RESUMO
Malakoplakia is a chronic granulomatous disease associated with incomplete clearance of bacterial pathogens. A multimodal approach to therapy includes antimicrobials with intracellular activity, reduction in immunosuppression, and debulking of lesions. Azithromycin has an intracellular mechanism of action and enhanced Gram-negative activity compared to other macrolides. Despite some in vitro data to support its use, there are no clinical breakpoints or epidemiological cut-off values for most Enterobacterales from the European Committee on Antimicrobial Susceptibility Testing (EUCAST) or the Clinical and Laboratory Standards Institute (CLSI). We present two cases, previously unreported, of Escherichia coli associated renal allograft malakoplakia successfully treated with azithromycin.
Assuntos
Aloenxertos/microbiologia , Antibacterianos/administração & dosagem , Azitromicina/administração & dosagem , Infecções por Escherichia coli/tratamento farmacológico , Transplante de Rim/efeitos adversos , Malacoplasia/tratamento farmacológico , Complicações Pós-Operatórias/tratamento farmacológico , Escherichia coli/efeitos dos fármacos , Escherichia coli/genética , Escherichia coli/fisiologia , Infecções por Escherichia coli/microbiologia , Feminino , Humanos , Malacoplasia/etiologia , Malacoplasia/microbiologia , Testes de Sensibilidade Microbiana , Pessoa de Meia-Idade , Complicações Pós-Operatórias/etiologia , Complicações Pós-Operatórias/microbiologiaRESUMO
Graft-derived cell-free DNA (donor-derived cell-free DNA) is an emerging marker of kidney allograft injury. Studies examining the clinical validity of this biomarker have previously used the graft fraction, or proportion of total cell-free DNA that is graft-derived. The present study evaluated the diagnostic validity of absolute measurements of graft-derived cell-free DNA, as well as calculated graft fraction, for the diagnosis of graft dysfunction. Plasma graft-derived cell-free DNA, total cell-free DNA, and graft fraction were correlated with biopsy diagnosis as well as individual Banff scores. Sixty-one samples were included in the analysis. For the diagnosis of antibody mediated rejection, the receiver-operator characteristic area under the curves of graft-derived cell-free DNA and graft fraction were 0.91 (95% CI 0.82-0.98) and 0.89 (95% CI 0.79-0.98), respectively. Both measures did not diagnose borderline or type 1A cellular mediated rejection. Graft fraction was associated with a broader range of Banff lesions, including lesions associated with cellular mediated rejection, while graft-derived cell-free DNA appeared more specific for antibody mediated rejection. Limitations of this study include a small sample size and lack of a validation cohort. The capacity for absolute quantification, and lower barriers to implementation of this methodology recommend it for further study.
Assuntos
Ácidos Nucleicos Livres/sangue , Rejeição de Enxerto/diagnóstico , Rejeição de Enxerto/genética , Transplante de Rim , Adulto , Estudos Transversais , Feminino , Humanos , Imunossupressores/administração & dosagem , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Transplante HomólogoRESUMO
The development of antiviral-resistant cytomegalovirus (CMV) infection complicates the management of transplant recipients. We describe the case of a 65-year-old male who developed CMV disease on valganciclovir prophylaxis (donor CMV IgG positive, recipient CMV IgG indeterminate) 30 days after combined liver-kidney transplantation for alcoholic cirrhosis and hepato-renal syndrome. After an initial complete response to treatment dose oral valganciclovir, he developed recurrent CMV viraemia. Resistance testing revealed a UL97 mutation with in-frame deletions of codons 595-596. He was treated successfully with foscarnet and reduction in immunosuppression. This mutation has not been described previously and was suspected to confer ganciclovir resistance. Ganciclovir resistance occurs most commonly due to mutations in the UL97 or UL54 genes, which encode a protein kinase and a DNA polymerase, respectively. The UL97-encoded protein kinase phosphorylates ganciclovir to ganciclovir triphosphate, which competitively inhibits viral replication. Mutations in the UL97 gene are typically point mutations or deletions. We describe a new mutation, del595-596 in the CMV UL97 gene, occurring in the context of clinical treatment failure with standard and double-dose ganciclovir, and successful virological control achieved with foscarnet. This mutation is likely to result in ganciclovir resistance, although recombinant phenotyping is required for confirmation.
Assuntos
Antivirais/farmacologia , Citomegalovirus/genética , Farmacorresistência Viral/genética , Transplante de Rim/efeitos adversos , Transplante de Fígado/efeitos adversos , Fosfotransferases (Aceptor do Grupo Álcool)/genética , Valganciclovir/farmacologia , Idoso , Antivirais/uso terapêutico , Citomegalovirus/imunologia , Foscarnet/farmacologia , Foscarnet/uso terapêutico , Síndrome Hepatorrenal/cirurgia , Humanos , Transplante de Rim/métodos , Transplante de Fígado/métodos , Masculino , Deleção de Sequência , Valganciclovir/uso terapêutico , Carga Viral/efeitos dos fármacos , Proteínas Virais/genética , Replicação Viral/efeitos dos fármacosRESUMO
Living kidney donors (LKD) for paediatric kidney transplant recipients (KTR) have a heightened motivation to donate for emotional reasons and the clear health benefits to the KTR. We hypothesized that the cohort of LKD for paediatric KTR (LKD-P) includes motivated young parents with a higher lifetime end-stage kidney disease (ESKD) risk compared to adult KTR (LKD-A). Data from the Australia and New Zealand Dialysis and Transplant LKD Registry (2004-2015) was analysed to compare baseline characteristics and predonation ESKD risk in LKD-P (n = 315) versus LKD-A (n = 3448). LKD-P were younger (median age 42 vs. 50 years; P < 0.001) and had a marginally higher lifetime ESKD risk (median 0.44% vs. 0.40%; P < 0.01), with a similar proportion of LKD exceeding 1% risk threshold (5.4% vs. 5.6%; P = NS). Compared to grandparents as LKD-P, parents (median age 41 vs. 59 years; P < 0.001) had a higher lifetime ESKD (0.44% vs. 0.25%; P < 0.001). Although unique benefits to paediatric KTR justify the minor increase in lifetime ESKD risk in young parents, carefully selected grandparents are an alternative LKD-P option, allowing parents to donate for subsequent transplants.
Assuntos
Falência Renal Crônica/diagnóstico , Falência Renal Crônica/cirurgia , Transplante de Rim/efeitos adversos , Adulto , Algoritmos , Austrália , Feminino , Humanos , Doadores Vivos , Masculino , Pessoa de Meia-Idade , Motivação , Nova Zelândia , Pediatria , Sistema de Registros , Estudos Retrospectivos , Risco , TransplantadosRESUMO
Kidney transplant recipients undergo lifelong monitoring of allograft function and evaluation for transplant complications. The current monitoring paradigm utilizes blood, urine, and tissue markers that are insensitive, nonspecific, or invasive to obtain. As a result, problems are detected late, after significant damage has accrued, and often beyond the time at which complete resolution is possible. Indeed, most kidney transplants eventually fail, usually because of chronic rejection and other undetected injury. There is a clear need for a transplant-specific biomarker that enables a proactive approach to monitoring via early detection of reversible pathology. A biomarker that supports timely and personalized treatment would assist in achieving the ultimate goal of improving allograft survival and limiting therapeutic toxicity to the recipient. Donor-derived cell-free DNA (ddcfDNA) has been proposed as one such transplant biomarker. Although the test is presently utilized most in the United States, it is conceivable that its use will become more widespread. This review covers aspects of ddcfDNA that support informed use of the test by general nephrologists, including the basic biology of ddcfDNA, methodological nuances of testing, and general recommendations for use in the kidney transplant population. Clinical contexts are used to illustrate evidence-supported interpretation of ddcfDNA results and subsequent management. Finally, knowledge gaps and areas for further study are discussed.
Assuntos
Ácidos Nucleicos Livres , Transplante de Rim , Humanos , Transplante de Rim/efeitos adversos , Rejeição de Enxerto/diagnóstico , Rejeição de Enxerto/prevenção & controle , Rejeição de Enxerto/etiologia , Doadores de Tecidos , BiomarcadoresRESUMO
We present a kidney-pancreas transplant recipient who achieved complete recovery from COVID-19. A 45-year-old patient with T3 paraplegia underwent kidney-pancreas transplantation 18 years ago, followed by a subsequent kidney transplant 9 years ago, and presented with fever, hypoxia and hypotension after exposure to two confirmed cases of COVID-19. History of solid organ transplant, pre-existing renal impairment, asthma and an elevated D-dimer were identified as established risk factors for severe COVID-19. Supportive management was provided, baseline immunosuppression with everolimus was continued, and oral prednisolone was increased. A complete recovery was observed. Given the favourable outcome despite risk factors for severe COVID-19, we identify and review the potential mitigating roles of immunosuppression and mammalian target of rapamycin (mTOR) inhibitors in this disease. Further investigation is required to establish whether mTOR inhibitors could be used as therapeutic agents to treat COVID-19, or as alternative immunosuppression implemented early in the COVID-19 disease course.
Assuntos
COVID-19/complicações , Glucocorticoides/uso terapêutico , Rejeição de Enxerto/prevenção & controle , Imunossupressores/uso terapêutico , Transplante de Rim , Transplante de Pâncreas , Paraplegia/complicações , Acidentes de Trânsito , Asma/complicações , COVID-19/metabolismo , COVID-19/fisiopatologia , COVID-19/terapia , Diabetes Mellitus Tipo 1/complicações , Diabetes Mellitus Tipo 1/cirurgia , Everolimo/uso terapêutico , Febre/fisiopatologia , Produtos de Degradação da Fibrina e do Fibrinogênio/metabolismo , Humanos , Hipotensão/fisiopatologia , Hipóxia/fisiopatologia , Masculino , Pessoa de Meia-Idade , Prednisolona/uso terapêutico , SARS-CoV-2 , Serina-Treonina Quinases TOR/antagonistas & inibidoresRESUMO
Increased viral risk donors (IVRDs) with increased risk behaviors for blood-borne virus infection and negative nucleic acid testing have a low absolute risk of "window period" infection. Utilization and allocation of IVRD organs differ between jurisdictions. METHODS: We examined the characteristics and utilization of deceased donor IVRD kidneys and recipient outcomes within a 2-y period (July 31, 2018-July 31, 2020) postimplementation of a new opt-in allocation pathway for preconsented recipients in Victoria, Australia. RESULTS: Fifty-six kidneys from 31 IVRDs were utilized, comprising 13% of donors. Preconsent rate to accept IVRD kidneys increased to 41% of the waitlist in the 2 y postimplementation, and IVRDs having no kidneys utilized reduced to 0%. Compared with non-IVRD kidneys, kidney offer declines >10 per donor were less likely from IVRDs (3% vs 19%; P < 0.05). IVRDs were younger (median age 36 [IQR 30-44] vs 51 [35-60] y; P < 0.0001), with lower kidney donor profile index (25% [13-40%] vs 57% [29-75%]; P < 0.0001), and less hypertension (0% vs 22%; P < 0.01). Estimated glomerular filtration rate 3 mo post-transplant was superior (P < 0.01). Injecting drug use (61%) was the most common increased risk behavior. 29% of IVRDs were hepatitis C antibody positive but nucleic acid testing negative. No active infection was detected in any recipient post-transplant. CONCLUSIONS: The described opt-in system permits efficient allocation and utilization of kidneys from IVRDs, with superior quality and graft function. Education is crucial to facilitate informed consent and equity of access to this donor pool.
RESUMO
Chimerism analysis has an important role in the management of allogeneic hematopoietic stem cell transplantation. It informs response to disease relapse, graft rejection, and graft-versus-host disease. We have developed a method for chimerism analysis using ubiquitous copy number variation (CNV), which has the benefit of a "negative background" against which multiple independent informative markers are quantified using digital droplet polymerase chain reaction. A panel of up to 38 CNV markers with homozygous deletion frequencies of approximately 0.4-0.6 were used. Sensitivity, precision, reproducibility, and informativity were assessed. CNV chimerism results were compared against established fluorescence in situ hybridization, single nucleotide polymorphism, and short tandem repeat-based methods with excellent correlation. Using 30 ng of input DNA per well, the limit of detection was 0.05% chimerism and the limit of quantification was 0.5% chimerism. High informativity was seen with a median of four informative markers detectable per individual in 39 recipients and 43 donor genomes studied. The strength of this approach was exemplified in a multiple donor case involving four genomes (three related). The precision, sensitivity, and informativity of this approach recommend it for use in clinical practice.