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1.
J Am Soc Nephrol ; 2024 Oct 16.
Artículo en Inglés | MEDLINE | ID: mdl-39412887

RESUMEN

BACKGROUND: Prognostic models are becoming increasingly relevant in clinical trials as potential surrogate endpoints, and for patient management as clinical decision support tools. However, the impact of competing risks on model performance remains poorly investigated. We aimed to carefully assess the performance of competing risk and noncompeting risk models in the context of kidney transplantation, where allograft failure and death with a functioning graft are two competing outcomes. METHODS: We included 11,046 kidney transplant recipients enrolled in 10 countries. We developed prediction models for long-term kidney graft failure prediction, without accounting (i.e., censoring) and accounting for the competing risk of death with a functioning graft, using Cox, Fine-Gray, and cause-specific Cox regression models. To this aim, we followed a detailed and transparent analytical framework for competing and noncompeting risk modelling, and carefully assessed the models' development, stability, discrimination, calibration, overall fit, clinical utility, and generalizability in external validation cohorts and subpopulations. More than 15 metrics were used to provide an exhaustive assessment of model performance. RESULTS: Among 11,046 recipients in the derivation and validation cohorts, 1,497 (14%) lost their graft and 1,003 (9%) died with a functioning graft after a median follow-up post-risk evaluation of 4.7 years (IQR 2.7-7.0). The cumulative incidence of graft loss was similarly estimated by Kaplan-Meier and Aalen-Johansen methods (17% versus 16% in the derivation cohort). Cox and competing risk models showed similar and stable risk estimates for predicting long-term graft failure (average mean absolute prediction error of 0.0140, 0.0138 and 0.0135 for Cox, Fine-Gray, and cause-specific Cox models, respectively). Discrimination and overall fit were comparable in the validation cohorts, with concordance index ranging from 0.76 to 0.87. Across various subpopulations and clinical scenarios, the models performed well and similarly, although in some high-risk groups (such as donors over 65 years old), the findings suggest a trend towards moderately improved calibration when using a competing risk approach. CONCLUSIONS: Competing and noncompeting risk models performed similarly in predicting long-term kidney graft failure.

2.
Am J Transplant ; 24(10): 1816-1827, 2024 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-38878866

RESUMEN

In the general population, decreases in glomerular filtration rate (GFR) are associated with subsequent development of chronic kidney disease (CKD), cardiovascular disease (CVD), and death. It is unknown if low estimated GFR (eGFR) before or early after kidney donation was also associated with these risks. One thousand six hundred ninety-nine living donors who had both predonation and early (4-10 weeks) postdonation eGFR were included. We studied the relationships between eGFR, age at donation, and the time to sustained eGFR<45 (CKD stage 3b) and <30 mL/min/1.73m2 (CKD stage 4), hypertension, diabetes mellitus (DM), CVD, and death. Median follow-up was 12 (interquartile range, 6-21) years. Twenty-year event rates were 5.8% eGFR<45 mL/min/1.73m2; 1.2% eGFR<30 mL/min/1.73m2; 29.0% hypertension; 7.8% DM; 8.0% CVD; and 5.2% death. The median time to eGFR<45 mL/min/1.73m2 (N = 79) was 17 years, and eGFR<30 mL/min/1.73m2 (N = 22) was 25 years. Both low predonation and early postdonation eGFR were associated with eGFR<45 mL/min/1.73m2 (P < .0001) and eGFR<30 mL/min/1.73m2 (P < .006); however, the primary driver of risk for all ages was low postdonation (rather than predonation) eGFR. Predonation and postdonation eGFR were not associated with hypertension, DM, CVD, or death. Low predonation and early postdonation eGFR are risk factors for developing eGFR<45 mL/min/1.73m2 (CKD stage 3b) and <30 mL/min/1.73m2 (CKD stage 4), but not CVD, hypertension, DM, or death.


Asunto(s)
Tasa de Filtración Glomerular , Trasplante de Riñón , Donadores Vivos , Humanos , Masculino , Femenino , Persona de Mediana Edad , Trasplante de Riñón/efectos adversos , Adulto , Estudios de Seguimiento , Factores de Riesgo , Pronóstico , Nefrectomía/efectos adversos , Pruebas de Función Renal , Insuficiencia Renal Crónica/fisiopatología , Insuficiencia Renal Crónica/etiología , Recolección de Tejidos y Órganos/efectos adversos , Enfermedades Cardiovasculares/etiología
3.
Ann Surg ; 280(4): 604-615, 2024 Oct 01.
Artículo en Inglés | MEDLINE | ID: mdl-38916985

RESUMEN

OBJECTIVE: To describe the evolution of pancreas transplantation, including improved outcomes and factors associated with improved outcomes over the past 5 decades. BACKGROUND: The world's first successful pancreas transplant was performed in December 1966 at the University of Minnesota. As new modalities for diabetes treatment mature, we must carefully assess the current state of pancreas transplantation to determine its ongoing role in patient care. METHODS: A single-center retrospective review of 2500 pancreas transplants was performed over >50 years in bivariate and multivariable models. Transplants were divided into 6 eras; outcomes are presented for the entire cohort and by era. RESULTS: All measures of patient and graft survival improved progressively through the 6 transplant eras. The overall death-censored pancreas graft half-lives were >35 years for simultaneous pancreas and kidney (SPK), 7.1 years for pancreas after kidney (PAK), and 3.3 years for pancreas transplants alone (PTA). The 10-year death-censored pancreas graft survival rate in the most recent era was 86.9% for SPK recipients, 58.2% for PAK recipients, and 47.6% for PTA. Overall, graft loss was most influenced by patient survival in SPK transplants, whereas graft loss in PAK and PTA recipients was more often due to graft failures. Predictors of improved pancreas graft survival were primary transplants, bladder drainage of exocrine secretions, younger donor age, and shorter preservation time. CONCLUSIONS: Pancreas outcomes have significantly improved over time through sequential, but overlapping, advances in surgical technique, immunosuppressive protocols, reduced preservation time, and the more recent reduction of immune-mediated graft loss.


Asunto(s)
Supervivencia de Injerto , Trasplante de Páncreas , Trasplante de Páncreas/métodos , Humanos , Estudios Retrospectivos , Adulto , Masculino , Femenino , Persona de Mediana Edad , Trasplante de Riñón , Resultado del Tratamiento , Adolescente , Niño , Adulto Joven , Tasa de Supervivencia
4.
Pharmacogenomics J ; 24(5): 29, 2024 Aug 23.
Artículo en Inglés | MEDLINE | ID: mdl-39179559

RESUMEN

African American (AA) kidney transplant recipients (KTRs) have poor outcomes, which may in-part be due to tacrolimus (TAC) sub-optimal immunosuppression. We previously determined the common genetic regulators of TAC pharmacokinetics in AAs which were CYP3A5 *3, *6, and *7. To identify low-frequency variants that impact TAC pharmacokinetics, we used extreme phenotype sampling and compared individuals with extreme high (n = 58) and low (n = 60) TAC troughs (N = 515 AA KTRs). Targeted next generation sequencing was conducted in these two groups. Median TAC troughs in the high group were 7.7 ng/ml compared with 6.3 ng/ml in the low group, despite lower daily doses of 5 versus 12 mg, respectively. Of 34,542 identified variants across 99 genes, 1406 variants were suggestively associated with TAC troughs in univariate models (p-value < 0.05), however none were significant after multiple testing correction. We suggest future studies investigate additional sources of TAC pharmacokinetic variability such as drug-drug-gene interactions and pharmacomicrobiome.


Asunto(s)
Negro o Afroamericano , Inmunosupresores , Trasplante de Riñón , Tacrolimus , Adulto , Femenino , Humanos , Masculino , Persona de Mediana Edad , Negro o Afroamericano/genética , Citocromo P-450 CYP3A/genética , Variación Genética , Secuenciación de Nucleótidos de Alto Rendimiento , Inmunosupresores/farmacocinética , Variantes Farmacogenómicas , Fenotipo , Tacrolimus/farmacocinética , Tacrolimus/uso terapéutico , Receptores de Trasplantes
5.
Br J Clin Pharmacol ; 2024 Jul 12.
Artículo en Inglés | MEDLINE | ID: mdl-38994750

RESUMEN

AIMS: Tacrolimus, metabolized by CYP3A4 and CYP3A5 enzymes, is susceptible to drug-drug interactions (DDI). Steroids induce CYP3A genes to increase tacrolimus clearance, but the effect is variable. We hypothesized that the extent of the steroid-tacrolimus DDI differs by CYP3A4/5 genotypes. METHODS: Kidney transplant recipients (n = 2462) were classified by the number of loss of function alleles (LOF) (CYP3A5*3, *6 and *7 and CYP3A4*22) and steroid use at each tacrolimus trough in the first 6 months post-transplant. A population pharmacokinetic analysis was performed by nonlinear mixed-effect modelling (NONMEM) and stepwise covariate modelling to define significant covariates affecting tacrolimus clearance. A stochastic simulation was performed and translated into a Shiny application with the mrgsolve and Shiny packages in R. RESULTS: Steroids were associated with modestly higher (3%-11.8%) tacrolimus clearance. Patients with 0-LOF alleles receiving steroids showed the greatest increase (11.8%) in clearance compared to no steroids, whereas those with 2-LOFs had a negligible increase (2.6%) in the presence of steroids. Steroid use increased tacrolimus clearance by 5% and 10.3% in patients with 1-LOF and 3/4-LOFs, respectively. CONCLUSIONS: Steroids increase the clearance of tacrolimus but vary slightly by CYP3A genotype. This is important in individuals of African ancestry who are more likely to carry no LOF alleles, may more commonly receive steroid treatment, and will need higher tacrolimus doses.

6.
Clin Transplant ; 38(8): e15386, 2024 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-39087488

RESUMEN

BACKGROUND: Chronic immunosuppression following pancreas transplantation carries significant risk, including posttransplant lymphoproliferative disease (PTLD). We sought to define the incidence, risk factors, and long-term outcomes of PTLD following pancreas transplantation at a single center. METHODS: All adult pancreas transplants between February 1, 1983 and December 31, 2023 at the University of Minnesota were reviewed, including pancreas transplant alone (PTA), simultaneous pancreas-kidney transplants (SPK), and pancreas after kidney transplants (PAK). RESULTS: Among 2353 transplants, 110 cases of PTLD were identified, with an overall incidence of 4.8%. 17.3% were diagnosed within 1 year of transplant, 32.7% were diagnosed within 5 years, and 74 (67.3%) were diagnosed after 5 years. The overall 30-year incidence of PTLD did not differ by transplant type-7.4% for PTA, 14.2% for SPK, and 19.4% for PAK (p = 0.3). In multivariable analyses, older age and Epstein-Barr virus seronegativity were risk factors for PTLD, and PTLD was a risk factor for patient death. PTLD-specific mortality was 32.7%, although recipients with PTLD had similar median posttransplant survival compared to those without PTLD (14.9 year vs. 15.6 year, p = 0.9). CONCLUSIONS: PTLD following pancreas transplantation is associated with significant mortality. Although the incidence of PTLD has decreased over time, a high index of suspicion for PTLD following PTx should remain in EBV-negative recipients.


Asunto(s)
Supervivencia de Injerto , Trastornos Linfoproliferativos , Trasplante de Páncreas , Complicaciones Posoperatorias , Humanos , Trasplante de Páncreas/efectos adversos , Masculino , Trastornos Linfoproliferativos/etiología , Trastornos Linfoproliferativos/epidemiología , Femenino , Adulto , Complicaciones Posoperatorias/epidemiología , Complicaciones Posoperatorias/etiología , Estudios de Seguimiento , Factores de Riesgo , Pronóstico , Persona de Mediana Edad , Incidencia , Tasa de Supervivencia , Estudios Retrospectivos , Rechazo de Injerto/etiología , Rechazo de Injerto/mortalidad , Trasplante de Riñón/efectos adversos , Adulto Joven
7.
Ther Drug Monit ; 2024 Jul 23.
Artículo en Inglés | MEDLINE | ID: mdl-39047238

RESUMEN

BACKGROUND: Therapeutic drug monitoring for mycophenolic acid (MPA) is challenging due to difficulties in measuring the area under the curve (AUC). Limited sampling strategies (LSSs) have been developed for MPA therapeutic drug monitoring but come with risk of unacceptable performance. The authors hypothesized that the poor predictive performance of LSSs were due to the variability in MPA enterohepatic recirculation (EHR). This study is the first to evaluate LSSs models performance in the context of EHR. METHODS: Adult kidney transplant recipients (n = 84) receiving oral mycophenolate mofetil underwent intensive MPA pharmacokinetic sampling. MPA AUC0-12hr and EHR were determined. Published MPA LSSs in kidney transplant recipients receiving tacrolimus were evaluated for their predictive performance in estimating AUC0-12hr in our full cohort and separately in individuals with high and low EHR. RESULTS: None of the evaluated LSS models (n = 12) showed good precision or accuracy in predicting MPA AUC0-12hr in the full cohort. In the high EHR group, models with late timepoints had better accuracy but low precision, except for 1 model with late timepoints at 6 and 10 hours postdose, which had marginally acceptable precision. For all models, the good guess of predicted AUC0-12hr (±15% of observed AUC0-12hr) was highly variable (range, full cohort = 19%-61.9%; high EHR = 4.5%-65.9%; low EHR = 27.5%-62.5%). CONCLUSIONS: The predictive performance of the LSS models varied according to EHR status. Timepoints ≥5 hours postdose in LSS models are essential to capture EHR. Models and strategies that incorporate EHR during development are required to accurately ascertain MPA exposure.

8.
Biometrics ; 79(4): 3165-3178, 2023 12.
Artículo en Inglés | MEDLINE | ID: mdl-37431172

RESUMEN

A difficult decision for patients in need of kidney-pancreas transplant is whether to seek a living kidney donor or wait to receive both organs from one deceased donor. The framework of dynamic treatment regimes (DTRs) can inform this choice, but a patient-relevant strategy such as "wait for deceased-donor transplant" is ill-defined because there are multiple versions of treatment (i.e., wait times, organ qualities). Existing DTR methods average over the distribution of treatment versions in the data, estimating survival under a "representative intervention." This is undesirable if transporting inferences to a target population such as patients today, who experience shorter wait times thanks to evolutions in allocation policy. We, therefore, propose the concept of a generalized representative intervention (GRI): a random DTR that assigns treatment version by drawing from the distribution among strategy compliers in the target population (e.g., patients today). We describe an inverse-probability-weighted product-limit estimator of survival under a GRI that performs well in simulations and can be implemented in standard statistical software. For continuous treatments (e.g., organ quality), weights are reformulated to depend on probabilities only, not densities. We apply our method to a national database of kidney-pancreas transplant candidates from 2001-2020 to illustrate that variability in transplant rate across years and centers results in qualitative differences in the optimal strategy for patient survival.


Asunto(s)
Trasplante de Riñón , Trasplante de Páncreas , Humanos , Trasplante de Páncreas/métodos , Causalidad , Riñón
9.
Clin Transplant ; 37(3): e14877, 2023 03.
Artículo en Inglés | MEDLINE | ID: mdl-36528870

RESUMEN

Dr John S Najarian (1927-2020), chairman of the Department of Surgery at the University of Minnesota from 1967 to 1993, was a pioneer in surgery, clinical immunology and transplantation. A Covid-delayed Festschrift was held in his honor on May 20, 2022. The speakers reflected on his myriad contributions to surgery, transplantation, and resident/fellow training, as well as current areas of ongoing research to improve clinical outcomes. Of note, Dr Najarian was a founder of the journal Clinical Transplantation.


Asunto(s)
Trasplante , Humanos , Historia del Siglo XX
10.
Clin Transplant ; 37(4): e14893, 2023 04.
Artículo en Inglés | MEDLINE | ID: mdl-36571802

RESUMEN

Kidney transplant recipients carrying the CYP3A5*1 allele have lower tacrolimus troughs, and higher dose requirements compared to those with the CYP3A5*3/*3 genotype. However, data on the effect of CYP3A5 alleles on post-transplant tacrolimus management are lacking. The effect of CYP3A5 metabolism phenotypes on the number of tacrolimus dose adjustments and troughs in the first 6 months post-transplant was evaluated in 78 recipients (64% Caucasians). Time to first therapeutic concentration, percentage of time in therapeutic range (TTR), and estimated glomerular filtration rate (eGFR) were also evaluated. Fifty-five kidney transplant recipients were CYP3A5 poor metabolizers (PM), 17 were intermediate metabolizers (IM), and 6 were extensive metabolizers (EM). Compared to PMs, EMs/IMs had significantly more dose adjustments (6.1 vs. 8.1, p = .015). Overall, 33.82% of trough measurements resulted in a dose change. There was no difference in the number of tacrolimus trough measurements between PMs and EM/IMs. The total daily tacrolimus dose requirements were higher in EMs and IMs compared to PMs (<.001). TTR was ∼50% in the PMs and EMs/IMs groups. CYP3A5 EM/IM metabolizers have more tacrolimus dose changes and higher dose requirements which increases clinical management complexity. Larger studies are needed to assess the cost and benefits of including genotyping data to improve clinical management.


Asunto(s)
Trasplante de Riñón , Tacrolimus , Humanos , Tacrolimus/uso terapéutico , Inmunosupresores/uso terapéutico , Trasplante de Riñón/métodos , Citocromo P-450 CYP3A/genética , Citocromo P-450 CYP3A/metabolismo , Genotipo , Receptores de Trasplantes , Polimorfismo de Nucleótido Simple
11.
BMC Nephrol ; 24(1): 121, 2023 05 01.
Artículo en Inglés | MEDLINE | ID: mdl-37127560

RESUMEN

BACKGROUND: There is uncertainty about the long-term risks of living kidney donation. Well-designed studies with controls well-matched on risk factors for kidney disease are needed to understand the attributable risks of kidney donation. METHODS: The goal of the Minnesota Attributable Risk of Kidney Donation (MARKD) study is to compare the long-term (> 50 years) outcomes of living donors (LDs) to contemporary and geographically similar controls that are well-matched on health status. University of Minnesota (n = 4022; 1st transplant: 1963) and Mayo Clinic LDs (n = 3035; 1st transplant: 1963) will be matched to Rochester Epidemiology Project (REP) controls (approximately 4 controls to 1 donor) on the basis of age, sex, and race/ethnicity. The REP controls are a well-defined population, with detailed medical record data linked between all providers in Olmsted and surrounding counties, that come from the same geographic region and era (early 1960s to present) as the donors. Controls will be carefully selected to have health status acceptable for donation on the index date (date their matched donor donated). Further refinement of the control group will include confirmed kidney health (e.g., normal serum creatinine and/or no proteinuria) and matching (on index date) of body mass index, smoking history, family history of chronic kidney disease, and blood pressure. Outcomes will be ascertained from national registries (National Death Index and United States Renal Data System) and a new survey administered to both donors and controls; the data will be supplemented by prior surveys and medical record review of donors and REP controls. The outcomes to be compared are all-cause mortality, end-stage kidney disease, cardiovascular disease and mortality, estimated glomerular filtration rate (eGFR) trajectory and chronic kidney disease, pregnancy risks, and development of diseases that frequently lead to chronic kidney disease (e.g. hypertension, diabetes, and obesity). We will additionally evaluate whether the risk of donation differs based on baseline characteristics. DISCUSSION: Our study will provide a comprehensive assessment of long-term living donor risk to inform candidate living donors, and to inform the follow-up and care of current living donors.


Asunto(s)
Fallo Renal Crónico , Trasplante de Riñón , Humanos , Estados Unidos , Estudios Retrospectivos , Trasplante de Riñón/efectos adversos , Minnesota , Nefrectomía/efectos adversos , Riñón , Factores de Riesgo , Fallo Renal Crónico/epidemiología , Tasa de Filtración Glomerular , Donadores Vivos , Estudios de Seguimiento
12.
Am J Transplant ; 22(11): 2509-2514, 2022 11.
Artículo en Inglés | MEDLINE | ID: mdl-35751488

RESUMEN

The kidney shortage continues to be a crisis for our patients. Despite numerous attempts to increase living and deceased donation, annually in the United States, thousands of candidates are removed from the kidney transplant waiting list because of either death or becoming too sick to transplant. To increase living donation, trials of a regulated system of incentives for living donation have been proposed. Such trials may show: (1) a significant increase in donation, and (2) that informed, incentivized donors, making an autonomous decision to donate, have the same medical and psychosocial outcomes as our conventional donors. Given the stakes, the proposal warrants careful consideration. However, to date, much discussion of the proposal has been unproductive. Objections commonly leveled against it: fail to engage with it; conflate it with underground, unregulated markets; speculate without evidence; and reason fallaciously, favoring rhetorical impact over logic. The present paper is a corrective. It identifies these common errors so they are not repeated, thus allowing space for an assessment of the proposal on its merits.


Asunto(s)
Trasplante de Riñón , Obtención de Tejidos y Órganos , Humanos , Estados Unidos , Donadores Vivos , Trasplante de Riñón/psicología , Motivación , Riñón
13.
J Am Soc Nephrol ; 32(11): 2933-2947, 2021 11.
Artículo en Inglés | MEDLINE | ID: mdl-34675059

RESUMEN

BACKGROUND: Obesity is associated with the two archetypal kidney disease risk factors: hypertension and diabetes. Concerns that the effects of diabetes and hypertension in obese kidney donors might be magnified in their remaining kidney have led to the exclusion of many obese candidates from kidney donation. METHODS: We compared mortality, diabetes, hypertension, proteinuria, reduced eGFR and its trajectory, and the development of kidney failure in 8583 kidney donors, according to body mass index (BMI). The study included 6822 individuals with a BMI of <30 kg/m2, 1338 with a BMI of 30-34.9 kg/m2, and 423 with a BMI of ≥35 kg/m2. We used Cox regression models, adjusting for baseline covariates only, and models adjusting for postdonation diabetes, hypertension, and kidney failure as time-varying covariates. RESULTS: Obese donors were more likely than nonobese donors to develop diabetes, hypertension, and proteinuria. The increase in eGFR in obese versus nonobese donors was significantly higher in the first 10 years (3.5 ml/min per 1.73m2 per year versus 2.4 ml/min per 1.73m2 per year; P<0.001), but comparable thereafter. At a mean±SD follow-up of 19.3±10.3 years after donation, 31 (0.5%) nonobese and 12 (0.7%) obese donors developed ESKD. Of the 12 patients with ESKD in obese donors, 10 occurred in 1445 White donors who were related to the recipient (0.9%). Risk of death in obese donors was not significantly increased compared with nonobese donors. CONCLUSIONS: Obesity in kidney donors, as in nondonors, is associated with increased risk of developing diabetes and hypertension. The absolute risk of ESKD is small and the risk of death is comparable to that of nonobese donors.


Asunto(s)
Enfermedades Cardiovasculares/epidemiología , Donadores Vivos , Nefrectomía/efectos adversos , Obesidad/epidemiología , Complicaciones Posoperatorias/epidemiología , Insuficiencia Renal/epidemiología , Índice de Masa Corporal , Enfermedades Cardiovasculares/mortalidad , Colesterol/sangre , Comorbilidad , Diabetes Mellitus Tipo 2/epidemiología , Diabetes Mellitus Tipo 2/mortalidad , Selección de Donante/normas , Femenino , Estudios de Seguimiento , Tasa de Filtración Glomerular , Humanos , Hipertensión/epidemiología , Hipertensión/mortalidad , Trasplante de Riñón , Donadores Vivos/estadística & datos numéricos , Masculino , Obesidad/mortalidad , Obesidad Mórbida/epidemiología , Obesidad Mórbida/mortalidad , Complicaciones Posoperatorias/mortalidad , Modelos de Riesgos Proporcionales , Proteinuria/epidemiología , Proteinuria/mortalidad , Insuficiencia Renal/mortalidad , Riesgo , Fumar/epidemiología , Triglicéridos/sangre
14.
Am J Transplant ; 21(5): 1866-1877, 2021 05.
Artículo en Inglés | MEDLINE | ID: mdl-33052625

RESUMEN

Inflammation in areas of fibrosis (i-IFTA) in posttransplant biopsies is part of the diagnostic criteria for chronic active TCMR (CA TCMR -- i-IFTA ≥ 2, ti ≥ 2, t ≥ 2). We evaluated i-IFTA and CA TCMR in the DeKAF indication biopsy cohorts: prospective (n = 585, mean time to biopsy = 1.7 years); cross-sectional (n = 458, mean time to biopsy = 7.8 years). Grouped by i-IFTA scores, the 3-year postbiopsy DC-GS is similar across cohorts. Although a previous acute rejection episode (AR) was more common in those with i-IFTA on biopsy, the majority of those with i-IFTA had not had previous AR. There was no association between type of previous AR (AMR, TCMR) and presence of i-IFTA. In both cohorts, i-IFTA was associated with markers of both cellular (increased Banff i, t, ti) and humoral (increased g, ptc, C4d, DSA) activity. Biopsies with i-IFTA = 1 and i-IFTA ≥ 2 with concurrent t ≥ 2 and ti ≥ 2 had similar DC-GS. These results suggest that (a) i-IFTA≥1 should be considered a threshold for diagnoses incorporating i-IFTA, ti, and t; (b) given that i-IFTA ≥ 2,t ≥ 2, ti ≥ 2 can occur in the absence of preceding TCMR and that the component histologic scores (i-IFTA,t,ti) each indicate an acute change (albeit i-IFTA on the nonspecific background of IFTA), the diagnostic category "CA TCMR" should be reconsidered.


Asunto(s)
Rechazo de Injerto , Trasplante de Riñón , Biopsia , Estudios Transversales , Rechazo de Injerto/diagnóstico , Rechazo de Injerto/etiología , Supervivencia de Injerto , Humanos , Inflamación , Estudios Prospectivos , Linfocitos T
15.
Liver Transpl ; 27(11): 1553-1562, 2021 11.
Artículo en Inglés | MEDLINE | ID: mdl-34145949

RESUMEN

There are several choices for induction immunosuppression in kidney-after-liver transplantation. We used the Scientific Registry of Transplant Recipients database. We assessed all kidney-after-liver transplant recipients in the United States between 1/1/2000 and 7/31/2017 to study kidney graft and patient outcomes by induction type. We only included patients discharged on tacrolimus and mycophenolate with or without steroids and had a negative crossmatch before kidney engraftment. We grouped recipients by kidney induction type into the following 3 groups: depletional (n = 550), nondepletional (n = 434), and no antibody induction (n = 144). We studied patient and kidney allograft survival using Cox proportional hazard regression, with transplant center included as a random effect. Models were adjusted for liver induction regimen, recipient and donor age, sex, human leukocyte antigen mismatches, payor type, living donor kidney transplantation, dialysis status, time from liver engraftment, hepatitis C virus status, and the presence of diabetes mellitus at time of kidney transplantation and transplantation year. The 6-month and 1-year rejection rates did not differ between groups. Compared with no induction, neither depletional nor nondepletional induction was associated with an improved recipient or graft survival in the multivariable models. Depletional induction at the time of liver transplantation was associated with worse patient survival after kidney transplantation (hazard ratio [HR], 1.7; 95% confidence interval [CI], 1.09-2.67; P = 0.02). Living donor kidney transplantation was associated with a 48.1% improved graft survival (HR, 0.52; 95% CI, 0.33-0.82; P = 0.00). In conclusion, in the settings of a negative cross-match and maintenance with tacrolimus and mycophenolate, induction use was not associated with a patient or graft survival benefit in kidney-after-liver transplantations.


Asunto(s)
Trasplante de Riñón , Trasplante de Hígado , Aloinjertos , Rechazo de Injerto/epidemiología , Rechazo de Injerto/prevención & control , Supervivencia de Injerto , Humanos , Inmunosupresores/uso terapéutico , Riñón , Trasplante de Riñón/efectos adversos , Trasplante de Hígado/efectos adversos , Estados Unidos/epidemiología
16.
Clin Transplant ; 35(7): e14337, 2021 07.
Artículo en Inglés | MEDLINE | ID: mdl-33955070

RESUMEN

Major gaps remain in our understanding of antibody-mediated rejection (AMR) after kidney transplant. We examined the incidence, risk factors, response to treatment, and effects on outcomes of AMR at seven transplant programs in the long-term Deterioration of Kidney Allograft Function prospective study cohort. Among 3131 kidney recipients, there were 194 observed AMR cases (6.2%) during (mean ± SD) 4.85 ± 1.86 years of follow-up. Time to AMR was 0.97 ± 1.17 (median, 0.48) years. Risk factors for AMR included younger recipient age, human leukocyte antigen DR mismatches, panel-reactive antibody >0%, positive T- or B-cell cross-match, and delayed graft function. Compared with no AMR, the adjusted time-dependent hazard ratio for death-censored graft failure is 10.1 (95% confidence interval, 6.5-15.7) for all AMR patients, 4.0 (2.5, 9.1) for early AMR (<90 days after transplant), and 24.0 (14.0-41.1) for late AMR (≥90 days after transplant). Patients were treated with different therapeutic combinations. Of 194 kidney transplant recipients with AMR, 50 (25.8%) did not respond to treatment, defined as second AMR within 100 days or no improvement in estimated glomerular filtration rate by 42 days. Long-term outcomes after AMR are poor, regardless of the initial response to treatment. Better prevention and new therapeutic strategies are needed to improve long-term allograft survival.


Asunto(s)
Rechazo de Injerto , Supervivencia de Injerto , Aloinjertos , Estudios de Cohortes , Rechazo de Injerto/epidemiología , Rechazo de Injerto/etiología , Humanos , Incidencia , Riñón , Estudios Prospectivos , Factores de Riesgo
17.
Am J Transplant ; 20(9): 2509-2521, 2020 09.
Artículo en Inglés | MEDLINE | ID: mdl-32185865

RESUMEN

Inflammation in areas of fibrosis (i-IFTA) in posttransplant biopsy specimens has been associated with decreased death-censored graft survival (DC-GS). Additionally, an i-IFTA score ≥ 2 is part of the diagnostic criteria for chronic active TCMR (CA TCMR). We examined the impact of i-IFTA and t-IFTA (tubulitis in areas of atrophy) in the first biopsy for cause after 90 days posttransplant (n = 598); mean (SD) 1.7 ± 1.4 years posttransplant. I-IFTA, present in 196 biopsy specimens, was strongly correlated with t-IFTA, and Banff i. Of the 196, 37 (18.9%) had a previous acute rejection episode; 96 (49%) had concurrent i score = 0. Unlike previous studies, i-IFTA = 1 (vs 0) was associated with worse 3-year DC-GS: (i-IFTA = 0, 81.7%, [95% CI 77.7 to 85.9%]); i-IFTA = 1, 68.1%, [95% CI 59.7 to 77.6%]; i-IFTA = 2, 56.1%, [95% CI 43.2 to 72.8%], i-IFTA = 3, 48.5%, [95% CI 31.8 to 74.0%]). The association of i-IFTA with decreased DC-GS remained significant when adjusted for serum creatinine at the time of the biopsy, Banff i, ci and ct, C4d and DSA. T-IFTA was similarly associated with decreased DC-GS. Of these indication biopsies, those with i-IFTA ≥ 2, without meeting other criteria for CA TCMR had similar postbiopsy DC-GS as those with CA TCMR. Those with i-IFTA = 1 and t ≥ 2, ti ≥ 2 had postbiopsy DC-GS similar to CA TCMR. Biopsies with i-IFTA = 1 had similar survival as CA TCMR when biopsy specimens also met Banff criteria for TCMR and/or AMR. Studies of i-IFTA and t-IFTA in additional cohorts, integrating analyses of Banff scores meeting criteria for other Banff diagnoses, are needed.


Asunto(s)
Rechazo de Injerto , Trasplante de Riñón , Biopsia , Fibrosis , Rechazo de Injerto/diagnóstico , Rechazo de Injerto/etiología , Humanos , Inflamación/etiología , Estudios Prospectivos
18.
Ann Surg ; 272(3): 458-466, 2020 09 01.
Artículo en Inglés | MEDLINE | ID: mdl-32740239

RESUMEN

OBJECTIVE: To identify factors that accurately predict 1-year survival for liver transplant recipients with a MELD score ≥40. BACKGROUND: Although transplant is beneficial for patients with the highest acuity (MELD ≥40), mortality in this group is high. Predicting which patients are likely to survive for >1 year would be medically and economically helpful. METHODS: The Scientific Registry of Transplant Recipients database was reviewed to identify adult liver transplant recipients from 2002 through 2016 with MELD score ≥40 at transplant. The relationships between 44 recipient and donor factors and 1-year patient survival were examined using random survival forests methods. Variable importance measures were used to identify the factors with the strongest influence on survival, and partial dependence plots were used to determine the dependence of survival on the target variable while adjusting for all other variables. RESULTS: We identified 5309 liver transplants that met our criteria. The overall 1-year survival of high-acuity patients improved from 69% in 2001 to 87% in 2016. The strongest predictors of death within 1 year of transplant were patient on mechanical ventilator before transplantation, prior liver transplant, older recipient age, older donor age, donation after cardiac death, and longer cold ischemia. CONCLUSIONS: Liver transplant outcomes continue to improve even for patients with high medical acuity. Applying ensemble learning methods to recipient and donor factors available before transplant can predict survival probabilities for future transplant cases. This information can be used to facilitate donor/recipient matching and to improve informed consent.


Asunto(s)
Isquemia Fría/métodos , Enfermedad Hepática en Estado Terminal/cirugía , Trasplante de Hígado/mortalidad , Donantes de Tejidos , Obtención de Tejidos y Órganos/métodos , Receptores de Trasplantes , Femenino , Estudios de Seguimiento , Supervivencia de Injerto , Humanos , Masculino , Persona de Mediana Edad , Pronóstico , Estudios Retrospectivos , Tasa de Supervivencia/tendencias , Estados Unidos/epidemiología
19.
Transpl Int ; 33(2): 181-201, 2020 02.
Artículo en Inglés | MEDLINE | ID: mdl-31557340

RESUMEN

Although rapid discontinuation of prednisone (RDP) after kidney transplantation has been successful in low-risk recipients, there is concern about RDP use in recipients at increased risk for rejection or recurrent disease. Using SRTR, we compared outcomes for RDP versus maintenance prednisone-treated recipients for all adult 1st and 2nd transplants (n = 169 479) and the following 1st transplant subgroups: African American (AA); highly sensitized; those with a potentially recurrent disease; and pediatric recipients. For all adult 1st LD and DD transplants, RDP was associated with better patient and graft survival. For all LD subgroups, RDP and maintenance prednisone were associated with similar patient, graft, and death-censored (DC) graft survival. For 1st transplant DD subgroups, RDP was associated with better patient survival in AA, those with potentially recurrent disease, and pediatric recipients; graft survival with RDP was better in AAs. For adult 2nd DD transplants, RDP was associated with worse DC-graft survival. Importantly, for all differences, the effect size was small. With the exception of 2nd DD transplants, RDP protocols can be used without decreasing patient or graft survival for subgroups of 1st DD and LD kidney transplant recipients and for 2nd LD transplant recipients, at increased risk of rejection or recurrent disease.


Asunto(s)
Rechazo de Injerto/prevención & control , Trasplante de Riñón , Prednisona/administración & dosificación , Adulto , Niño , Supervivencia de Injerto , Humanos , Prednisona/uso terapéutico , Receptores de Trasplantes
20.
Pediatr Transplant ; 24(5): e13717, 2020 08.
Artículo en Inglés | MEDLINE | ID: mdl-32447837

RESUMEN

BACKGROUND: Little data exist on re-hospitalization rates in pediatric kidney recipients (KTx) particularly with the evolution of transplant immunosuppression. METHODS: In a single-center, retrospective study of pediatric KTx between 2006 and 2016, we assessed re-hospitalization after KTx admission, stratified by whether the re-admit was early (<30 days post-KTx discharge) or late (>30 days), and compared two different immunosuppression eras (one with and one without steroids). RESULTS: Of 197 KTx, 156 (79%) patients were re-hospitalized in 1st year, 85 (56%) within 30 days of discharge (total 490 1st year re-hospitalizations). Younger age was associated with early and late re-hospitalizations. African American race was associated with early re-hospitalizations. Of the 123 and 74 discharged on steroid-avoidance (maintenance immunosuppression included MMF in 95%; FK in 50%; CSA in 50%) and steroid-inclusive (AZA in 66%; MMF in 34%; FK in 30%; CSA in 70%), re-hospitalization rates, timing post-transplant, length, and number were not significantly different (P .38; .1; .56; .11). Admission diagnoses analysis demonstrated that steroid-avoidance recipients had anemia/leucopenia/thrombocytopenia, significantly more often, as one of their admission diagnoses (16% vs 4%; P < .001) and had a rejection diagnosis significantly less often (6% vs 18%; P < .001). Infection diagnoses were not statistically different between groups. Re-hospitalization, early or late, did not predict worse graft/ patient survival but predicted further hospitalizations. CONCLUSIONS: Re-hospitalization is common after pediatric transplant discharge and predicts further hospitalization regardless of discharge on or off steroids.


Asunto(s)
Rechazo de Injerto/epidemiología , Trasplante de Riñón , Readmisión del Paciente/estadística & datos numéricos , Complicaciones Posoperatorias/epidemiología , Adolescente , Negro o Afroamericano , Factores de Edad , Niño , Preescolar , Femenino , Rechazo de Injerto/diagnóstico , Rechazo de Injerto/prevención & control , Supervivencia de Injerto , Humanos , Inmunosupresores/uso terapéutico , Lactante , Masculino , Complicaciones Posoperatorias/diagnóstico , Complicaciones Posoperatorias/etiología , Complicaciones Posoperatorias/terapia , Pronóstico , Estudios Retrospectivos , Factores de Riesgo , Factores de Tiempo
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