RESUMO
Transplant recipients are at an increased risk of malignant melanoma, a result of chronic immunosuppression. Ipilimumab is a newer biological agent targeting T lymphocytes to potentiate an immune response against melanoma, and the use of this agent results in a new adverse effect profile that the clinician must be aware of while a patient is on therapy. We report the case of a male renal transplant recipient who developed graft failure while treated with ipilimumab and minimal immunosuppressive therapy for metastatic ocular melanoma, with biopsy evidence of glomerulonephritis and acute rejection. We highlight the immunological side effects that can manifest from ipilimumab therapy and conclude that it did influence graft function in this patient. Our case illustrates the importance of weighing the risks and benefits to graft function and long-term survival as well as the importance of considering other treatment modalities in this specific group of melanoma patients.
Assuntos
Anticorpos Monoclonais/efeitos adversos , Antineoplásicos/efeitos adversos , Rejeição de Enxerto/induzido quimicamente , Melanoma/tratamento farmacológico , Neoplasias Uveais/tratamento farmacológico , Rejeição de Enxerto/imunologia , Humanos , Ipilimumab , Rim/imunologia , Transplante de Rim , Masculino , Pessoa de Meia-Idade , Insuficiência Renal/induzido quimicamente , Transplante HomólogoRESUMO
Epstein-Barr virus (EBV) DNAemia in the first year posttransplantation has been studied extensively. There is a paucity of information on prevalence and sequelae of EBV infection in adult renal transplantation beyond the first year. This single-center study examines the relationship between EBV DNAemia and demographic, immunosuppressive, hematologic and infection-related parameters in 499 renal transplant recipients between 1 month and 33 years posttransplant. Participants were tested repeatedly for EBV DNAemia detection over 12 months and clinical progress followed for 3 years. Prevalence of DNAemia at recruitment increased significantly with time from transplant. In multivariate adjusted analyses, variables associated with DNAemia included EBV seronegative status at transplant (p = 0.045), non-White ethnicity (p = 0.014) and previous posttransplant lymphoproliferative disease (PTLD) diagnosis (p = 0.006), while low DNAemia rates were associated with mycophenolate mofetil use (p < 0.0001) and EBV viral capsid antigen positive Epstein-Barr nuclear antigen-1 positive serostatus at transplant (p = 0.044). Patient and graft survival, rate of kidney function decline and patient reported symptoms were not significantly different between EBV DNAemia positive and negative groups. EBV DNAemia is common posttransplant and increases with time from transplantation, but EBV DNAemia detection in low-risk (seropositive) patients has poor specificity as a biomarker for future PTLD risk.
Assuntos
DNA Viral/análise , Infecções por Vírus Epstein-Barr/diagnóstico , Sobrevivência de Enxerto , Falência Renal Crônica/cirurgia , Transplante de Rim , Transtornos Linfoproliferativos/diagnóstico , Transplantados , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Antivirais/imunologia , Antígenos Virais/imunologia , Estudos Transversais , DNA Viral/genética , Infecções por Vírus Epstein-Barr/virologia , Feminino , Seguimentos , Taxa de Filtração Glomerular , Herpesvirus Humano 4/genética , Herpesvirus Humano 4/isolamento & purificação , Humanos , Incidência , Testes de Função Renal , Transtornos Linfoproliferativos/virologia , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Prospectivos , Fatores de Risco , Adulto JovemRESUMO
In a reference set of 403 kidney transplant biopsies, we recently developed a microarray-based test that diagnoses antibody-mediated rejection (ABMR) by assigning an ABMR score. To validate the ABMR score and assess its potential impact on practice, we performed the present prospective INTERCOM study (clinicaltrials.gov NCT01299168) in 300 new biopsies (264 patients) from six centers: Baltimore, Barcelona, Edmonton, Hannover, Manchester and Minneapolis. We assigned ABMR scores using the classifier created in the reference set and compared it to conventional assessment as documented in the pathology reports. INTERCOM documented uncertainty in conventional assessment: In 41% of biopsies where ABMR features were noted, the recorded diagnoses did not mention ABMR. The ABMR score correlated with ABMR histologic lesions and donor-specific antibodies, but not with T cell-mediated rejection lesions. The agreement between ABMR scores and conventional assessment was identical to that in the reference set (accuracy 85%). The ABMR score was more strongly associated with failure than conventional assessment, and when the ABMR score and conventional assessment disagreed, only the ABMR score was associated with early progression to failure. INTERCOM confirms the need to reduce uncertainty in the diagnosis of ABMR, and demonstrates the potential of the ABMR score to impact practice.
Assuntos
Biomarcadores/análise , Rejeição de Enxerto/diagnóstico , Rejeição de Enxerto/imunologia , Isoanticorpos/imunologia , Falência Renal Crônica/imunologia , Transplante de Rim/efeitos adversos , Complicações Pós-Operatórias , Adolescente , Seguimentos , Perfilação da Expressão Gênica , Sobrevivência de Enxerto/imunologia , Humanos , Agências Internacionais , Falência Renal Crônica/mortalidade , Falência Renal Crônica/cirurgia , Análise de Sequência com Séries de Oligonucleotídeos , Prognóstico , Estudos Prospectivos , Fatores de Risco , Taxa de SobrevidaRESUMO
We previously developed a microarray-based test for T cell-mediated rejection (TCMR) in a reference set of 403 biopsies. To determine the potential impact of this test in clinical practice, we undertook INTERCOM, a prospective international study of 300 indication biopsies from 264 patients (ClinicalTrials.gov NCT01299168). Biopsies from six centers-Baltimore, Barcelona, Edmonton, Hannover, Manchester and Minneapolis-were analyzed by microarrays, assigning TCMR scores by an algorithm developed in the reference set and comparing TCMR scores to local histology assessment. The TCMR score correlated with histologic TCMR lesions-tubulitis and interstitial infiltration. The accuracy for primary histologic diagnoses (0.87) was similar to the reference set (0.89). The TCMR scores reclassified 77/300 biopsies (26%): 16 histologic TCMR were molecularly non-TCMR; 15 histologic non-TCMR were molecularly TCMR, including 6 with polyoma virus nephropathy; and all 46 "borderline" biopsies were reclassified as TCMR (8) or non-TCMR (38). Like the reference set, discrepancies were primarily in situations where histology has known limitations, for example, in biopsies with scarring and inflammation/tubulitis potentially from other diseases. Neither the TCMR score nor histologic TCMR was associated with graft loss. Thus the molecular TCMR score has potential to add new insight, particularly in situations where histology is ambiguous or potentially misleading.
Assuntos
Anticorpos/imunologia , Rejeição de Enxerto/diagnóstico , Transplante de Rim , Análise de Sequência com Séries de Oligonucleotídeos , Linfócitos T/imunologia , Rejeição de Enxerto/imunologia , Rejeição de Enxerto/patologia , Humanos , Técnicas de Diagnóstico Molecular , Polyomavirus , Infecções por Polyomavirus/patologia , Estudos Prospectivos , Infecções Tumorais por Vírus/patologiaRESUMO
A 79-year-old man, newly started on carbamazepine, presented with rash, eosinophilia and liver dysfunction progressing to acute renal failure despite discontinuation of the anti-epileptic agent. Percutaneous renal biopsy revealed acute granulomatous interstitial nephritis, which responded successfully to high-dose oral steroid therapy.
Assuntos
Anticonvulsivantes/efeitos adversos , Carbamazepina/efeitos adversos , Nefrite Intersticial/induzido quimicamente , Doença Aguda , Idoso , Biópsia , Toxidermias/diagnóstico , Granuloma/induzido quimicamente , Granuloma/patologia , Humanos , Rim/efeitos dos fármacos , Rim/patologia , MasculinoAssuntos
Cateterismo Periférico/efeitos adversos , Cateteres de Demora/efeitos adversos , Constrição Patológica/etiologia , Veia Ilíaca , Falência Renal Crônica/terapia , Diálise Peritoneal Ambulatorial Contínua , Anticorpos Antifosfolipídeos/sangue , Feminino , Artéria Femoral , Humanos , Pessoa de Meia-IdadeRESUMO
BACKGROUND: Resistance to the action of parathyroid hormone (PTH) has been demonstrated in end-stage renal failure and is considered to be important in the pathogenesis of secondary hyperparathyroidism. The mechanism of resistance is unknown. However, altered regulation of cellular PTH/PTH-related protein (PTH/PTHrP) receptor (PTH1R) has been assumed to be important. METHODS: We have used in situ hybridization to examine PTH1R mRNA expression by osteoblasts in human bone and have compared the expression in high- and low-turnover renal bone disease, high-turnover nonrenal bone disease (healing fracture callus and Pagetic bone), and normal bone. Bone biopsies were formalin fixed, ethylenediaminetetraacetic acid decalcified, and paraffin wax embedded. A 1.8 kb PTH1R cDNA probe, labeled with 35S, was used, and the hybridization signal was revealed by autoradiography. The density of signal over osteoblasts was quantitated using a semiautomated Leica image analysis software package. RESULTS: The mean density of PTH1R mRNA signal over osteoblasts in renal high-turnover bone was only 36% of that found in nonrenal high-turnover bone (P < 0.05) and 51% of that found in normal bone (P < 0.05). Osteoblast PTH1R mRNA signal in adynamic bone from individuals with diabetes mellitus was 28% of normal bone (P < 0.05) and 54% of that found in renal high-turnover bone (P < 0.05). CONCLUSIONS: These results demonstrate a down-regulation of osteoblast PTH1R mRNA in end-stage renal failure in comparison to normal and high-turnover bone from otherwise healthy individuals, and provide an insight into the mechanisms of "skeletal resistance" to the actions of PTH.
Assuntos
Falência Renal Crônica/metabolismo , Falência Renal Crônica/fisiopatologia , Osteoblastos/metabolismo , Receptores de Hormônios Paratireóideos/genética , Adulto , Osso e Ossos/metabolismo , Calo Ósseo/metabolismo , Calo Ósseo/fisiopatologia , Distúrbio Mineral e Ósseo na Doença Renal Crônica/metabolismo , Distúrbio Mineral e Ósseo na Doença Renal Crônica/fisiopatologia , Nefropatias Diabéticas/metabolismo , Nefropatias Diabéticas/fisiopatologia , Regulação para Baixo/genética , Feminino , Expressão Gênica/fisiologia , Humanos , Hibridização In Situ , Masculino , Pessoa de Meia-Idade , Osteíte Deformante/metabolismo , Osteíte Deformante/fisiopatologia , Osteoclastos/metabolismo , RNA Mensageiro/metabolismo , Receptor Tipo 1 de Hormônio Paratireóideo , Receptores de Hormônios Paratireóideos/metabolismo , Uremia/metabolismo , Uremia/fisiopatologiaRESUMO
Hypertension typically worsens with declining renal function, and is an almost universal feature of end-stage renal disease. Treating hypertension clearly reduces the likelihood of cardiovascular disease in nonrenal populations, with greater absolute benefit in those who have greater severity of underlying cardiovascular disease. Patients with chronic renal diseases are at enormous cardiovascular risk. Although our approach to hypertension in patients with early renal insufficiency has become more aggressive, the rationale has switched over the past decade from cardiovascular risk reduction to slowing the loss of renal function. Reliance on observational studies, especially using mortality as the outcome, has not allowed a consistent, rational approach to the treatment of hypertension in dialysis patients.
Assuntos
Doenças Cardiovasculares/mortalidade , Doenças Cardiovasculares/prevenção & controle , Hipertensão/complicações , Falência Renal Crônica/complicações , Doenças Cardiovasculares/epidemiologia , Doenças Cardiovasculares/etiologia , Progressão da Doença , Humanos , Falência Renal Crônica/terapia , Diálise Renal , Fatores de RiscoRESUMO
BACKGROUND: The Banff classification of renal allograft rejection grades acute tubulointerstitial rejection (AIR) by severity of tubulitis and acute vascular rejection (AVR) by severity of arteritis. The intensity of tubulitis has not, however, been demonstrated to be of prognostic value and other features such as glomerulitis and eosinophil infiltration are of uncertain significance. This study was performed in order to determine the clinical value of this pathological classification. METHODS: Banff criteria were correlated with outcome in 134 consecutive graft recipients transplanted in our unit over a 3-year period (1994 1996) who experienced at least one biopsy-confirmed acute rejection episode. Of 197 biopsies performed for the diagnosis of rejection, 177 contained at least one artery and were suitable for Banff grading. Tissue eosinophil counts were available for 101 biopsies. Clinical severity of rejection was classified as mild (fully responsive to pulse steroid therapy), moderate (partially steroid responsive) and severe (steroid unresponsive/requiring ATG therapy). RESULTS: Graft failure ensued in 18 of 58 patients with AVR compared with 10 of 65 patients with AIR (P= < 0.05). Clinical severity of rejection correlated with the presence of arteritis, but not severity of tubulitis; rejections graded I, IIA and IIB according to the Banff' 93 classification were clinically severe in 3/68 (4%), 2/28 (7%) and 15/67 (22%) respectively (P= <0.05). The presence of glomerulitis showed no correlation with clinical severity or graft loss. Tissue eosinophilia (>10 eosinophils/mm2) was present in 18 of 33 patients who had at least one episode of AVR (v1/2), compared with 11 of 45 patients who suffered only AIR (P= <0.02). CONCLUSIONS: We conclude that: arteritis, but not severe tubulitis or glomerulitis, is an adverse prognostic factor in acute rejection and that tissue eosinophilia is associated with vascular rejection. Our findings support the 1997 revision of the Banff classification, replacing grades with types of acute rejection.
Assuntos
Rejeição de Enxerto/patologia , Transplante de Rim , Doença Aguda , Adolescente , Adulto , Biomarcadores , Biópsia , Eosinofilia/etiologia , Feminino , Rejeição de Enxerto/complicações , Humanos , Rim/patologia , Masculino , Pessoa de Meia-Idade , Resultado do TratamentoRESUMO
Renal osteodystrophy affects all patients with end-stage renal failure, resulting in significant skeletal and extra-skeletal morbidity. The patterns of disease seen in bone are the result of changes in calcium, phosphate, parathyroid hormone (PTH), and vitamin D metabolism, as well as the effects of uremia. Standard histological techniques, however, give little insight into the altered biological activity or mechanisms of disease at the cellular level. In order to examine the cellular abnormalities in renal bone disease we have performed a series of in situ hybridization studies to examine renal bone cell expression of genes for PTH receptor (PTHR1), transforming growth factor beta (TGF-beta) and insulin growth factor 1 (IGF-I). PTHR1 mRNA was expressed predominantly by osteoblasts, but also by resorbing osteoclasts, suggesting that these cells may be stimulated directly by PTH. Semi-quantitative analysis of gene expression showed down-regulation of PTHR1 mRNA by osteoblasts in renal bone compared with normal, fracture and Pagetic bone. This may be important in the pathogenesis of skeletal resistance seen in end-stage renal failure, altering the "threshold" at which PTH has its effects on bone cells. TGF-beta and IGF-I mRNA expression was also decreased, suggesting that synthesis of these factors, postulated to be mediators of PTH, is also downregulated.