Emerging role of pharmacogenetic in organ transplantation

The currently used immunosuppressive drugs have a narrow therapeutic index which required to individualize the dose regimen for different recipients. Pharmacogenetic is the use of genetic screening to prevent metabolic responses to different immunosuppressive drugs. Since the oxidative enzymes cytochrome P450 CYP3A and the drug efflux pump P-glycoprotein (P-gp) play a pivotal role in immunosuppressive drugs metabolism, pharmacogenetic studies have been mainly focused on these two enzymes. This would provide an important aid toward drug regimen individualization during the post-transplant therapy and has potential to improve graft outcome

JC polyomavirus infections in transplant patients

The polyomavirus JC virus (JCV) is a small nonenveloped DNA virus that asymptomatically infects about 80% of healthy adults and establishes latency in the kidney tissue. In case of immunodeficient hosts, JCV can lytically infect the oligodendrocytes, causing a fatal demyelinating disease, known as Progressive Multifocal Leukoencephalopathy (PML). Although the reactivation of another human polyomavirus, BK Virus (BKV), is relatively common and its association with the Polyomavirus Associated Nephropathy (PVAN) following renal transplantation is assessed, JCV replication and its impact on graft function and survival is less well studied. In addition, none of the performed studies ruled out the hypothesis that JCV could be associated with certain post-trasplantation clinical syndromes. Thus, monitoring of Polyomaviruses infection, especially during the first 24 months post-transplantation, is recommended

Hypothermic Machine Perfusion in Kidney Transplantation: Back to the Future?

Static cold storage is currently the most used method of organ preservation worldwide. However, cutting edge technology and dramatic changes in the donor pattern have lately renewed the interest toward hypothermic machine perfusion. Marginal and cardiac death donors show higher rates of primary non function and delayed graft function compared to standard criteria donors. In this setting, machine perfusion may offer several theoretical advantages such as improved organ preservation, continuous graft evaluation, and ex-vivo conditioning of the graft before implantation. These topics have been recently reassessed by several studies. In particular, perfusion characteristics (renal resistance) and perfusate biomarker concentrations (lactate dehydrogenase, aspartate aminotransferase, heart-type fatty acid binding protein, and IL-18) during machine preservation, proved to be reliable tools to rule out graft viability and predict outcomes after transplantation. Treatment strategies acting on tissue repair, cell metabolism, and allorecognition pathway are also under investigation with promising results. Machine perfusion has finally shown its real potential however, stronger evidences and updated cost-effectiveness analysis are needed to fully support its role for the next future

APAP titration in patients with mild to moderate OSAS and periodic limb movement syndrome

(APAP) titration in a partially attended setting; 2) to verify whether APAP performance depends on the apneahypopnea and periodic limb movement indexes (PLMI). Methods. 65 CPAP naïve subjects with a sleep disorder of breathing and daytime sleepiness underwent a standard polysomnography (first night), APAP titration (second night, partially attended), and a standard polysomnography using continuous positive airway pressure (CPAP) at the effective pressure (Peff) established from the APAP titration (third night) in a sleep disorder laboratory in a 400-bed community hospital. We examined the apnea-hypopnea index (AHI), sleep stages, arousals induced by respiratory events (RESPa) and PLM (PLMa), and oxygen saturation during the first and third nights on CPAP at the Peff. Patients were divided into three groups according to their AHI and PLMI. Results. At the Peff defined using APAP on the third night, the mean AHI dropped from 29.6 ± 21.8 to 3.1 ± 3.4, and the RESPa index from 16.5 ± 16.2 to 1.7 ± 2.6. No differences emerged in sleep stages or spontaneous arousals (first vs third night). Overall, 92% of the patients met the standard for an acceptable outcome of positive pressure titration. Baseline AHI and PLMI did not affect the outcome of titration. Conclusions. In patients with mild to moderate OSAS and PLMS, APAP titration enables the optimal fixed pressure for CPAP home therapy to be determined in at least 90% of patients

Re: Kidney-Failure Risk Projection for the Living Kidney-Donor Candidate

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Treatment options for localised renal cell carcinoma of the transplanted kidney

Currently, there is no consensus among the transplant community about the treatment of renal cell carcinoma (RCC) of the transplanted kidney. Until recently, graftectomy was universally considered the golden standard, regardless of the characteristics of the neoplasm. Due to the encouraging results observed in native kidneys, conservative options such as nephron-sparing surgery (NSS) (enucleation and partial nephrectomy) and ablative therapy (radiofrequency ablation, cryoablation, microwave ablation, high-intensity focused ultrasound, and irreversible electroporation) have been progressively used in carefully selected recipients with early-stage allograft RCC. Available reports show excellent patient survival, optimal oncological outcome, and preserved renal function with acceptable complication rates. Nevertheless, the rarity and the heterogeneity of the disease, the number of options available, and the lack of long-term follow-up data do not allow to adequately define treatment-specific advantages and limitations. The role of active surveillance and immunosuppression management remain also debated. In order to offer a better insight into this difficult topic and to help clinicians choose the best therapy for their patients, we performed and extensive review of the literature. We focused on epidemiology, clinical presentation, diagnostic work up, staging strategies, tumour characteristics, treatment modalities, and follow-up protocols. Our research confirms that both NSS and focal ablation represent a valuable alternative to graftectomy for kidney transplant recipients with American Joint Committee on Cancer stage T1aN0M0 RCC. Data on T1bN0M0 lesions are scarce but suggest extra caution. Properly designed multi-centre prospective clinical trials are warranted

Posttransplant lymphoproliferative disorders in neuronal xenotransplanted macaques

Posttransplant lymphoproliferative disorders (PTLDs) are a heterogeneous group of lymphoid proliferations that occur in the setting of depressed T-cell function due to immunosuppressive therapy used following solid organ transplantation, hematopoietic stem cell transplantation, and also xenotransplantation. In the present study, 28 immunosuppressed parkinsonian Macaca fascicularis were intracerebrally injected with wild-type or CTLA4-Ig transgenic porcine xenografts to identify a suitable strategy to enable long-term cell survival, maturation, and differentiation. Nine of 28 (32%) immunosuppressed primates developed masses compatible with PTLD, located mainly in the gastrointestinal tract and/or nasal cavity. The masses were classified as monomorphic PTLD according to the World Health Organization classification. Immunohistochemistry and polymerase chain reaction (PCR) analyses revealed that the PTLDs were associated with macaca lymphocryptovirus as confirmed by double-labeling immunohistochemistry for CD20 and Epstein-Barr nuclear antigen 2 (EBNA-2), where the viral protein was located within the CD20+ neoplastic B cells. In sera from 3 distinct phases of the experimental life of the primates, testing by quantitative PCR revealed a progression of the viral load that paralleled the PTLD progression and no evidence of zoonotic transmission of porcine lymphotropic herpesvirus through xenoneuronal grafts. These data suggest that monitoring the variation of macaca lymphocryptovirus DNA in primates could be used as a possible early diagnostic tool for PTLD progression, allowing preemptive treatment such as immunosuppression therapy reduction

Allograft artery mycotic aneurysm after kidney transplantation: A case report and review of literature

BACKGROUND Allograft artery mycotic aneurysm (MA) represents a rare but life-threatening complication of kidney transplantation. Graftectomy is widely considered the safest option. Due to the rarity of the disease and the substantial risk of fatal consequences, experience with conservative strategies is limited. To date, only a few reports on surgical repair have been published. We describe a case of true MA successfully managed by aneurysm resection and arterial re-anastomosis. CASE SUMMARY An 18-year-old gentleman, on post-operative day 70 after deceased donor kidney transplantation, presented with malaise, low urinary output, and worsening renal function. Screening organ preservation fluid cultures, collected at the time of surgery, were positive for Candida albicans. Doppler ultrasound and contrastenhanced computer tomography showed a 4-cm-sized, saccular aneurysm of the iuxta-anastomotic segment of the allograft artery, suspicious for MA. The lesion was wide-necked and extended to the distal bifurcation of the main arterial branch, thus preventing endovascular stenting and embolization. After multidisciplinary discussion, the patient underwent surgical exploration, aneurysm excision, and re-anastomosis between the stump of the allograft artery and the internal iliac artery. The procedure was uneventful. Histology and microbiology evaluation of the surgical specimen confirmed the diagnosis of MA caused by Candida infection. Three years after the operation, the patient is doing very well with excellent allograft function and no signs of recurrent disease. CONCLUSION Surgical repair represents a feasible option in carefully selected patients with allograft artery MA. Anti-fungal prophylaxis is advised when preservation fluid cultures are positive

Array Comparative Genomic Hybridization Analysis Reveals Significantly Enriched Pathways in Canine Oral Melanoma

Human Mucosal Melanoma (hMM) is an aggressive neoplasm of neuroectodermal origin with distinctive features from the more common cutaneous form of malignant melanoma (cMM). At the molecular level, hMMs are characterized by large chromosomal aberrations rather than single-nucleotide mutations, typically observed in cMM. Given the scarcity of available cases, there have been many attempts to establish a reliable animal model. In pet dogs, Canine Oral Melanoma (COM) is the most common malignant tumor of the oral cavity, sharing clinical and histological aspects with hMM. To improve the knowledge about COM\u2019s genomic DNA alterations, in the present work, formalin-fixed, paraffin-embedded (FFPE) samples of COM from different European archives were collected to set up an array Comparative Genomic Hybridization (aCGH) analysis to estimate recurrent Copy Number Aberrations (CNAs). DNA was extracted in parallel from tumor and healthy fractions and 19 specimens were successfully submitted to labeling and competitive hybridization. Data were statistically analyzed through GISTIC2.0 and a pathway-enrichment analysis was performed with ClueGO. Recurrent gained regions were detected, affecting chromosomes CFA 10, 13 and 30, while lost regions involved chromosomes CFA 10, 11, 22, and 30. In particular, CFA 13 showed a whole-chromosome gain in 37% of the samples, while CFA 22 showed a whole-chromosome loss in 25%. A distinctive sigmoidal trend was observed in CFA 10 and 30 in 25 and 30% of the samples, respectively. Comparative analysis revealed that COM and hMM share common chromosomal changes in 32 regions. MAPK- and PI3K-related genes were the most frequently involved, while pathway analysis revealed statistically significant perturbation of cancer-related biological processes such as immune response, drug metabolism, melanocytes homeostasis, and neo-angiogenesis. The latter is a new evidence of a significant involvement of neovascularization-related pathways in COMs and can provide the rationale for future application in anti-cancer targeted therapies