the cadaver to the operating room. In type I and type II nonheart-beating donors, the femoral vein and artery are cannulated via an incision in the right side of the groin and are connected to a cardiopulmonary bypass machine with external oxygenation and hypothermia. The maximum time of warm ischemia (from the start of cardiac arrest until bypass) should not exceed 120 minutes. Maximum pump cold perfusion time is 240 minutes. While the organ is being perfused, the transplant coordination team fulfills the legal requirements for donation. The first step is to locate the family of the deceased person and obtain consent for organ extraction. Organ retrieval is performed according to the Maastricht protocol, which requires a diagnosis of death by physicians independent of those of the procurement team and a procurement protocol approved by the local medical ethics committee according to the current organ procurement legislation. Since 1999, Spain has had a law (Real Decreto 2070/1999) that allows organ donation after cardiac arrest. Under this law, the donor can undergo cardiopulmonary bypass until the necessary consent is obtained for organ extraction. In the past year, only 7% of families declined consent for organ extraction. Study Design and Sample From January 1989 to December 2004, our center transplanted 342 kidneys from nonheart-beating donors. According to the modified Maastricht donor classification scheme (3), these graft donors are classified as follows: 273 (79.8%) type I donors (dead on arrival), 47 (13.7%) type II donors (unsuccessful resuscitation in the emergency department), 6 (1.8%) type III donors (cardiac arrest in intensive care), 4 (1.2%) type IV donors (cardiac arrest during or after a diagnosis of brain death), and 12 (3.5%) type V donors (unexpected cardiac arrest in intensive care). In our retrospective study of procedures at our center, we compared data from 320 recipients of kidneys from uncontrolled, nonheart-beating donors (type I or type II Maastricht donor category) with those from 584 recipients of kidneys from adult cadaveric heart-beating donors between January 1989 and December 2004. We divided the heart-beating donor transplants into 2 groups according to donor age: younger than 60 years of age (n= 458) and 60 years of age or older (n= 126). Figure 1 shows data on the transplantations performed per year. We excluded transplantations from types III, IV, and V nonheart-beating donors and those from heart-beating donors other than adult cadaveric donors (en bloc pediatric renal transplantations or double renal transplantations from older donors). Figure 1. Kidney transplantations at the Hospital Clnico San Carlos, Madrid, Spain, January 1989December 2004. Other transplantations are those involving other than single adult cadaveric heart-beating donors (en bloc pediatric renal transplantations or double renal transplantations from donors 60 years of age) and those involving types III, IV, and V nonheart-beating donors. Treatment and Outcome Measures We treated transplant recipients with quadruple sequential therapy (antithymocyte globulin for 7 days, azathioprine, prednisone from the time of transplantation, and cyclosporine from day 5) from January 1989 to July 1996. From July 1996 to March 2001, the immunosuppression regimen used was triple therapy with cyclosporine or tacrolimus (plus prednisone and mycophenolate). After March 2001, recipients of kidneys from nonheart-beating donors and from heart-beating donors 60 years of age or older received daclizumab and a half-dosage of tacrolimus (0.1 mg/kg of body weight per day to achieve trough levels between 5 ng/mL and 8 ng/mL) during the first 2 weeks to avoid delayed graft function, whereas recipients of kidneys from heart-beating donors younger than 60 years of age did not receive daclizumab and were treated with full-dosage tacrolimus (0.2 mg/kg per day to achieve trough levels between 8 ng/mL and 12 ng/mL). The dosages of mycophenolate and steroids were similar for the 3 groups. Hyperimmunized patients (preformed reactive antibodies 50%) were treated with the monoclonal antibody muromonab-CD3 or antithymocyte globulin. We defined delayed graft function as the need for dialysis during the immediate post-transplantation period. Patients who showed delayed graft function underwent a biopsy every 7 days until renal function started to improve. We graded acute rejection according to the Banff 97 classification (27). We treated grade I rejection (interstitial infiltration and tubulitis) with high doses of pulse steroids. We treated grade II (intimal arteritis) or grade III (transmural arteritis) rejection with either muromonab-CD3 or antithymocyte globulin. Our policy is to discharge patients when graft function starts to improve. Subsequent ambulatory patient management does not vary according to donor type. The end point of the study was graft loss, defined as nephrectomy, retransplantation, or permanent return to dialysis. We followed pa

Does renal mass exert an independent effect on the determinants of antigen-dependent injury?

The aim of this retrospective study was to determine whether nephron mass may exert a direct, independent effect on immunological tolerance. To this end, data corresponding to patients transplanted with en block pediatric kidneys (EBPK) (n=48) were compared with those of renal transplants with a low risk of hyperfiltration (LRH) comprised of recipients of a kidney from young donors (age 5–40 years) (n=173), and transplants with a high risk of hyperfiltration (HRH) comprised of patients who had received a graft from an elderly donor (older than 55 years) (n=91). All the patients had been subjected to the same immunosuppressive treatment. The median follow-up period was 54 months (6–127 months). The EBPK group showed lowest serum creatinine and highest creatinine clearance levels at each follow-up time. The rate of proteinuria >500 mg/day was 5.7% in EBPK, 7.4% in LRH, and 27.3% in HRH (P =0.000). The incidence of acute corticoresistant rejection was minor in EBPK (7.0% in EBPK, 21.3% in LRH, and 23.3% in HRH;P =0.04). Logistic regression analysis showed that the type of transplant was predictive of acute corticoresistant rejection [RR 5.33 (95% confidence interval (CI) 1.15–24.62) for HRH and RR 4.75 (95%CI 1.06–21.27) for LRH, P =0.03]. Multivariate analyses for graft failure due to chronic rejection and for graft failure due to acute rejection according to Cox’s regression analysis demonstrated that HRH transplant was a significant predictive variable of both types of failure [4.08 (95%CI 1.27–13.04) for graft loss due to chronic rejection and 8.69 (95%CI 1.69–44.67) for graft loss due to acute rejection]. The present stratification of data according to nephronal mass would appear to indicate that the greater the mass, the lower the incidence of both acute and chronic rejection. This finding lends support to the hypothesis that a large mass of transplanted tissue relative to recipient mass may dampen the immune response.

Functional glomerular reserve in recipients of en bloc pediatric transplant kidneys

BACKGROUND The transplantation of an adequate renal mass is increasingly recognized to be of importance. The improved graft survival is probably due to a lesser risk of developing hyperfiltration-associated lesions. METHODS We have reviewed the glomerular reserve in our recipients of en bloc pediatric transplant kidneys after an intravenous amino acid overload and compared them to single adult kidney transplant recipients. RESULTS En bloc transplants evidenced increased glomerular filtration rate as compared with baseline as from the second hour of amino acid infusion (from 71+/-14 to 84.9+/-17 ml/min, 1.73 m2, P<0.05) and increased renal plasma flow as from the third hour (from 335+/-116 to 402+/-155 ml/min, 1.73 m2, P<0.05). In the single adult kidney recipient group, no change was seen either in the glomerular filtration rate (from 62.5+/-13 to 58.1+/-13 ml/min, 1.73 m2, P=NS) nor in renal plasma flow (from 354+/-125 to 304+/-98 ml/min, 1.73 m2, P=NS). CONCLUSIONS These results show that patients receiving en bloc pediatric kidney transplantations have a greater renal functional reserve and show a lesser risk of hyperfiltration.

Sirolimus and Everolimus Induced Pneumonitis in Adult Renal Allograft Recipients: Experience in a Center

Mammalian target of rapamycin (mTOR) inhibitors induce pneumonitis, an unusual but potentially fatal side effect of this drug group. We retrospectively collected the cases of pneumonitis induced by sirolimus or everolimus among 1471 adult cadaveric renal transplant recipients who were grafted at our institution from 1980-2008. Due to chronic transplant dysfunction or tumor, 205 patients were switched from calcineurin inhibitors to sirolimus (n = 88) or to everolimus (n = 117). Six patients (2.9%) developed pneumonitis: 1 was associated with sirolimus and 5 with everolimus (5 males and 1 female; median age, 60 years [range, 47-73 years]). Median times from conversion to pneumonitis onset were 34 days in 4 patients (range, 24-46 days) and 491 days in 2 subjects (range, 454-528 days). The mean drug trough level at presentation was 8.2 microg/L (range, 5.5-13.8 microg/L). The most common symptoms were dry cough (n = 6), fever (n = 5), and dyspnea (n = 4). Imaging tests revealed lower lobe involvement in all patients. Bronchoalveolar lavage performed in 4 patients showed lymphocytic alveolitis. All patients completely recovered after drug withdrawal. Five patients received steroids, 5 were switched to a calcineurin inhibitor, and 1 was switched to the other mTOR inhibitor. In conclusion, mTOR inhibitor-associated pneumonitis is a rare disease. Sirolimus did not cause more cases of pneumonitis than everolimus. Pneumonitis development was not dependent upon the drug blood level. Lower lobe involvement and lymphocytic alveolitis were usually present. Discontinuation of the mTOR inhibitor with steroid prescription resulted in adequate outcomes. A change to the other mTOR inhibitor should be contemplated if patient circumstances require this type of immunosuppression.

The Prevalence of Uridine Diphosphate-Glucuronosyltransferase 1A9 (UGT1A9) Gene Promoter Region Single-Nucleotide Polymorphisms T-275A and C-2152T and Its Influence on Mycophenolic Acid Pharmacokinetics in Stable Renal Transplant Patients

UNLABELLED The aim of this study was to evaluate the distribution of UGT1A9 promoter region T-275A and C-2152T single nucleotide polymorphisms (SNPs) in stable transplant patients and to investigate the impact of these SNPs on mycophenolic acid (MPA) pharmacokinetics. METHODS In total, 133 Caucasian renal transplant recipients were studied. Also a complete 12-hour pharmacokinetic profile was recorded for 15 transplant patients who had the polymorphism and for 15 controls who were randomly chosen since they received the same type and dosage of mycophenolate, same posttransplant time and similar renal function. RESULTS The T-275A promoter mutation was detected in 12.03% of patients and the C-2152T in 9.77%. All patients with the mutation C-2152T had associated the mutation T-275A. Patients who carried either the T-275A or the C-2152T polymorphism (or both) experienced more admissions owing to gastrointestinal side effects (P < .05). The pharmacokinetics studies showed that carriers of T-275A and/or C-2152T displayed a smaller area under-concentration time curve (AUC): 57.8 +/- 4.3 vs 78.9 +/- 10.8 mg/L*h (P < .03). CONCLUSION It seemed that carriers of T-275A and C-2152T SNPs of the UGT1A9 gene promoter region in the late posttransplant recipient group, showed a greater incidence of gastrointestinal side effects and a lower MPA exposure.

A novel risk score for mortality in renal transplant recipients beyond the first posttransplant year.

Background. All-cause mortality is high after kidney transplantation (KT), but no prognostic index has focused on predicting mortality in KT using baseline and emergent comorbidity after KT. Methods. A total of 4928 KT recipients were used to derive a risk score predicting mortality. Patients were randomly assigned to two groups: a modeling population (n=2452), used to create a new index, and a testing population (n=2476), used to test this index. Multivariate Cox regression model coefficients of baseline (age, weight, time on dialysis, diabetes, hepatitis C, and delayed graft function) and emergent comorbidity within the first posttransplant year (diabetes, proteinuria, renal function, and immunosuppressants) were used to weigh each variable in the calculation of the score and allocated into risk quartiles. Results. The probability of death at 3 years, estimated by baseline cumulative hazard function from the Cox model [P (death)=1−0.993592764exp(score/100)], increased from 0.9% in the lowest-risk quartile (score=40) to 4.7% in the highest risk-quartile (score=200). The observed incidence of death increased with increasing risk quartiles in testing population (log-rank analysis, P<0.0001). The overall C-index was 0.75 (95% confidence interval: 0.72–0.78) and 0.74 (95% confidence interval: 0.70–0.77) in both populations, respectively. Conclusion. This new index is an accurate tool to identify high-risk patients for mortality after KT.

Long-term graft function changes in kidney transplant recipients

Background. Monitoring changes in glomerular filtration rate (GFR) is the recommended method for assessing the progression of kidney disease. The aim of this study was to assess the decline of graft function defined by the annualized change in GFR and the factors which affect it. Methods. Four thousand four hundred and eighty-eight patients, transplanted during the years 1990, 1994, 1998 and 2002 in 34 centres in Spain with allograft survival of at least 1 year, were included in the study. GFR was estimated using the four-variable equation of the Modification of Diet in Renal Diseases (MDRD) study. Linear mixed effects model was applied to determine the relation between the covariates and the annualized change in GFR after transplantation. Results. The average GFR at 12 months was 51.4 ± 18.9 mL/min/1.73 m2; most patients were in stage 3 of chronic kidney disease classification. The average patient slope, calculated in a linear model with varying-intercept and varying-slope without covariates, was −1.12 ± 0.05 mL/min/year (slope ± standard error). Some variables were related to both the 12-month GFR (intercept) and the slope: recipient gender, hepatitis C virus (HCV) status, estimated GFR (eGFR) at 3 months and proteinuria at 12 months. Some variables were only related to the slope of eGFR: time on dialysis, primary renal disease and immunosuppression. Others affected only the 12-month GFR: donor age, delayed graft function, acute rejection and systolic blood pressure at 12 months. Higher graft function at 3 months had a negative impact on the GFR slope. Cyclosporine-based immunosuppression had a less favourable effect on the rates of change in allograft function. Conclusions. There was a slow decline in GFR. Poor graft function was not associated with an increased rate of decline of allograft function. Immunosuppression with cyclosporine displayed the worst declining GFR rate.

Candiduria in renal transplant recipients: incidence, clinical repercussion, and treatment indication.

INTRODUCTION The incidence of candiduria in renal transplant recipients is unknown. In clinical practice, the indications for antifungal therapy are not well established. Furthermore, there is the problem of the choice of the antifungal drug since some of them may select resistant Candida species, or interact with immunosuppressive agents or only be used intravenously. AIM We sought to study the incidence, clinical repercussions and effectiveness of antifungal treatment to prevent recurrence of candiduria. MATERIALS AND METHODS We examined all episodes of Candida-positive urine cultures (>50,000 cfu/mL) in 996 recipients over 2 years. We considered the Candida species, administered treatment, presence of fever, requirement for hospital admission versus outpatient case, occurrence of simultaneous bacterial urinary tract infection (UTI), antibiotic use during the week before candiduria, and presence of an indwelling urinary catheter. RESULTS Among 996 subjects, 34 displayed 83 episodes of candiduria, yielding an accumulated incidence of 3.4% after 2 years. The frequency was higher among women (6.3% vs 1.7%, P<.001). Of the 45 outpatient episodes (54.2%), 17 were treated and one required hospitalization (5.9%). Of the 28 nontreated outpatients, two were hospitalized (7.1%, P=.68 vs treated patients). All cases of hospital admission presented simultaneous bacterial UTI, none developed candidemia, and two patients did not receive any antifungal therapy. With respect to the first episodes of each patient (n=34), 5/11 treated (45.5%) and 4/23 untreated (17.4%) patients developed recurrences (P=.095). Selection of more resistant Candida species was not observed. Fifty cases (60%) were associated with antibiotic therapy and 34 (41%) the presence of a urinary catheter. CONCLUSIONS It does not seem necessary to treat candiduria in this setting. Antifungal therapy was not associated with either a reduction in recurrence or the appearance of more resistant species in this study. We observed no important clinical repercussions.

Everolimus as primary immunosuppression in kidney transplantation: experience in conversion from calcineurin inhibitors.

Background. We analyzed our clinical experience with everolimus (EVL) and identified prognostic factors for a successful conversion. Methods. Retrospective study of 220 kidney recipients consecutively converted to EVL with calcineurin inhibitor elimination. We studied risk factors for proteinuria at 1 year after conversion, decline in renal function, and graft survival. Results. Baseline creatinine clearance was 52.4±17.8 mL/min vs. 53.4±20.1 mL/min 1 year after conversion (P=0.150). Median proteinuria increased from 304 mg/day (interquartile range 160–507) to 458 mg/day (interquartile range 238–892; P<0.001). Risk factors for development of proteinuria ≥900 mg/day (P75) at 1-year postconversion were creatinine clearance less than 60 mL/min (odds ratio [OR] 3.37; 95% confidence interval [CI]: 1.15–9.89), serum triglycerides ≥150 mg/day (OR 4.35; 95% CI: 1.70–11.17), no treatment with prednisone (OR 3.04; 95% CI: 1.22–7.59), baseline proteinuria ≥550 mg/day (OR 10.37; 95% CI: 3.99–26.99), and conversion ≥3 years after transplant (OR 5.77; 95% CI: 1.89–17.59). An interaction was observed between baseline proteinuria and time to conversion: in patients with baseline proteinuria ≥550 mg/day, the risk of developing proteinuria ≥900 mg/day was 77.1% if they were converted after ≥3 years posttransplant. However, this risk was 29.8% in the subgroup converted before (P=0.02). Actuarial graft survival at 1 and 4 years postconversion was 98.2% and 86.5%, respectively. Baseline proteinuria ≥550 mg/day was a risk factor for graft loss in patients converted after the third year but not in patients converted before this time. EVL discontinuation rate was 24% in the first year postconversion. Conclusions. Conversion to EVL and elimination of calcineurin inhibitors is safe. Success depends on not making late conversions and not converting patients with high baseline proteinuria.

Use of different immunosuppressive strategies in recipients of kidneys from nonheart‐beating donors

In nonheart‐beating donor (NHBD) kidney transplants, immunosuppressive management is difficult mainly because of the high incidence of acute tubular necrosis. This has meant that since the start of our NHBD transplant program, several immunosuppression regimes have been used. The aim of this retrospective study was to evaluate the results obtained over 7 years using different treatment protocols. A total of 172 consecutive NHBD transplants performed between April 1996 and December 2002 were treated as follows: G‐I (n = 21), cyclosporine (8 mg/kg/day) plus azathioprine plus steroids; G‐II (n = 65), low‐dose cyclosporine (5 mg/kg/day) plus mycophenolate plus steroids; G‐III (n =17), low‐dose tacrolimus (0.1 mg/kg/day) plus mycophenolate plus steroids; and G‐IV (n = 69), daclizumab plus low‐dose tacrolimus plus mycophenolate plus steroids. Delayed graft function rates were 76.2%, 72.3%, 76.5%, and 42%, respectively, for the four groups (P = 0.000). Rejection‐free patient rates were 76.2%, 46.2%, 35.3%, and 71% (P < 0.001). Vascular rejection rates were 19%, 30.8%, 52.9%, and 18.8%, (P = 0.025). Two‐year graft survival was 71.4% in group I, 95.4% in group II, 94.1 in group III, and 93.8% in group IV (P =0.004). Patient survival was worse in group I (75.2% in group I, 100% in group II, 100% in group III, and 96.7% in group IV at 2 years; P < 0.001). The use of daclizumab and low‐dose tacrolimus could be effective at lowering the incidence of delayed graft function in NHBDT, with no negative repercussions on acute rejection.