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BACKGROUND: Complement 3 glomerulopathy (C3G) and immune complex membranoproliferative glomerulonephritis (IC-MPGN) are ultra-rare chronic kidney diseases with an overall poor prognosis, with approximately 40-50% of patients progressing to kidney failure within 10 years of diagnosis. C3G is characterized by a high rate of disease recurrence in the transplanted kidney. However, there is a lack of published data on clinical outcomes in the pediatric population following transplantation. METHODS: In this multicenter longitudinal cohort study of the Cooperative European Paediatric Renal Transplant Initiative (CERTAIN) registry, we compared the post-transplant outcomes of pediatric patients with C3G (n = 17) or IC-MPGN (n = 3) with a matched case-control group (n = 20). RESULTS: Eleven of 20 children (55%) with C3G or IC-MPGN experienced a recurrence within 5 years post-transplant. Patients with C3G or IC-MPGN had a 5-year graft survival of 61.4%, which was significantly (P = 0.029) lower than the 5-year graft survival of 90% in controls; five patients with C3G or IC-MPGN lost their graft due to recurrence during this observation period. Both the 1-year (20%) and the 5-year (42%) rates of biopsy-proven acute rejection episodes were comparable between patients and controls. Complement-targeted therapy with eculizumab, either as prophylaxis or treatment, did not appear to be effective. CONCLUSIONS: These data in pediatric patients with C3G or IC-MPGN show a high risk of post-transplant disease recurrence (55%) and a significantly lower 5-year graft survival compared to matched controls with other primary kidney diseases. These data underscore the need for post-transplant patients for effective and specific therapies that target the underlying disease mechanism.
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Introduction: We investigated the relationship between metabolic acidosis over time and allograft outcome in pediatric kidney transplantation (KTx). Methods: This registry study collected data up to 10 years posttransplant. Survival analysis for a composite end point of graft loss or estimated glomerular filtration rate (eGFR) ≤ 30 ml/min per 1.73 m2 or ≥50% decline from eGFR at month 3 posttransplant was performed. The association of serum bicarbonate concentration (HCO3 -) < 22 mmol/l (metabolic acidosis) and HCO3 - < 18 mmol/l (severe metabolic acidosis) with allograft outcome was investigated using stratified Cox models and marginal structural models. Secondary analyses included the identification of risk factors for metabolic acidosis and the relationship between alkali supplementation and allograft outcome. Results: We report on 1911 patients, of whom 347 reached the composite end point. The prevalence of metabolic acidosis over time ranged from 20.4% to 38.9%. In the adjusted Cox models, metabolic acidosis (hazard ratio [HR], 2.00; 95% confidence interval [CI], 1.54-2.60) and severe metabolic acidosis (HR, 2.49; 95% CI, 1.56-3.99) were associated with allograft dysfunction. Marginal structural models showed similar results (HR, 1.75; 95% CI, 1.32-2.31 and HR, 2.09; 95% CI, 1.23-3.55, respectively). Older age was associated with a lower risk of metabolic acidosis (odds ratio [OR] 0.93/yr older; 95% CI, 0.91-0.96) and severe metabolic acidosis (OR, 0.89; 95% CI, 0.84-0.95). Patients with uncontrolled metabolic acidosis had the worst outcome compared to those without metabolic acidosis and without alkali (HR, 3.70; 95% CI, 2.54-5.40). Conclusion: The degree of metabolic acidosis is associated with allograft dysfunction.
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BACKGROUND: Kidney transplantation (KTx) from small donors is associated with inferior graft survival in registry studies, whereas single-center studies show favorable results. METHODS: We compared 175 pediatric KTx from small donors ≤20 kg (SDKTx) with 170 age-matched recipients from adult donors (ADKTx) from 20 centers within the Cooperative European Paediatric Renal Transplant Initiative registry. Graft survival and estimated glomerular filtration rate (eGFR) were analyzed by Cox regression and mixed models. Detailed data on surgical and medical management were tested for association with graft survival. RESULTS: One-year graft survival was lower after SDKTx compared with ADKTx (90.9% versus 96.5%; odds ratio of graft loss, 2.92; 95% confidence interval [CI], 1.10-7.80; P â =â 0.032), but 5-y graft survival was comparable (90.9% versus 92.7%; adjusted hazard ratio of graft loss 1.9; 95% CI, 0.85-4.25; P â =â 0.119). SDKTx recipients had an annual eGFR increase of 8.7â ±â 6.2 mL/min/1.73 m² compared with a decrease of 6.9â ±â 5.7 mL/min/1.73 m² in ADKTx recipients resulting in a superior 5-y eGFR (80.5â ±â 25.5 in SDKTx versus 65.7â ±â 23.1 mL/min/1.73 m² in ADKTx; P â =â 0.008). At 3 y posttransplant, eGFR after single SDKTx was lower than after en bloc SDKTx (86.6â ±â 20.4 versus 104.6â ±â 35.9; P â =â 0.043) but superior to ADKTx (68.1â ±â 23.9 mL/min/1.73 m²). Single-kidney SDKTx recipients had a lower rate of hypertension at 3 y than ADKTx recipients (40.0% versus 64.7%; P â =â 0.008). CONCLUSIONS: Compared with ADKTx, 5-y graft function is superior in SDKTx and graft survival is similar, even when performed as single KTx. Utilizing small donor organs, preferably as single kidneys in experienced centers, is a viable option to increase the donor pool for pediatric recipients.
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Tasa de Filtración Glomerular , Supervivencia de Injerto , Trasplante de Riñón , Sistema de Registros , Donantes de Tejidos , Humanos , Trasplante de Riñón/efectos adversos , Masculino , Femenino , Niño , Resultado del Tratamiento , Adolescente , Preescolar , Adulto , Lactante , Modelos de Riesgos Proporcionales , Europa (Continente) , Factores de Tiempo , Factores de Riesgo , Factores de EdadRESUMEN
BACKGROUND: Little is known about the time-varying determinants of kidney graft failure in children. METHODS: We performed a retrospective study of primary pediatric kidney transplant recipients (younger than 18 years) from the Eurotransplant registry (1990-2020). Piece-wise exponential additive mixed models were applied to analyze time-varying recipient, donor, and transplant risk factors. Primary outcome was death-censored graft failure. RESULTS: We report on 4528 kidney transplantations, of which 68% with deceased and 32% with living donor. One thousand six hundred and thirty-eight recipients experienced graft failure, and 168 died with a functioning graft. Between 2011 and 2020, the 5-year graft failure risk was 10% for deceased donor and 4% for living donor kidney transplant recipients. Risk of graft failure decreased five-fold from 1990 to 2020. The association between living donor transplantation and the lower risk of graft failure was strongest in the first month post-transplant (adjusted hazard ratio, 0.58; 95% confidence interval, 0.46 to 0.73) and remained statistically significant until 12 years post-transplant. Risk factors for graft failure in the first 2 years were deceased donor younger than 12 years or older than 46 years, potentially recurrent kidney disease, and panel-reactive antibody >0%. Other determinants of graft failure included dialysis before transplantation (until 5 years post-transplant), human leukocyte antigen mismatch 2-4 (0-15 years post-transplant), human leukocyte antigen mismatch 5-6 (2-12 years post-transplant), and hemodialysis (8-14 years post-transplant). Recipients older than 11 years at transplantation had a higher risk of graft failure 1-8 years post-transplant compared with other age groups, whereas young recipients had a lower risk throughout follow-up. Analysis of the combined effect of post-transplant time and recipient age showed a higher rate of graft failure during the first 5 years post-transplant in adolescents compared with young transplant recipients. In contrast to deceased donor younger than 12 years, deceased donor older than 46 years was consistently associated with a higher graft failure risk. CONCLUSIONS: We report a long-term inverse association between living donor kidney transplantation and the risk of graft failure. The determinants of graft failure varied with time. There was a significant cumulative effect of adolescence and time post-transplant. The ideal donor age window was dependent on time post-transplant.
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Enfermedades Renales , Trasplante de Riñón , Adolescente , Humanos , Niño , Preescolar , Trasplante de Riñón/efectos adversos , Estudios Retrospectivos , Supervivencia de Injerto , Donantes de Tejidos , Donadores Vivos , Enfermedades Renales/etiología , Europa (Continente)/epidemiología , Antígenos HLA , Rechazo de Injerto/epidemiología , Resultado del TratamientoRESUMEN
Introduction: Patient data are increasingly available in (multi)national registries, especially for rare diseases. This study aims to provide an overview of current European registries of paediatric kidney transplantation (PKT) care, their coverage, and their focus. Based on these data, we assess whether the current status is optimal for achieving our common goal: the optimalisation of health care. Methods: A list of all PKT centres within the European Union (EU) as well as active PKT registries was compiled using existing literature and the European Platform on Rare Disease Registration. Registry staff members were contacted to obtain information about the parameters collected and the registry design. These data were compared between registries. Results: In total, 109 PKT centres performing PKT surgery were identified in the 27 EU Member States. Currently, five European PKT registries are actively collecting data. In 39% of these centres, no data were registered within any of these five existing international registries. A large variety was observed in the number of patients, centres, and countries involved in the registries. Furthermore, variability existed regarding the inclusion criteria, definitions used, and parameters collected. Collection of perioperative urologic data are currently underrepresented in the registries. Discussion: Currently, multiple registries are collecting valuable information in the field of PKT, covering the majority of PKT centres in Europe. Due to a large variety in the parameters collected as well as different focuses, data collection is currently fragmented and suboptimal; therefore, the current existing data are incomplete. In addition, a considerable proportion of the transplantation centres do not enter data in any international registry. Combining available information and harmonising future data collection could empower the aim of these registries-namely increasing insights into the strengths and potential of current care and therefore improve healthcare.
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Introduction: Rejection remains the main cause of allograft failure in paediatric kidney transplantation and is driven by donor-recipient HLA mismatching. Modern computational algorithms enable assessment of HLA mismatch immunogenicity at the molecular level (molecular-mismatch, molMM). Whilst molMM has been shown to correlate with alloimmune outcomes, evidence demonstrating improved prediction performance against traditional antigen mismatching (antMM) is lacking. Methods: We analysed 177 patients from the CERTAIN registry (median follow-up 4.5 years). molMM scores included Amino-Acid-Mismatch-Score (AAMS), Electrostatic-Mismatch-Score (EMS3D) and netMHCIIpan (netMHC1k: peptide binding affinity ≤1000 nM; netMHC: binding affinity ≤500 nM plus rank <2%). We stratified patients into high/low-risk groups based on risk models of DSA development. Results: Donor-specific HLA antibodies (DSA) predominantly targeted the highest scoring molMM donor antigen within each HLA locus. MolMM scores offered superior discrimination versus antMM in predicting de novo DSA for all HLA loci; the EMS3D algorithm had particularly consistent performance (area under the receiver operating characteristic curve (AUC) >0.7 for all HLA loci vs. 0.52-0.70 for antMM). ABMR (but not TCMR) was associated with HLA-DQ molMM scores (AAMS, EMS3D and netMHC). Patients with high-risk HLA-DQ molMM had increased risk of graft function deterioration (50% reduction in baseline eGFR (eGFR50), adjusted HR: 3.5, 95% CI 1.6-8.2 high vs. low EMS3D). Multivariable modelling of the eGFR50 outcome using EMS3D HLA-DQ stratification showed better discrimination (AUC EMS3D vs. antMM at 2 years: 0.81 vs. 0.77, at 4.5 years: 0.72 vs. 0.64) and stratified more patients into the low-risk group, compared to traditional antMM. Conclusion: Molecular mismatching was superior to antigen mismatching in predicting humoral alloimmunity. Molecular HLA-DQ mismatching appears to be a significant prognostic factor for graft function deterioration in paediatric kidney transplantation.
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Trasplante de Riñón , Humanos , Niño , Trasplante de Riñón/efectos adversos , Prueba de Histocompatibilidad , Trasplante Homólogo , Anticuerpos , Antígenos HLA-DQ , Factores de RiesgoRESUMEN
[This corrects the article DOI: 10.3389/fimmu.2023.1092335.].
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Introduction: Little is known about the consequences of deranged chronic kidney disease-mineral and bone disorder (CKD-MBD) parameters on kidney allograft function in children. We examined a relationship between these parameters over time and allograft outcome. Methods: This registry study from the Cooperative European Paediatric Renal Transplant Initiative (CERTAIN) collected data at baseline, months 1, 3, 6, 9, and 12 after transplant; and every 6 months thereafter up to 5 years. Survival analysis for a composite end point of graft loss or estimated glomerular filtration rate (eGFR) ≤30 ml/min per 1.73 m2 or a ≥50% decline from eGFR at month 1 posttransplant was performed. Associations of parathyroid hormone (PTH), calcium, phosphate, and 25-hydroxyvitamin D (25(OH)D) with allograft outcome were investigated using conventional stratified Cox proportional hazards models and further verified with marginal structural models with time-varying covariates. Results: We report on 1210 patients (61% boys) from 16 European countries. The composite end point was reached in 250 grafts (21%), of which 11 (4%) were allograft losses. In the conventional Cox proportional hazards models adjusted for potential confounders, only hyperparathyroidism (hazard ratio [HR], 2.94; 95% confidence interval [CI], 1.82-4.74) and hyperphosphatemia (HR, 1.94; 95% CI, 1.28-2.92) were associated with the composite end point. Marginal structural models showed similar results for hyperparathyroidism (HR, 2.74; 95% CI, 1.71-4.38), whereas hyperphosphatemia was no longer significant (HR, 1.35; 95% CI, 0.87-2.09), suggesting that its association with graft dysfunction can be ascribed to a decline in eGFR. Conclusion: Hyperparathyroidism is a potential independent risk factor for allograft dysfunction in children.
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BACKGROUND: Randomized controlled trials in pediatric kidney transplantation are hampered by low incidence and prevalence of kidney failure in children. Real-World Data from patient registries could facilitate the conduct of clinical trials by substituting a control cohort. However, the emulation of a control cohort by registry data in pediatric kidney transplantation has not been investigated so far. METHODS: In this multicenter comparative analysis, we emulated the control cohort (n = 54) of an RCT in pediatric kidney transplant patients (CRADLE trial; ClinicalTrials.gov NCT01544491) with data derived from the Cooperative European Paediatric Renal Transplant Initiative (CERTAIN) registry, using the same inclusion and exclusion criteria (CERTAIN cohort, n = 554). RESULTS: Most baseline patient and transplant characteristics were well comparable between both cohorts. At year 1 posttransplant, a composite efficacy failure end point comprising biopsy-proven acute rejection, graft loss or death (5.8% ± 3.3% vs. 7.5% ± 1.1%, P = 0.33), and kidney function (72.5 ± 24.9 vs. 77.3 ± 24.2 mL/min/1.73 m2 P = 0.19) did not differ significantly between CRADLE and CERTAIN. Furthermore, the incidence and severity of BPAR (5.6% vs. 7.8%), the degree of proteinuria (20.2 ± 13.9 vs. 30.6 ± 58.4 g/mol, P = 0.15), and the key safety parameters such as occurrence of urinary tract infections (24.1% vs. 15.5%, P = 0.10) were well comparable. CONCLUSIONS: In conclusion, usage of Real-World Data from patient registries such as CERTAIN to emulate the control cohort of an RCT is feasible and could facilitate the conduct of clinical trials in pediatric kidney transplantation. A higher resolution version of the Graphical abstract is available as Supplementary information.
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Trasplante de Riñón , Niño , Humanos , Trasplante de Riñón/efectos adversos , Rechazo de Injerto/epidemiología , Rechazo de Injerto/prevención & control , Rechazo de Injerto/tratamiento farmacológico , Supervivencia de Injerto , Sistema de Registros , Ensayos Clínicos Controlados Aleatorios como AsuntoRESUMEN
BACKGROUND: Methylmalonic acidemia (MMAemia) is characterized by accumulation of methylmalonic acid (MMA) in all body tissues. To minimize disease-related complications, isolated kidney (KTx), liver (LTx) or combined liver-kidney transplantation (LKTx) have been suggested. However, the impact of these different transplant strategies on outcome are unclear. METHODS: In this multicenter retrospective observational study, we compared plasma MMA levels and estimated glomerular filtration rate (eGFR) data of 83 patients. Sixty-eight patients (82%) had a mut0-type MMAemia, one patient had a mut--type MMAemia, and seven (7.3%) had an inherited defect in cobalamin metabolism (cblA- or cblB-type MMAemia). Median observation period was 3.7 years (0-15.1 years). RESULTS: Twenty-six (31%) patients underwent KTx, 24 (29%) LTx and 33 (40%) LKTx. Posttransplant, mean plasma MMA concentration significantly decreased in all three cohorts; but at month 12, plasma MMA in KTx (1372 ± 1101 µmol/L) was 7.8-fold higher than in LTx (176 ± 103 µmol/L; P < 0.001) and 6.4-fold higher than in LKTx (215 ± 110 µmol/L; P < 0.001). Comparable data were observed at month 24. At time of transplantation, mean eGFR in KTx was 18.1 ± 24.3 mL/min/1.73 m2, in LTx 99.8 ± 29.9 mL/min/1.73 m2, and in LKTx 31.5 ± 21.2 mL/min/1.73 m2. At month 12 posttransplant, mean eGFR in KTx (62.3 ± 30.3 mL/min/1.73 m2) was 33.4% lower than in LTx (93.5 ± 18.3 mL/min/1.73 m2; P = 0.0053) and 25.4% lower than in LKTx (83.5 ± 26.9 mL/min/1.73 m2; P = 0.0403). CONCLUSIONS: In patients with isolated MMAemia, LTx and LKTx lead to markedly lower plasma MMA levels during the first 2 years posttransplant than KTx and are associated with a better preservation of kidney function. LTx should therefore be part of the transplant strategy in MMAemia.
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Errores Innatos del Metabolismo de los Aminoácidos , Trasplante de Riñón , Humanos , Ácido Metilmalónico , Errores Innatos del Metabolismo de los Aminoácidos/genética , Errores Innatos del Metabolismo de los Aminoácidos/complicaciones , Riñón , HígadoRESUMEN
BACKGROUND: Preexistent LUTD are considered a hostile environment, which might negatively impact KTx survival. In such cases, surgical reconstruction of the bladder is required. However, there is still disagreement on the optimal timing of the reconstruction procedure. METHODS: This is a multicenter analysis of data from the CERTAIN Registry. Included were 62 children aged 8.18 ± 4.90 years, with LUTD. Study endpoints were the duration of initial posttransplant hospitalization, febrile UTIs, and a composite failure endpoint comprising decline of eGFR, graft loss, or death up to 5 years posttransplant. Outcome was compared to matched controls without bladder dysfunction. RESULTS: Forty-one patients (66.1%) underwent pretransplant and 14 patients (22.6%) posttransplant reconstruction. Bladder augmentation was performed more frequently in the pretransplant (61%) than in the posttransplant group (21%, p = .013). Outcome in the pre- and posttransplant groups and in the subgroups of patients on pretransplant PD with major bladder surgery either pre- (n = 14) or posttransplant (n = 7) was comparable. Outcomes of the main study cohort and the matched control cohort (n = 119) were comparable during the first 4 years posttransplant; at year 5, there were more events of transplant dysfunction in the study cohort with LUTD than in controls (p = .03). CONCLUSIONS: This multicenter analysis of the current practice of LUTD reconstruction in pediatric KTx recipients shows that pre- or posttransplant surgical reconstruction of the lower urinary tract is associated with a comparable 5-year outcome.
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Trasplante de Riñón , Infecciones Urinarias , Niño , Estudios de Cohortes , Supervivencia de Injerto , Humanos , Receptores de Trasplantes , Vejiga Urinaria/cirugía , Infecciones Urinarias/etiologíaRESUMEN
BACKGROUND: There are several databases across the world that collect pediatric KT data. We compare the hospitalization outcomes for pediatric KT recipients from a large Canadian transplant center (SickKids database; The Hospital for Sick Children Kidney Transplantation Institutional Database), United States (NAPRTCS), and Europe (CERTAIN registry). METHODS: An institutional retrospective review of KT was performed between 2000 and 2015. Baseline characteristics, duration of initial hospitalization/readmission at 1-5 and 6- to 11-month posttransplant, and 1-year graft survival data were collected. Corresponding data from the NAPRTCS 2014 Annual Transplant Report and CERTAIN registry were compared. RESULTS: Posttransplant, patients from NAPRTCS had the shortest duration of hospitalization within the first month (10.4 days, SE 0.2), followed by SickKids (20.3 days, SE 0.7) and CERTAIN (25.5 days, SE 0.7). For both living and deceased donor populations, patients from SickKids were most likely to be hospitalized at 1- to 5-month posttransplant (82.4% [89/108]; 72.1% [98/136]), followed by Europe (52.1% [198/380]; 61.6% [501/813]) and United States (45.4% [2379/5241]; 51.4% [2517/4896]). Patients from Europe were most likely to be hospitalized at 6- to 12-month posttransplant (42.1% [160/380]; 51.7% [420/813]), followed by SickKids (35.2% [38/108]; 37.5% [51/136]) and United States (28.3% [1387/4901]; 31.6% [1411/4465]). Across all databases, the most commonly addressed issues during readmissions were infectious complications. CONCLUSION: The differences observed in this investigation may reflect the local reimbursement models, resources for outpatient management, and practice variations across a large Canadian transplant center, United States, and European countries.
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Trasplante de Riñón , Canadá , Niño , Rechazo de Injerto/etiología , Supervivencia de Injerto , Hospitalización , Humanos , Sistema de Registros , Estados UnidosRESUMEN
BACKGROUND: Asymptomatic hyperuricemia is frequently observed in pediatric kidney transplant recipients; symptomatic hyperuricemia, however, is a rare complication. Only few data are available in this patient population. We, therefore, investigated the prevalence of hyperuricemia and its association with kidney transplant function and blood pressure in a multicenter cohort of pediatric kidney transplant recipients. METHODS: This is a retrospective, observational multicenter registry study. All pediatric kidney transplant recipients in the CERTAIN database with at least one documented serum uric acid level and a follow-up of 5 years posttransplant were eligible. We identified 151 patients with 395 measurements of serum uric acid. We calculated the prevalence of hyperuricemia, analyzed potential risk factors and clinical consequences such as elevated blood pressure and reduced estimated glomerular filtration rate (eGFR). Statistical analysis was performed using IBM SPSS Statistics 26. RESULTS: One hundred and ten of 395 (27.8%) serum uric acid levels were above 416 µmol/L (7.0 mg/dL), defined as the upper limit of normal. Univariate analysis showed a significant (p = .026) inverse association of serum uric acid with eGFR overtime. There was no significant association of serum uric acid concentrations with body mass index (z-score), blood pressure (z-score), or sex. No episodes of gout were documented. CONCLUSION: This study shows that hyperuricemia is present in a considerable number of patients sometime after pediatric kidney transplantation and is associated with lower eGFR. Whether hyperuricemia contributes to faster decline of graft function or to the overall cardiovascular risk of these patients remains to be elucidated.
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Hiperuricemia , Trasplante de Riñón , Niño , Tasa de Filtración Glomerular/fisiología , Humanos , Hiperuricemia/complicaciones , Hiperuricemia/diagnóstico , Hiperuricemia/epidemiología , Trasplante de Riñón/efectos adversos , Prevalencia , Sistema de Registros , Factores de Riesgo , Ácido ÚricoRESUMEN
BACKGROUND: Secondary hyperparathyroidism (SHPT) may persist after renal transplantation (RTx), inducing hypophosphatemia and hypercalcemia that precludes the use of vitamin D analogs. The calcimimetic cinacalcet improved plasma calcium and parathyroid hormone (PTH) levels in randomized controlled trials in adults after RTx, but pediatric data are scarce. METHODS: In this retrospective study, we analyzed 20 pediatric patients from the Cooperative European Paediatric Renal TransplAnt Initiative (CERTAIN) Registry who received cinacalcet after RTx. The results are presented as median and interquartile range (25th-75th percentile). RESULTS: At 13.7 (11.0-16.5) years of age, 20 pediatric patients received a renal allograft. Cinacalcet was introduced at 0.4 (0.3-2.7) years post-transplant at an estimated glomerular filtration rate (eGFR) of 50 (34-66) mL/min/1.73 m2, plasma calcium of 2.58 (2.39-2.71) mmol/L, age-standardized (z score) phosphate of - 1.7 (- 2.7-- 0.4), and PTH of 136 (95-236) ng/L. The starting dose of cinacalcet was 0.5 (0.3-0.8) mg/kg per day, with a maximum dose of 1.1 (0.5-1.3) mg/kg per day. With a follow-up of 3.0 (1.5-3.6) years on cinacalcet therapy, eGFR remained stable; PTH levels decreased to 66 (56-124) ng/L at the last follow-up (p = 0.015). One patient displayed hypocalcemia (1.8 mmol/L). Cinacalcet was withdrawn in three patients (hypocalcemia, parathyroidectomy, incompliance). Nephrocalcinosis of the graft was not reported. CONCLUSIONS: This pilot study suggests that cinacalcet as off-label therapy for SHPT after pediatric RTx is efficacious in controlling post-transplant SHPT with acceptable tolerability. Continuing cinacalcet even with normal PTH can lead to dangerous life-threatening hypocalcemia. Therefore, at each subsequent visit, the need to continue cinacalcet must be assessed.
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Calcimiméticos/administración & dosificación , Cinacalcet/administración & dosificación , Hiperparatiroidismo Secundario/tratamiento farmacológico , Hiperparatiroidismo Secundario/etiología , Fallo Renal Crónico/complicaciones , Adolescente , Calcimiméticos/efectos adversos , Niño , Cinacalcet/efectos adversos , Relación Dosis-Respuesta a Droga , Femenino , Humanos , Fallo Renal Crónico/cirugía , Trasplante de Riñón , Masculino , Uso Fuera de lo Indicado , Proyectos Piloto , Sistema de Registros , Estudios Retrospectivos , Receptores de TrasplantesRESUMEN
BACKGROUND: High prevalence of arterial hypertension is known in pediatric renal transplant patients, but how blood pressure (BP) distribution and control differ between age groups and whether sex and age interact and potentially impact BP after transplantation have not been investigated. METHODS: This retrospective analysis included 336 pediatric renal transplant recipients (62% males) from the Cooperative European Pediatric Renal Transplant Initiative Registry (CERTAIN) with complete BP measurement at discharge and 1, 2 and 3 years post-transplant. RESULTS: At discharge and 3 years post-transplant, arterial hypertension was highly prevalent (84% and 77%); antihypertensive drugs were used in 73% and 68% of the patients. 27% suffered from uncontrolled and 9% from untreated hypertension at 3 years post-transplant. Children transplanted at age < 5 years showed sustained high systolic BP z-score and received consistently less antihypertensive treatment over time. Younger age, shorter time since transplantation, male sex, higher body mass index (BMI), high cyclosporine A (CSA) trough levels, and a primary renal disease other than congenital anomalies of the kidney and urinary tract (CAKUT) were significantly associated with higher systolic BP z-score. Sex-stratified analysis revealed a significant association between high CSA and higher systolic BP in older girls that likely had started puberty already. An association between BP and estimated glomerular filtration rate was not detected. CONCLUSIONS: BP control during the first 3 years was poor in this large European cohort. The description of age- and sex-specific risk profiles identified certain recipient groups that may benefit from more frequent BP monitoring (i.e. young children) or different choices of immunosuppression (i.e. older girls).
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Hipertensión/epidemiología , Trasplante de Riñón/efectos adversos , Adolescente , Factores de Edad , Determinación de la Presión Sanguínea/estadística & datos numéricos , Niño , Preescolar , Ciclosporina/administración & dosificación , Ciclosporina/efectos adversos , Ciclosporina/farmacocinética , Europa (Continente)/epidemiología , Femenino , Estudios de Seguimiento , Rechazo de Injerto/inmunología , Rechazo de Injerto/prevención & control , Humanos , Hipertensión/diagnóstico , Hipertensión/etiología , Inmunosupresores/administración & dosificación , Inmunosupresores/efectos adversos , Inmunosupresores/farmacocinética , Estudios Longitudinales , Masculino , Prevalencia , Sistema de Registros/estadística & datos numéricos , Estudios Retrospectivos , Factores Sexuales , Tacrolimus/administración & dosificación , Tacrolimus/efectos adversos , Tacrolimus/farmacocinética , Factores de Tiempo , Receptores de Trasplantes/estadística & datos numéricosRESUMEN
Chronic antibody-mediated rejection (cABMR) is the main cause of long-term renal graft loss. Late-stage diagnosis is made by detecting donor-specific antibodies (DSA) in blood combined with typical histomorphological lesions in renal allografts. There is a need for noninvasive biomarkers for cABMR that might permit screening and earlier diagnosis. In a case control study of 24 pediatric renal transplant recipients, urine samples were analyzed using capillary electrophoresis and mass spectrometry. Patients were matched with 36 pediatric renal transplant patients without cABMR. Statistical analysis used the nonparametric Wilcoxon test to identify 79 significant biomarkers, which were combined to a support vector machine-based classifier. After validation in an independent test cohort of eight pediatric patients with and 12 without cABMR, the area under the receiver operating characteristic (ROC) curve (AUC) for detection of cABMR was 0.92 (95% CI 0.71-0.99) with a sensitivity of 100% (95% CI 63-100%) and a specificity of 75% (95% CI 43-95%). Combining this classifier with the urinary proteomic marker CKD273 improved the detection of patients with cABMR with misclassification in only 2/20 of the patients. These data indicate that a biomarker pattern derived from urinary proteomics allows the detection of cABMR in pediatric renal transplant recipients with high sensitivity and moderate specificity.
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Anticuerpos/inmunología , Biomarcadores/orina , Rechazo de Injerto/inmunología , Trasplante de Riñón , Proteómica , Insuficiencia Renal/orina , Adolescente , Área Bajo la Curva , Biopsia , Estudios de Casos y Controles , Niño , Preescolar , Femenino , Supervivencia de Injerto , Humanos , Inmunosupresores/uso terapéutico , Donadores Vivos , Masculino , Proyectos Piloto , Curva ROC , Sensibilidad y EspecificidadRESUMEN
BACKGROUND: BK polyomavirus-associated nephropathy (BKPyVAN) constitutes a serious cause of kidney allograft failure, but large-scale data in pediatric renal transplant recipients and a comprehensive analysis of specific risk factors are lacking. METHODS: We analyzed the data of 313 patients in the Cooperative European Pediatric Renal Transplant Initiative Registry, with an observation period of 3.3 years (range, 1-5). The net state of immunosuppressive therapy was assessed by the modified Vasudev score. RESULTS: Presumptive BKPyVAN (defined as sustained [>3 wk] high-level BK viremia >10 copies/mL) within 5 years posttransplant occurred in 49 (15.8%) of 311 patients, and biopsy-proven BKPyVAN in 14 (4.5%) of 313. BKPyV viremia was observed in 115 (36.7%) of 311 patients, of whom 11 (9.6%) of 115 developed viremia late, that is, after the second year posttransplant. In 6 (12.5%) of 48 patients with high-level viremia and in 3 (21.4%) of 14 with BKPyVAN, this respective event occurred late. According to multivariable analysis, BKPyV viremia and/or BKPyVAN were associated not only with a higher net state of immunosuppression (odds ratio [OR], 1.3; P < 0.01) and with tacrolimus-based versus ciclosporin-based immunosuppression (OR, 3.6; P < 0.01) but also with younger recipient age (OR, 1.1 per y younger; P < 0.001) and obstructive uropathy (OR, 12.4; P < 0.01) as primary renal disease. CONCLUSIONS: Uncontrolled BKPyV replication affects a significant proportion of pediatric renal transplant recipients and is associated with unique features of epidemiology and risk factors, such as young recipient age, obstructive uropathy, and overall intensity of immunosuppressive therapy. BKPyV surveillance should be considered beyond 2 years posttransplant in pediatric patients at higher risk.
Asunto(s)
Virus BK/crecimiento & desarrollo , Inmunosupresores/efectos adversos , Enfermedades Renales/epidemiología , Trasplante de Riñón/efectos adversos , Infecciones Oportunistas/epidemiología , Infecciones por Polyomavirus/epidemiología , Infecciones Tumorales por Virus/epidemiología , Replicación Viral , Adolescente , Factores de Edad , Antivirales/uso terapéutico , Virus BK/efectos de los fármacos , Virus BK/inmunología , Niño , Preescolar , Europa (Continente)/epidemiología , Femenino , Humanos , Huésped Inmunocomprometido , Enfermedades Renales/inmunología , Enfermedades Renales/virología , Estudios Longitudinales , Masculino , Infecciones Oportunistas/tratamiento farmacológico , Infecciones Oportunistas/inmunología , Infecciones Oportunistas/virología , Infecciones por Polyomavirus/tratamiento farmacológico , Infecciones por Polyomavirus/inmunología , Infecciones por Polyomavirus/virología , Sistema de Registros , Estudios Retrospectivos , Medición de Riesgo , Factores de Riesgo , Factores de Tiempo , Resultado del Tratamiento , Infecciones Tumorales por Virus/tratamiento farmacológico , Infecciones Tumorales por Virus/inmunología , Infecciones Tumorales por Virus/virología , Carga ViralRESUMEN
BACKGROUND: JC polyomavirus (JCPyV)-associated nephropathy (JCPyVAN) is a severe, but rare complication in adult renal transplant (RTx) recipients. Related data in pediatric patients are scarce. METHODS: Based on the CERTAIN Registry, we therefore performed a multi-center, retrospective study on the JCPyV antibody status, prevalence of JCPyV replication, and its associated disease in 139 pediatric RTx recipients (mean age, 8.5 ± 5.3 years). JCPyV DNA in plasma and/or urine was measured by quantitative PCR at a median time of 3.2 (IQR, 0.3-8.1) years post-transplant. RESULTS: 53.2% of patients were JCPyV-seronegative prior to transplantation; younger age was associated with JCPyV seronegativity. 34/139 (24.5%) patients post-transplant showed active JCPyV replication in either urine (22.0%), plasma (13.4%), or both (7.6%). JCPyV viremia occurred significantly (p < 0.001) more often in patients with viruria (34.6%) than in those without (7.6%), but 7/118 (5.9%) had isolated viremia. High-level viruria (> 107 copies/mL) was found in 29.6% of viruric patients. A higher net state of immunosuppression constituted an independent risk factor for JCPyV replication both in urine and plasma (OR 1.2, p < 0.02). Male patients tended to have a higher risk of JCPyV viremia than females (OR 4.3, p = 0.057). There was one male patient (0.7%) with JCPyVAN 7 years post-transplant, which resolved after reduction of immunosuppressive therapy. No patient exhibited progressive multifocal leukoencephalopathy. CONCLUSIONS: This first multi-center study on JCPyV in pediatric renal transplant recipients shows that JCPyV replication is common (24.5%), with strong immunosuppression being a significant risk factor, but associated nephropathy is rare.
Asunto(s)
Virus JC/aislamiento & purificación , Enfermedades Renales/epidemiología , Trasplante de Riñón/efectos adversos , Infecciones por Polyomavirus/epidemiología , Viremia/epidemiología , Adolescente , Niño , Preescolar , Femenino , Rechazo de Injerto/inmunología , Rechazo de Injerto/prevención & control , Humanos , Terapia de Inmunosupresión/efectos adversos , Enfermedades Renales/inmunología , Enfermedades Renales/virología , Masculino , Infecciones por Polyomavirus/inmunología , Infecciones por Polyomavirus/virología , Prevalencia , Sistema de Registros/estadística & datos numéricos , Estudios Retrospectivos , Receptores de Trasplantes/estadística & datos numéricos , Viremia/inmunología , Viremia/virologíaRESUMEN
BACKGROUND: Infants with a body weight of less than 10 kg are often not considered to be suitable candidates for renal transplantation (RTx). The objective of this study was to evaluate this arbitrary weight threshold for pediatric RTx. METHODS: We conducted a multicenter, retrospective, match-controlled cohort study on infants weighing less than 10 kg at time of engrafting (low-weight group [LWG], n = 38) compared to a matched control group (n = 76) with a body weight of 10-15 kg, using data from the first 2 years post-transplant derived from the CERTAIN Registry. RESULTS: Patient survival was 97 and 100% in the LWG and control groups, respectively (P = 0.33), and death-censored graft survival was 100 and 95% in the LWG and control groups, respectively (P = 0.30). Estimated glomerular filtration rate at 2 years post-transplant was excellent and comparable between the groups (LWG 77.6 ± 34.9 mL/min/1.73 m2; control 74.8 ± 29.1 mL/min/1.73 m2; P = 0.68). The overall incidences of surgery-related complications (LWG 11%, control 23%; P = 0.12) and medical outcome measures (LWG 23%, control 36%, P = 0.17) were not significantly different between the groups. The medical outcome measures included transplant-related viral diseases (LWG 10%, control 21%; P = 0.20), acute rejection episodes (LWG 14%, control 29%; P = 0.092), malignancies (LWG 3%, control 0%; P = 0.33) and arterial hypertension (LWG 73%, control 67%; P = 0.57). CONCLUSIONS: These data suggest that RTx in low-weight children is a feasible option, at least in selected centers with appropriate surgical and medical expertise.
Asunto(s)
Peso Corporal , Fallo Renal Crónico/cirugía , Trasplante de Riñón/métodos , Complicaciones Posoperatorias/etiología , Delgadez/complicaciones , Estudios de Casos y Controles , Preescolar , Estudios de Cohortes , Femenino , Supervivencia de Injerto , Humanos , Lactante , Trasplante de Riñón/efectos adversos , Masculino , Complicaciones Posoperatorias/epidemiología , Sistema de Registros , Estudios Retrospectivos , Factores de Riesgo , Resultado del TratamientoRESUMEN
BACKGROUND: Avoidance of vaccine-preventable infections in paediatric renal allograft recipients is of utmost importance. However, the development and maintenance of protective vaccination titres may be impaired in this patient population owing to their need for immunosuppressive medication. METHODS: In the framework of the Cooperative European Paediatric Renal Transplant Initiative (CERTAIN), we therefore performed a multi-centre, multi-national study and analysed vaccination titres pre- and post-transplant in 155 patients with serial titre measurements in comparison with published data in healthy children. RESULTS: The percentage of patients with positive vaccination titres before renal transplantation (RTx) was low, especially for diphtheria (38.5%, control 75%) and pertussis (21.3%, control 96.3%). As few as 58.1% of patients had a hepatitis B antibody (HBsAb) titre >100 IU/L before RTx. 38.1% of patients showed a vaccination titre loss post-transplant. Patients with an HBsAb titre between 10 and 100 IU/L before RTx experienced a significantly (p < 0.05) more frequent hepatitis B vaccination titre loss post-transplant than patients with an HBsAb titre >100 IU/L. The revaccination rate post-transplant was low and revaccination failed to induce positive titres in a considerable number of patients (27.3 to 83.3%). Treatment with rituximab was associated with a significantly increased risk of a vaccination titre loss post-transplant (odds ratio 4.26, p = 0.033). CONCLUSIONS: These data show a low percentage of patients with positive vaccination titres pre-transplant, a low revaccination rate post-transplant with limited antibody response, and a high rate of vaccination titre losses.