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1.
Transpl Infect Dis ; 26(2): e14237, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38341645

RESUMO

BACKGROUND: BK polyomavirus (BKV) can cause permanent loss of allograft function due to BKV-associated nephropathy (BKVN) in kidney transplant recipients. Besides immunosuppression reduction, there are no consistently effective interventions for BKV infection. Study purpose was to define natural history of BKV infection, identify risk factors for BKV reactivation and BKVN in kidney transplant recipients, and inform the design/conduct of future clinical trials of BKV-targeted therapeutics. METHODS: We conducted a multicenter prospective observational study of incident kidney transplant recipients at six U.S. transplant centers. Participants were monitored every 4 weeks for BKV reactivation and followed for up to 24 months post-transplant. We used regression models (logistic, survival, mixed models) to study relationships between BK viremia/BKVN, clinical characteristics, and allograft function. RESULTS: We enrolled 335 participants. Fifty-eight (17%) developed BK viremia, 6 (2%) developed biopsy-proven BKVN, and 29 (9%) developed suspected/presumed BKVN (defined as BKV viral load > 10,000 copies/mL without biopsy). Male donor sex was associated with lower odds for BK viremia, whereas recipient Black race was associated with two-fold increased odds for BK viremia. Recipient female sex was associated with more rapid clearance of BK viremia. Persistent BK viremia/BKVN was associated with poorer allograft function by 24 months post-transplant. CONCLUSIONS: We identified multiple donor and recipient demographic factors associated with risk for BKV infection and poorer allograft function by 24 months post-transplant. This may help design future clinical trials of therapies to prevent or mitigate the deleterious impact of BKV reactivation on kidney transplant outcomes.


Assuntos
Vírus BK , Nefropatias , Transplante de Rim , Infecções por Polyomavirus , Infecções Tumorais por Vírus , Humanos , Masculino , Feminino , Transplante de Rim/efeitos adversos , Estudos Prospectivos , Viremia/complicações , Infecções por Polyomavirus/complicações , Infecções Tumorais por Vírus/tratamento farmacológico
2.
Pediatr Transplant ; 28(1): e14617, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-37750353

RESUMO

BACKGROUND: Incomplete resolution of T cell-mediated rejection (TCMR) after treatment may not be detected with serum creatinine monitoring and is associated with donor-specific antibodies and chronic rejection. We evaluate the utility of follow-up biopsies (FUB) to identify and characterize rates of persistent TCMR after treatment in pediatric kidney transplant patients. METHODS: Patients from two pediatric transplant centers performing standard of care FUB at 1.5-2 months after treatment for TCMR were included. FUB were evaluated for extent of rejection resolution (complete vs. incomplete) and grade. Clinical data at time of FUB and later were reported, where available. RESULTS: Fifty-eight patients underwent FUB, at mean of 1.7 months (SD 0.7) post-index biopsy. Rejection grade on index biopsy was Banff borderline (≥i1t1 and

Assuntos
Transplante de Rim , Humanos , Criança , Transplante de Rim/efeitos adversos , Linfócitos T , Seguimentos , Biópsia , Resultado do Tratamento , Transplantados , Rejeição de Enxerto , Rim/patologia
3.
Pediatr Transplant ; 28(1): e14628, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-37877312

RESUMO

BACKGROUND: Mycophenolate Mofetil (MMF) is an effective immunosuppressant used in kidney transplant recipients to prevent acute rejection. Complications such as diarrhea, leukopenia, and infections may necessitate the reduction or discontinuation of MMF. The objective of the study was to investigate the prevalence, timing, and reasons for MMF discontinuation and its association with outcomes in pediatric kidney transplant recipients. METHODS: Seven Pediatric Nephrology Research Consortium (PNRC) centers participated in a retrospective analysis of kidney transplant recipients <21 years of age. Characteristics and outcomes of patients in whom MMF was discontinued were compared to those who continued taking MMF throughout the first 2 years post-transplant. RESULTS: The study population included 288 participants (mean age 11.2 years) from 7 North American transplant centers. MMF was discontinued in 93/288 (32%) of participants. Common reasons for discontinuation included infections (35%), diarrhea (32%), leukopenia (15%), and others (18%). Increased cumulative alloimmunity (55% vs. 42%, p = .02), increased number of hospitalizations (82% vs. 67%, p = .01), and viral replications (79% vs. 47%, p < .0001) were observed in the MMF discontinuation group compared to the continuation group. Greater eGFR decline also occurred in the MMF discontinuation group over 2 years of follow-up (-7 vs. -1 mL/min/1.73 m2 , p = .05). CONCLUSIONS: Almost a third of pediatric kidney transplant recipients who begin MMF for maintenance immunosuppression have it discontinued within the first 2 years post-transplant, and this subset of patients is more likely to experience adverse outcomes. New strategies are needed to manage MMF therapy and improve post-transplant outcomes.


Assuntos
Transplante de Rim , Leucopenia , Nefrologia , Humanos , Criança , Ácido Micofenólico , Estudos Retrospectivos , Prevalência , Rejeição de Enxerto/prevenção & controle , Rejeição de Enxerto/epidemiologia , Imunossupressores/efeitos adversos , Diarreia/epidemiologia , Diarreia/etiologia , Leucopenia/etiologia , Leucopenia/induzido quimicamente
4.
Pediatr Transplant ; 28(6): e14836, 2024 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-39147695

RESUMO

INTRODUCTION: The successes in the field of pediatric kidney transplantation over the past 60 years have been extraordinary. Year over year, there have been significant improvements in short-term graft survival. However, improvements in longer-term outcomes have been much less apparent. One important contributor has been the phenomenon of low-level rejection in the absence of clinical manifestations-so-called subclinical rejection (SCR). METHODS: Traditionally, rejection has been diagnosed by changes in clinical parameters, including but not limited to serum creatinine and proteinuria. This review examines the shortcomings of this approach, the effects of SCR on kidney allograft outcome, the benefits and drawbacks of surveillance biopsies to identify SCR, and new urine and blood biomarkers that define the presence or absence of SCR. RESULTS: Serum creatinine is an unreliable index of SCR. Surveillance biopsies are the method most utilized to detect SCR. However, these have significant drawbacks. New biomarkers show promise. These biomarkers include blood gene expression profiles and donor derived-cell free DNA; urine gene expression profiles; urinary cytokines, chemokines, and metabolomics; and other promising blood and urine tests. CONCLUSION: Specific emphasis is placed on studies carried out in pediatric kidney transplant recipients. TRIAL REGISTRATION: ClinicalTrials.gov: NCT03719339.


Assuntos
Biomarcadores , Rejeição de Enxerto , Transplante de Rim , Humanos , Rejeição de Enxerto/diagnóstico , Rejeição de Enxerto/sangue , Criança , Biomarcadores/sangue , Biomarcadores/urina , Biópsia , Creatinina/sangue , Sobrevivência de Enxerto
5.
Clin Genet ; 103(1): 97-102, 2023 01.
Artigo em Inglês | MEDLINE | ID: mdl-36071576

RESUMO

The Crumbs homolog-2 (CRB2)-related syndrome (CRBS-RS) is a rarely encountered condition initially described as a triad comprising ventriculomegaly, Finnish nephrosis, and elevated alpha-fetoprotein levels in maternal serum and amniotic fluid. CRB2-related syndrome is caused by biallelic, pathogenic variants in the CRB2 gene. Recent reports of CRB2-RS have highlighted renal disease with persistent proteinuria and steroid-resistant nephrotic syndrome (SRNS). We report six new and review 28 reported patients with pathogenic variants in CRB2. We compare clinical features and variant information in CRB2 in patients with CRB2-RS and in those with isolated renal disease. The kidneys were the most frequently involved body system and 11 patients had only renal manifestations with SRNS or nephrotic syndrome. Central nervous system involvement was the next most common manifestation, followed by cardiac findings that included Scimitar syndrome. There was a significant clustering of pathogenic variants for CRB2-RS in exons 8 and 10, whereas pathogenic variants in exons 12 and 13 were associated with isolated renal disease. Further information is needed to determine optimal management but monitoring for renal and ocular complications should be considered.


Assuntos
Proteínas de Transporte , Família , Humanos , Proteínas de Membrana/genética
6.
Psychosom Med ; 85(2): 118-129, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-36728859

RESUMO

OBJECTIVE: Early life stress (ELS) occurring during childhood and adolescence is an established risk factor for later cardiovascular disease and dysregulated reactivity to acute social stress. This study examined whether ELS associations with baseline cardiovascular functioning, cardiovascular stress reactivity and recovery, and emotional stress reactivity vary across levels of emotion-oriented, task-oriented, and avoidant coping styles. METHODS: The sample included 1027 adolescents and young adults (mean age = 19.29 years; 50% female; 64% Black, 34% non-Hispanic White) who reported on their ELS exposure and coping styles. Participants completed a standardized acute social stress test (the Trier Social Stress Test [TSST]), with heart rate (HR) and blood pressure (BP) measured before, during, and after the TSST. Self-reports of negative emotions during the TSST indexed emotional stress reactivity. RESULTS: Multiple regression models adjusting for demographic factors and body mass index showed that ELS was associated with lower HR stress reactivity, avoidant coping was related to lower systolic BP and diastolic BP during stress and lower systolic BP during recovery, and higher emotion-oriented coping and lower task-oriented coping predicted greater emotional stress reactivity. A consistent pattern emerged where emotion-oriented coping amplified the associations between ELS and maladaptive stress responses (blunted cardiovascular stress reactivity and recovery; enhanced emotional stress reactivity), whereas lower levels of emotion-oriented coping were associated with resilient profiles among those who experienced ELS (lower resting HR, lower emotional stress reactivity, average HR and BP stress reactivity and recovery). However, low levels of emotion-oriented coping also conferred a risk of higher BP during recovery for those with high levels of ELS. CONCLUSIONS: These results suggest that low to moderate levels of emotion-oriented coping promote optimal cardiovascular and emotional reactivity to acute stress among individuals exposed to ELS.


Assuntos
Experiências Adversas da Infância , Adolescente , Adulto Jovem , Humanos , Feminino , Adulto , Masculino , Estresse Psicológico , Adaptação Psicológica , Emoções/fisiologia , Autorrelato
7.
Pediatr Nephrol ; 38(7): 2155-2163, 2023 07.
Artigo em Inglês | MEDLINE | ID: mdl-36622441

RESUMO

BACKGROUND: Adverse childhood experiences (ACEs), such as abuse, neglect, and household dysfunction, are associated with a higher risk of cardiovascular disease (CVD) and indicators of future CVD risk in adulthood, such as greater vascular stiffness. The impact of ACEs in adolescence is unclear, and understanding how ACEs relate to blood pressure (BP) and vascular function during early life is key for the development of prevention strategies to reduce CVD risk. We hypothesized that exposure to ACEs would be associated with changes in central hemodynamics such as increased vascular stiffness and higher BP during adolescence. METHODS: This pilot study enrolled 86 adolescents recruited from the Children's of Alabama. A validated ACE questionnaire was employed, and ACEs were modeled both as a continuous variable and a categorical variable (ACE ≥ 1 vs. ACE = 0). The primary outcomes used are considered to be indicators of future cardio-renal disease risk: aortic augmentation index normalized to 75 bpm (Alx75, a surrogate for vascular stiffness), carotid-femoral PWV (m/s), and ambulatory BP patterns. RESULTS: Adolescents with ACE ≥ 1 had significantly higher Alx75 (ACE: 5.2% ± 2.2 compared to no ACE: - 1.4% ± 3.0; p = 0.043). PWV only reflected this trend when adjustments were made for the body mass index. Adolescents with ACEs showed no differences in ambulatory BP patterns during the 24-h, wake, or sleep periods compared to adolescents with no ACEs. CONCLUSIONS: ACEs were associated with higher AIx75 in adolescence, which is a risk factor for future CVD. Adolescence could present an opportunity for early detections/interventions to mitigate adverse cardiovascular outcomes in adulthood. A higher resolution version of the Graphical abstract is available as Supplementary information.


Assuntos
Experiências Adversas da Infância , Doenças Cardiovasculares , Maus-Tratos Infantis , Humanos , Adolescente , Criança , Doenças Cardiovasculares/epidemiologia , Doenças Cardiovasculares/etiologia , Projetos Piloto , Fatores de Risco
8.
Pediatr Nephrol ; 38(2): 537-547, 2023 02.
Artigo em Inglês | MEDLINE | ID: mdl-35538239

RESUMO

BACKGROUND: We report follow-up data from an ongoing prospective cohort study of COVID-19 in pediatric kidney transplantation through the Improving Renal Outcomes Collaborative (IROC). METHODS: Patient-level data from the IROC registry were combined with testing, indication, and outcomes data collected to describe the epidemiology of COVID testing, treatment, and clinical outcomes; determine the incidence of a positive COVID-19 test; describe rates of COVID-19 testing; and assess for clinical predictors of a positive COVID-19 test. RESULTS: From September 2020 to February 2021, 21 centers that care for 2690 patients submitted data from 648 COVID-19 tests on 465 patients. Most patients required supportive care only and were treated as outpatients, 16% experienced inpatient care, and 5% experienced intensive care. Allograft complications were rare, with acute kidney injury most common (7%). There was 1 case of respiratory failure and 1 death attributed to COVID-19. Twelve centers that care for 1730 patients submitted complete testing data on 351 patients. The incidence of COVID-19 among patients at these centers was 4%, whereas the incidence among tested patients was 19%. Risk factors to predict a positive COVID-19 test included age > 12 years, symptoms consistent with COVID-19, and close contact with a confirmed case of COVID-19. CONCLUSIONS: Despite the increase in testing and positive tests over this study period, the incidence of allograft loss or death related to COVID-19 remained extremely low, with allograft loss or death each occurring in < 1% of COVID-19-positive patients and in less than < 0.1% of all transplant patients within the IROC cohort. A higher resolution version of the Graphical abstract is available as Supplementary information.


Assuntos
COVID-19 , Transplante de Rim , Humanos , Criança , Transplante de Rim/efeitos adversos , Teste para COVID-19 , Seguimentos , Estudos Prospectivos
9.
Clin Transplant ; 36(7): e14676, 2022 07.
Artigo em Inglês | MEDLINE | ID: mdl-35437836

RESUMO

INTRODUCTION: Time-zero biopsies can detect donor-derived lesions at the time of kidney transplantation, but their utility in predicting long-term outcomes is unclear under the updated Kidney Allocation System. METHODS: We conducted a single-center retrospective cohort study of 272 consecutive post-reperfusion time-zero biopsies. We tested the hypothesis that abnormal time-zero histology is a strong indicator of donor quality that increases the precision of the kidney donor profile index (KDPI) score to predict long-term outcomes. RESULTS: We detected abnormal biopsies in 42% of the cohort, which were independently associated with a 1.2-fold increased hazard for a composite of acute rejection, allograft failure, and death after adjusting for clinical characteristics including KDPI. By Kaplan-Meier analysis, the relationship between abnormal time-zero histology and the composite endpoint was only significant in the subgroup of deceased donor kidney transplants with KDPI scores >35. Abnormal time-zero histology, particularly vascular intimal fibrosis and arteriolar hyalinosis scores, was independently associated with lower 12-month estimated GFR. CONCLUSION: In conclusion, abnormal time-zero histology is relatively common and identifies a group of kidney recipients at increased risk for worse long-term outcomes. Further studies are needed to determine the optimal patient population in which to deploy time-zero biopsies as an additional surveillance tool.


Assuntos
Transplante de Rim , Transplantes , Sobrevivência de Enxerto , Humanos , Rim/patologia , Transplante de Rim/efeitos adversos , Estudos Retrospectivos , Doadores de Tecidos
10.
Pediatr Nephrol ; 37(7): 1453-1467, 2022 07.
Artigo em Inglês | MEDLINE | ID: mdl-34453600

RESUMO

Research indicates that severe acute respiratory syndrome coronavirus 2 (SARS-CoV2) infection can impact every organ, and the effects can range from asymptomatic to severe disease. Since it was first discovered in December 2019, our understanding has grown about its impact on kidney disease. In general, children have less severe disease than adults, and this tendency appears to extend to special pediatric kidney populations (e.g., chronic kidney disease and immunosuppressed patients with solid organ transplants or nephrotic syndrome). However, in a fraction of infected children, SARS-CoV2 causes an array of kidney manifestations, ranging from acute kidney injury to thrombotic microangiopathy, with potential implications for increased risk of morbidity and mortality. Additional considerations surround the propensity for clotting extracorporeal circuits in children with SARS-CoV2 infection that are receiving kidney replacement therapy. This review provides an update on our current understanding of SARS-CoV2 for pediatric nephrologists and highlights knowledge gaps to be addressed by future research during this ongoing pandemic, particularly the social disparities magnified during this period.


Assuntos
Injúria Renal Aguda , COVID-19 , Injúria Renal Aguda/epidemiologia , Injúria Renal Aguda/etiologia , Injúria Renal Aguda/terapia , Adulto , COVID-19/complicações , Criança , Humanos , Rim , RNA Viral , SARS-CoV-2
11.
Am J Transplant ; 19(10): 2833-2845, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-30916889

RESUMO

Microvascular injury is associated with accelerated kidney transplant dysfunction and allograft failure. Molecular pathology can identify new mechanisms of microvascular injury while improving on the diagnostic and prognostic capabilities of traditional histology. We conducted a case-control study of archived kidney biopsy specimens stored up to 10 years with microvascular injury (n = 50) compared with biopsy specimens without histologic injury (n = 45) from patients of similar age, race, and sex. We measured WNT gene expression with a multiplex quantification platform by using digital barcoding, given the importance of WNT reactivation to the response to wounding in the kidney microvasculature and other compartments. Of 210 genes from a commercial WNT panel, 71 were associated with microvascular injury and 79 were associated with allograft failure, with considerable overlap of genes between each set. Molecular pathology identified 46 biopsy specimens with molecular evidence of microvascular injury; 18 (39%) were either C4d negative, donor-specific antibody negative, or had no microvascular injury by histology. The majority of cases with molecular evidence of microvascular injury had poor long-term outcomes. We identified novel WNT pathway genes associated with microvascular injury and allograft failure in residual clinical biopsy specimens obtained up to 10 years earlier. Further mechanistic studies may identify the WNT pathway as a new diagnostic and therapeutic target.


Assuntos
Rejeição de Enxerto/diagnóstico , Isoanticorpos/efeitos adversos , Falência Renal Crônica/cirurgia , Transplante de Rim/efeitos adversos , Microvasos/patologia , Complicações Pós-Operatórias/diagnóstico , Via de Sinalização Wnt , Biomarcadores/metabolismo , Estudos de Casos e Controles , Estudos Transversais , Feminino , Seguimentos , Rejeição de Enxerto/etiologia , Rejeição de Enxerto/metabolismo , Sobrevivência de Enxerto , Humanos , Estudos Longitudinais , Masculino , Microvasos/lesões , Microvasos/metabolismo , Pessoa de Meia-Idade , Complicações Pós-Operatórias/etiologia , Complicações Pós-Operatórias/metabolismo , Prognóstico , Fatores de Risco
12.
Pediatr Transplant ; 23(5): e13494, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31124575

RESUMO

BACKGROUND: Optimal management of immunosuppression in kidney transplantation requires a delicate balance of efficacy and toxicity. Tacrolimus (TAC) dose requirements are significantly impacted by genetic variation in CYP3A5 polymorphisms, however the impact that genotype has on clinical outcomes in the pediatric kidney transplant population remains unclear. METHODS: We evaluated a retrospective cohort of 98 pediatric kidney transplant recipients. The primary exposure was CYP3A5 genotype, which classified each recipient into the expresser (at least one CYP3A5*1 allele) or non-expresser group (only CYP3A5*3 alleles). The primary outcome was time to achieve a steady therapeutic TAC concentration. Secondary outcomes include incidence of early allograft rejection and calcineurin inhibitor (CNI) nephrotoxicity during the first year post-transplant. RESULTS: The study cohort included 55 (56%) expressers and 43 (44%) non-expressers of the CYP3A5*1 allele. Expressers had a significantly longer time to achieve a steady therapeutic TAC concentration than non-expressers (log rank, P = 0.03). Expressers had a trend for higher incidence of early allograft rejection (29.1% vs 16.3%, log rank, P = 0.16). Early biopsy-proven CNI nephrotoxicity was seen in 60% of recipients, with no differences in the rate between expressers and non-expressers. CONCLUSIONS: Pediatric kidney transplant recipients with the CYP3A5*1 allele (expressers) take a longer time to achieve therapeutic TAC levels than those with the CYP3A5*3 allele (non-expressers). However, we observed no significant differences in acute rejection or CNI nephrotoxicity based on CYP3A5 genotype. Thus CYP3A5 genotype was not observed to have an immediate impact on early transplant outcomes.


Assuntos
Citocromo P-450 CYP3A/genética , Imunossupressores/uso terapêutico , Transplante de Rim , Tacrolimo/uso terapêutico , Adolescente , Criança , Relação Dose-Resposta a Droga , Feminino , Variação Genética , Genótipo , Rejeição de Enxerto , Humanos , Masculino , Estudos Retrospectivos , Fatores de Tempo
13.
Am J Transplant ; 18(9): 2189-2199, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-29766640

RESUMO

The implementation of surveillance biopsies in pediatric kidney transplantation remains controversial. Surveillance biopsies detect subclinical injury prior to clinical dysfunction, which could allow for early interventions that prolong allograft survival. We conducted a single-center retrospective cohort study of 120 consecutive pediatric kidney recipients, of whom 103 had surveillance biopsies ≤6 months posttransplant. We tested the hypothesis that subclinical inflammation (borderline or T cell-mediated rejection without clinical dysfunction) is associated with a 5-year composite endpoint of acute rejection and allograft failure. Overall, 36% of subjects had subclinical inflammation, which was associated with increased hazard for the composite endpoint (adjusted hazard ratio 2.89 [1.27, 6.57]; P < .01). Subjects with treated vs untreated subclinical borderline rejection had a lower incidence of the composite endpoint (41% vs 67%; P < .001). Subclinical vascular injury (subclinical inflammation with Banff arteritis score > 0) had a 78% incidence of the composite endpoint vs 11% in subjects with no major surveillance abnormalities (P < .001). In summary, we showed that subclinical inflammation phenotypes were prevalent in pediatric kidney recipients without clinical dysfunction and were associated with increased acute rejection and allograft failure. Once prospectively validated, our data would support implementation of surveillance biopsies as standard of care in pediatric kidney transplantation.


Assuntos
Rejeição de Enxerto/etiologia , Inflamação/epidemiologia , Falência Renal Crônica/cirurgia , Transplante de Rim/efeitos adversos , Complicações Pós-Operatórias , Doenças Vasculares/epidemiologia , Adolescente , Alabama/epidemiologia , Criança , Feminino , Seguimentos , Taxa de Filtração Glomerular , Sobrevivência de Enxerto , Humanos , Imunossupressores/uso terapêutico , Incidência , Testes de Função Renal , Masculino , Fenótipo , Prognóstico , Estudos Retrospectivos , Fatores de Risco
14.
J Am Soc Nephrol ; 28(4): 1314-1325, 2017 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-27821629

RESUMO

Humoral immune responses against donor antigens are important determinants of long-term transplant outcomes. Reactivation of the polyomavirus BK has been associated with de novo antibodies against mismatched donor HLA antigens in kidney transplantation. The effect of polyomavirus reactivation (BK viremia or JC viruria) on antibodies to kidney-specific self-antigens is unknown. We previously reported excellent 5-year outcomes after minimization of immunosuppression for BK viremia and after no intervention for JC viruria. Here, we report the 10-year results of this trial (n=193) along with a nested case-control study (n=40) to explore associations between polyomavirus reactivation and immune responses to the self-antigens fibronectin (FN) and collagen type-IV (Col-IV). Consistent with 5-year findings, subjects taking tacrolimus, compared with those taking cyclosporin, had less acute rejection (11% versus 22%, P=0.05) and graft loss (9% versus 22%, P=0.01) along with better transplant function (eGFR 65±19 versus 50±24 ml/min per 1.73 m2, P<0.001) at 10 years. Subjects undergoing immunosuppression reduction for BK viremia had 10-year outcomes similar to those without viremia. In the case-control study, antibodies to FN/Col-IV were more prevalent during year 1 in subjects with polyomavirus reactivation than in those without reactivation (48% versus 11%, P=0.04). Subjects with antibodies to FN/Col-IV had more acute rejection than did those without these antibodies (38% versus 8%, P=0.02). These data demonstrate the long-term safety and effectiveness of minimizing immunosuppression to treat BK viremia. Furthermore, these results indicate that polyomavirus reactivation associates with immune responses to kidney-specific self-antigens that may increase the risk for acute rejection through unclear mechanisms.


Assuntos
Autoantígenos , Transplante de Rim , Rim/imunologia , Infecções por Polyomavirus/imunologia , Polyomavirus/fisiologia , Complicações Pós-Operatórias/imunologia , Complicações Pós-Operatórias/virologia , Infecções Tumorais por Vírus/imunologia , Viremia/imunologia , Autoantígenos/sangue , Estudos de Casos e Controles , Estudos de Coortes , Feminino , Humanos , Terapia de Imunossupressão , Masculino , Pessoa de Meia-Idade , Infecções por Polyomavirus/sangue , Complicações Pós-Operatórias/sangue , Estudos Retrospectivos , Fatores de Tempo , Resultado do Tratamento , Infecções Tumorais por Vírus/sangue , Viremia/sangue
15.
Health Qual Life Outcomes ; 15(1): 166, 2017 Aug 23.
Artigo em Inglês | MEDLINE | ID: mdl-28835233

RESUMO

BACKGROUND: Nephrotic syndrome represents a condition in pediatric nephrology typified by a relapsing and remitting course, proteinuria and the presence of edema. The PROMIS measures have previously been studied and validated in cross-sectional studies of children with nephrotic syndrome. This study was designed to longitudinally validate the PROMIS measures in pediatric nephrotic syndrome. METHODS: One hundred twenty seven children with nephrotic syndrome between the ages of 8 and 17 years participated in this prospective cohort study. Patients completed a baseline assessment while their nephrotic syndrome was active, a follow-up assessment at the time of their first complete proteinuria remission or study month 3 if no remission occurred, and a final assessment at study month 12. Participants completed six PROMIS measures (Mobility, Fatigue, Pain Interference, Depressive Symptoms, Anxiety, and Peer Relationships), the PedsQL version 4.0, and two global assessment of change items. RESULTS: Disease status was classified at each assessment: nephrotic syndrome active in 100% at baseline, 33% at month 3, and 46% at month 12. The PROMIS domains of Mobility, Fatigue, Pain Interference, Depressive Symptoms, and Anxiety each showed a significant overall improvement over time (p < 0.001). When the PROMIS measures were compared to the patients' global assessment of change, the domains of Mobility, Fatigue, Pain Interference, and Anxiety consistently changed in an expected fashion. With the exception of Pain Interference, change in PROMIS domain scores did not correlate with changes in disease activity. PROMIS domain scores were moderately correlated with analogous PedsQL domain scores. CONCLUSION: This study demonstrates that the PROMIS Mobility, Fatigue, Pain Interference, and Anxiety domains are sensitive to self-reported changes in disease and overall health status over time in children with nephrotic syndrome. The lack of significant anchoring to clinically defined nephrotic syndrome disease active and remission status may highlight an opportunity to improve the measurement of HRQOL in children with nephrotic syndrome through the development of a nephrotic syndrome disease-specific HRQOL measure.


Assuntos
Nível de Saúde , Síndrome Nefrótica/psicologia , Medidas de Resultados Relatados pelo Paciente , Qualidade de Vida , Autorrelato/normas , Adolescente , Ansiedade/psicologia , Criança , Depressão/psicologia , Fadiga/psicologia , Feminino , Humanos , Relações Interpessoais , Masculino , Dor/psicologia , Estudos Prospectivos
16.
Kidney Int ; 89(6): 1231-43, 2016 06.
Artigo em Inglês | MEDLINE | ID: mdl-27165838

RESUMO

The causes of cardiovascular mortality associated with chronic kidney disease (CKD) are partly attributed to the CKD-mineral bone disorder (CKD-MBD). The causes of the early CKD-MBD are not well known. Our discovery of Wnt (portmanteau of wingless and int) inhibitors, especially Dickkopf 1, produced during renal repair as participating in the pathogenesis of the vascular and skeletal components of the CKD-MBD implied that additional pathogenic factors are critical. In the search for such factors, we studied the effects of activin receptor type IIA (ActRIIA) signaling by using a ligand trap for the receptor, RAP-011 (a soluble extracellular domain of ActRIIA fused to a murine IgG-Fc fragment). In a mouse model of CKD that stimulated atherosclerotic calcification, RAP-011 significantly increased aortic ActRIIA signaling assessed by the levels of phosphorylated Smad2/3. Furthermore, RAP-011 treatment significantly reversed CKD-induced vascular smooth muscle dedifferentiation as assessed by smooth muscle 22α levels, osteoblastic transition, and neointimal plaque calcification. In the diseased kidneys, RAP-011 significantly stimulated αklotho levels and it inhibited ActRIIA signaling and decreased renal fibrosis and proteinuria. RAP-011 treatment significantly decreased both renal and circulating Dickkopf 1 levels, showing that Wnt activation was downstream of ActRIIA. Thus, ActRIIA signaling in CKD contributes to the CKD-MBD and renal fibrosis. ActRIIA signaling may be a potential therapeutic target in CKD.


Assuntos
Receptores de Activinas Tipo II/metabolismo , Aterosclerose/prevenção & controle , Distúrbio Mineral e Ósseo na Doença Renal Crônica/tratamento farmacológico , Substâncias Protetoras/uso terapêutico , Proteínas Recombinantes de Fusão/uso terapêutico , Calcificação Vascular/prevenção & controle , Animais , Aorta/metabolismo , Aterosclerose/sangue , Distúrbio Mineral e Ósseo na Doença Renal Crônica/sangue , Distúrbio Mineral e Ósseo na Doença Renal Crônica/metabolismo , Modelos Animais de Doenças , Fibrose , Glucuronidase , Humanos , Injeções Subcutâneas , Peptídeos e Proteínas de Sinalização Intercelular/sangue , Rim/patologia , Proteínas Klotho , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Proteínas dos Microfilamentos/metabolismo , Proteínas Musculares/metabolismo , Fosforilação , Substâncias Protetoras/administração & dosagem , Proteinúria , Receptores de Superfície Celular/metabolismo , Proteínas Recombinantes de Fusão/administração & dosagem , Transdução de Sinais , Proteína Smad2/metabolismo , Proteína Smad3/metabolismo , Calcificação Vascular/sangue
17.
Pediatr Transplant ; 20(3): 378-87, 2016 May.
Artigo em Inglês | MEDLINE | ID: mdl-26880121

RESUMO

The chronic kidney disease-mineral bone disorder (CKD-MBD) produces fibroblast growth factor-23 (FGF-23) and related circulating pathogenic factors that are strongly associated with vascular injury and declining kidney function in native CKD. Similarly, chronic renal allograft injury (CRAI) is characterized by vascular injury and declining allograft function in transplant CKD. We hypothesized that circulating CKD-MBD factors could serve as non-invasive biomarkers of CRAI. We conducted a cross-sectional, multicenter case-control study. Cases (n = 31) had transplant function >20 mL/min/1.73 m(2) and biopsy-proven CRAI. Controls (n = 31) had transplant function >90 mL/min/1.73 m(2) and/or a biopsy with no detectable abnormality in the previous six months. We measured plasma CKD-MBD factors at a single time point using ELISA. Median (range) FGF23 levels were over twofold higher in CRAI vs. controls [106 (10-475) pg/mL vs. 45 (8-91) pg/mL; p < 0.001]. FGF23 levels were inversely correlated with transplant function (r(2) = -0.617, p < 0.001). Higher FGF23 levels were associated with increased odds of biopsy-proven CRAI after adjusting for transplant function, clinical, and demographic factors [OR (95% CI) 1.43 (1.23, 1.67)]. Relationships between additional CKD-MBD factors and CRAI were attenuated in multivariable models. Higher FGF23 levels were independently associated with biopsy-proven CRAI in children.


Assuntos
Fatores de Crescimento de Fibroblastos/sangue , Falência Renal Crônica/cirurgia , Transplante de Rim/efeitos adversos , Transplante de Rim/métodos , Nefrologia/métodos , Adolescente , Aloenxertos , Biomarcadores/sangue , Biópsia , Estudos de Casos e Controles , Estudos Transversais , Ensaio de Imunoadsorção Enzimática , Feminino , Fator de Crescimento de Fibroblastos 23 , Taxa de Filtração Glomerular , Humanos , Masculino , Análise Multivariada , Análise de Regressão , Sensibilidade e Especificidade , Resultado do Tratamento , Adulto Jovem
18.
Pediatr Nephrol ; 31(3): 465-72, 2016 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-26498119

RESUMO

BACKGROUND: Cross-sectional studies of children with prevalent nephrotic syndrome (NS) have shown 25-vitamin D (25(OH)D) deficiency rates of 20-100 %. Information on 25(OH)D status in incident patients or following remission is limited. This study aimed to assess 25(OH)D status of incident idiopathic NS children at presentation and longitudinally with short-term observation. METHODS: Multicenter longitudinal study of children (2-18 years old) from 14 centers across the Midwest Pediatric Nephrology Consortium with incident idiopathic NS. 25(OH)D levels were assessed at diagnosis and 3 months later. RESULTS: Sixty-one children, median age 5 (3, 11) years, completed baseline visit and 51 completed second visit labs. All 61 (100 %) had 25(OH)D < 20 ng/ml at diagnosis. Twenty-seven (53 %) had 25(OH)D < 20 ng/ml at follow-up. Fourteen (28 %) children were steroid resistant. Univariate analysis showed that children prescribed vitamin D supplements were less likely to have 25(OH)D deficiency at follow-up (OR 0.2, 95 % CI 0.04, 0.6). Steroid response, age, and season did not predict 25(OH)D deficiency. Multivariable linear regression modeling showed higher 25(OH)D levels at follow-up by 13.2 ng/ml (SE 4.6, p < 0.01) in children supplemented with vitamin D. CONCLUSIONS: In this incident idiopathic NS cohort, all children at diagnosis had 25(OH)D deficiency and the majority continued to have a deficiency at 2-4 months. Supplemental vitamin D decreased the odds of 25(OH)D deficiency at follow-up, supporting a role for supplementation in incident NS.


Assuntos
Síndrome Nefrótica/epidemiologia , Deficiência de Vitamina D/epidemiologia , Vitamina D/análogos & derivados , Adolescente , Biomarcadores/sangue , Criança , Pré-Escolar , Suplementos Nutricionais , Feminino , Humanos , Incidência , Modelos Lineares , Modelos Logísticos , Estudos Longitudinais , Masculino , Meio-Oeste dos Estados Unidos/epidemiologia , Análise Multivariada , Síndrome Nefrótica/diagnóstico , Razão de Chances , Hormônio Paratireóideo/sangue , Estudos Prospectivos , Fatores de Tempo , Resultado do Tratamento , Vitamina D/sangue , Vitamina D/uso terapêutico , Deficiência de Vitamina D/sangue , Deficiência de Vitamina D/diagnóstico , Deficiência de Vitamina D/tratamento farmacológico
19.
Kidney Int ; 87(3): 492-4, 2015 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-25723630

RESUMO

Early kidney transplant results in children lagged behind corresponding results in adults. Multiple advances over the past three decades have eliminated that gap. Most children now have equal or superior long-term allograft and patient survival compared with adult recipients. However, black children in the United States continue to have allograft survival results inferior to those of non-black children, even after extensive adjustments for socioeconomic status and access to transplantation.


Assuntos
Negro ou Afro-Americano/estatística & dados numéricos , Rejeição de Enxerto/etnologia , Rejeição de Enxerto/mortalidade , Sobrevivência de Enxerto , Disparidades nos Níveis de Saúde , Hispânico ou Latino/estatística & dados numéricos , Falência Renal Crônica/mortalidade , Transplante de Rim/mortalidade , Transplante de Rim/estatística & dados numéricos , Taxa de Sobrevida/tendências , População Branca/estatística & dados numéricos , Feminino , Humanos , Masculino
20.
Pediatr Nephrol ; 30(9): 1467-76, 2015 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-25784017

RESUMO

BACKGROUND: The Patient Reported Outcomes Measurement Information System (PROMIS) II is a prospective study that evaluates patient reported outcomes in pediatric chronic diseases as a measure of health-related quality of life (HRQOL). We have evaluated the influence of disease duration on HRQOL and, for the first time, compared the findings of the PROMIS measures to those of the PedsQL™ 4.0 Generic Scales (PedsQL) from the PROMIS II nephrotic syndrome (NS) longitudinal cohort. METHODS: This was a prospective study in which 127 children (age range 8-17 years) with active NS from 14 centers were enrolled. Children with active NS defined as the presence of nephrotic range proteinuria (>2+ urinalysis and edema or urine protein/creatinine ratio >2 g/g) were eligible. Comparisons were made between children with prevalent (N = 67) and incident (N = 60) disease at the study enrollment visit. RESULTS: The PROMIS scores were worse in prevalent patients in the domains of peer relationship (p = 0.01) and pain interference (p < 0.01). The PedsQL showed worse scores in prevalent patients for social functioning (p < 0.01) and school functioning (p = 0.03). Multivariable analyses showed that prevalent patients had worse scores in PROMIS pain interference (p = 0.02) and PedsQL social functioning (p < 0.01). CONCLUSION: The PROMIS measures detected a significant impact of disease duration on HRQOL in children, such that peer relationships were worse and pain interfered with daily life to a greater degree among those with longer disease duration. These findings were in agreement with those for similar domains in the PedsQL legacy instrument.


Assuntos
Síndrome Nefrótica , Qualidade de Vida , Habilidades Sociais , Adolescente , Criança , Estudos de Coortes , Avaliação Educacional/estatística & dados numéricos , Feminino , Humanos , Estudos Longitudinais , Masculino , Síndrome Nefrótica/complicações , Síndrome Nefrótica/epidemiologia , Síndrome Nefrótica/psicologia , Dor/etiologia , Pediatria/métodos , Pediatria/estatística & dados numéricos , Proteinúria/etiologia , Tempo , Estados Unidos/epidemiologia
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