Emerging viral diseases in kidney transplant recipients

Viruses are the most important cause of infections and a major source of mortality in Kidney Transplant Recipients (KTRs). These patients may acquire viral infections through exogenous routes including community exposure, donor organs, and blood products or by endogenous reactivation of latent viruses. Beside major opportunistic infections due to CMV and EBV and viral hepatitis B and C, several viral diseases have recently emerged in KTRs. New medical practices or technologies, implementation of new diagnostic tools, and improved medical information have contributed to the emergence of these viral diseases in this special population. The purpose of this review is to summarize the current knowledge on emerging viral diseases and newly discovered viruses in KTRs over the last two decades. We identified viruses in the field of KT that had shown the greatest increase in numbers of citations in the NCBI PubMed database. BKV was the most cited in the literature and linked to an emerging disease that represents a great clinical concern in KTRs. HHV‐8, PVB19, WNV, JCV, H1N1 influenza virus A, HEV, and GB virus were the main other emerging viruses. Excluding HHV8, newly discovered viruses have been infrequently linked to clinical diseases in KTRs. Nonetheless, pathogenicity can emerge long after the discovery of the causative agent, as has been the case for BKV. Overall, antiviral treatments are very limited, and reducing immunosuppressive therapy remains the cornerstone of management. Copyright © 2012 John Wiley & Sons, Ltd.     

Cytomegalovirus-specific antibody responses in renal transplant patients with primary and recurrent CMV infections

Cytomegalovirus (CMV) specific immunoglobulin G (IgG) and immunoglobulin M (IgM) antibody responses were measured before and after renal transplantation in 20 patients with primary CMV infection and in 16 patients with recurrent CMV infection. In primary CMV infection IgG antibody titres to late antigen (IgG-LA) measured by indirect fluorescence (IFA) were approximately seven times higher than those obtained by the complement fixation test (CFT). In contrast, in recurrent CMV infection this difference was found to be about twofold. Virus-specific IgM antibody to late antigen (IgM-LA) was detected in 100 percent of patients with primary CMV infection and in only 50 percent of patients with recurrent CMV infection. The IgM-LA titres were highest in primary CMV infection and reached peak levels at approximately 10 weeks post transplantation, whereas in recurrent CMV infection the IgM-LA titres were lower and reached peak levels at three months post transplantation. Moreover, IgM-LA was found to persist in patients from both groups at nine months post transplantation. IgM antibody to early antigen (IgM-EA) was not detected in any patient in this study. However, significant fourfold titre rises in IgG antibody to EA (IgG-EA) were detected in 100 percent of patients with recurrent CMV infection and in 50 percent of patients with primary CMV infection. These results clearly show the difference in antibody responses to the various antigens of CMV in patients with primary and recurrent CMV infection.     

Genomic mutations of viral protein 1 and BK virus nephropathy in kidney transplant recipients

Genomic variability in the viral protein 1 region of BK polyomavirus (BKV) may change the ability of the virus to replicate. The significance of such changes was studied in clinical samples taken from kidney transplant patients with and without BKV nephropathy. A 94 base‐pair fragment of viral protein 1 was amplified from 68 urine, 28 blood, and 12 renal biopsy samples from eight patients with BKV nephropathy, and from 100 urine samples, 17 blood and three renal biopsy samples from 41 of 218 controls. The DNA was sequenced and the amino acid changes were predicted by the Expert Protein Analysis System program (ExPASy, Swiss Institute of Bioinformatics, Geneva, Switzerland). Single base‐pair mutations were detected more frequently in the samples from the BKV nephropathy patients than in the controls, and this was the only statistically significant finding of the study (P < 0.05), thus suggesting a greater genetic instability in BKV nephropathy associated strains. The amino acid changes were distributed at random in both BKV nephropathy patients and controls. However, one aspartic acid‐to‐asparagine substitution at residue 75 was detected in all samples of the one patient with BKV‐associated nephropathy, who developed disease progression confirmed by histology, and not in any of the other patient or control samples. Whether this specific amino acid change plays a role in disease deserves further study. J. Med. Virol. 81:1385–1393, 2009. © 2009 Wiley‐Liss, Inc.     

BK virus-associated nephropathy in kidney transplant recipients

Polyomavirus BK has emerged as an important cause of renal allograft infection leading to allograft dysfunction and loss in kidney transplant recipients. Significant progress has been made, particularly in the area of diagnostic methods for BK virus, thereby facilitating diagnosis, screening and monitoring of infection. This review outlines current concepts on the epidemiology, pathogenesis, diagnosis and therapy of BK virus nephropathy. The precise risk factors that are important for induction and progression of infection to invasive disease, the most effective diagnostic strategies, and the efficacy of current therapeutic approaches, all remain to be defined fully. It is to be hoped that these deficiencies will stimulate research to address these important questions.     

JC病毒在肾移植受者中的感染状况

目的 探究多瘤JC病毒(JC virus,JCV)在肾移植受者中的感染情况及其感染对移植肾功能的影响,并初步探索JCV感染的影响因素.方法 采用巢式PCR方法检测49例肾移植病人术后尿液标本中的JCV DNA,并以24例健康体检者为对照;定性PCR方法检测病人尿液标本中的巨细胞病毒(cytomegalovirus,CMV)DNA;Binary Logistic回归方法分析JCV感染的可能影响因素:病人的年龄、性别、免疫抑制方案、CMV感染;以肾小球滤过率(glomerular filtration rate,GFR)作为肾功能的指标,t检验方法比较JCV感染和非感染者GFR有无差别.结果 JCV在肾移植病人中的感染率为42.9%,健康体检者为4.2%.移植后CMV感染和强的松+MMF+环孢素三联免疫抑制方案是JCV感染的危险因素(OR=10.101,P=0.049;OR=6.286,P=0.008).JCV感染者和非感染者的GFR分别为86.470±29.990和84.060±33.729,两者间的差异无统计学意义(t=0.259,P=0.797).结论 JCV在肾移植病人中有很高的感染率,CMV感染和使用强的松+MMF+环孢素三联免疫抑制方案可明显增加JCV感染的危险性;JCV感染对移植肾功能无影响.     

Impact of alloimmune T cell responses on hepatitis C virus replication in liver transplant recipients

We investigated the influence of alloimmune T cell responses on hepatitis C virus (HCV) replication in HCV-infected patients after liver transplantation (LT). To monitor the immune-status in 27 HCV-infected LT recipients, we routinely performed mixed lymphocyte reaction (MLR) assays within 4 weeks after LT. HCV RNA titers in most patients fluctuated in inverse proportion to the stimulation index (SI) of anti-donor reactive T cells early after LT. Two weeks after LT, recipients with high HCV RNA titers (>1000 KIU/mL) displayed a significantly lower SI for anti-donor reactive T cells than recipients with low HCV RNA titers did (<1000 KIU/mL). An in vitro transwell assay mimicking the anatomical features of the interaction between HCV-infected hepatocytes and alloreactive T cells in allograft livers demonstrated that interferon (IFN)-γ was necessary to suppress HCV replication. This study proves the significant impact of alloimmune T cell responses on HCV replication in HCV-infected LT recipients.     

Management of viral hepatitis in liver transplant recipients

Recurrence of viral hepatitis after liver transplantation (LT) can progress to graft failure and lead to a decrease in long-term survival. Recently, there have been remarkable improvement in the treatment of chronic hepatitis B (CHB) using potent antiviral agents. Combination of hepatitis B immunoglobulin and potent antiviral therapy has brought marked advances in the management of CHB for liver transplant recipients. Post-transplant antiviral therapy for hepatitis C virus infection is generally reserved for patients showing progressive disease. Acheiving a sustained virological response in patients with LT greatly ameliorates graft and overall survival, however this only occurs in 30% of transplant recipient using pegylated interferon and ribavirin (RBV). Direct acting antivirals such as protease inhibitors, polymerase or other non-structural proteins inhibitors are anticipated to establish the new standard of care for transplant recipients. In liver transplant recipients, hepatitis E virus infection is an uncommon disease. However, it can lead to chronic hepatitis and cirrhosis and may require retransplantation. Recently, 3-month course of RBV monotherapy has been reported as an effective treatment. This review focuses on the recent management and therapeutic approaches of viral hepatitis in liver transplant recipient.     

Cytomegalovirus-specific CD4 T-cell and glycoprotein B specific antibody response in recipients of allogenic stem cell transplantation.

BACKGROUND: The human cytomegalovirus (HCMV) causes severe complications in immunosuppressed patients, resulting in increased morbidity and mortality. The immunological components important for the control of HCMV are still not completely understood. OBJECTIVE AND STUDY DESIGN: To evaluate the importance of cellular and humoral immunity in stem cell transplant (SCT) recipients, we analysed levels of HCMV specific IFN-gamma producing CD4+ cells and glycoprotein B (gB) specific antibodies in HCMV positive SCT patients with and without reactivation episodes after SCT. RESULTS AND CONCLUSION: Patients without HCMV reactivation episodes showed a slow but steady increase in both parameters after SCT, indicating that initial high levels of gB specific antibodies or HCMV specific CD4+ IFN-gamma+ cells are not necessary to prevent reactivation of HCMV. In contrast, patients with reactivation episodes showed a steep, significant increase in HCMV specific CD4+ IFN-gamma+ counts just prior to HCMV reactivation, followed by a decline after the reactivation period. Patients who underwent only a single reactivation generated significant higher amounts of CD4+ IFN-gamma+ cells, than did patients with further reactivation episodes. The course of gB specific antibodies for reactivating patients was different, with significantly higher average values in the patients with HCMV reactivation. This indicates that patients with a HCMV reactivation exhibit a stronger humoral dominated immune response.     

Fibronectin in immune responses in organ transplant recipients

The immune response to an organ allograft involves perpetuation of T cell infiltration and activation. Advances in understanding the mechanisms of T cell activation have placed particular emphasis on the interactions between the T-cell receptor and antigen presenting cells, with little reference to the fact that in vivo activation occurs in the physical context of extracellular matrix proteins (ECM). Indeed, the possibility that ECM proteins may have a determining role in lymphocyte adhesion and tissue localization and function is now becoming more appreciated in view of growing evidence indicating that integrins and other T cell antigens bind ECM components, with some of these components exerting synergistic effects on T-cell activation. This review focuses on the importance of interactions between lymphocytes and fibronectin, a prominent ECM component, for cell migration and function in organ allograft recipients. It explores novel therapeutic approaches based on the assumption that fibronectin represents an active element in the process of T cell activation in the immune cascade triggered by organ transplantation.     

Serum antibody and opsonic responses after immunization with pneumococcal vaccine in kidney transplant recipients and controls.

We immunized 31 renal transplant patients and 6 control subjects with a pneumococcal vaccine containing 14 capsular polysaccharides. Antibody levels to Streptococcus pneumoniae types 3 and 6A were measured by a radioimmunoassay, and opsonic activity to S. pneumoniae types 3 and 6B was determined by using a luminol-enhanced chemiluminescence phagocytic assay on serum samples obtained before and 1 month after immunization. There was a 10.2-fold and a 2.9-fold increase in antibody to S. pneumoniae type 3 (P less than 0.005) and type 6A (P less than 0.01), respectively, but only a 1.3-fold (P greater than 0.05) and 1.1-fold (P greater than 0.05) increase in opsonic activity. For S. pneumoniae type 3, changes in opsonic activity correlated well with antibody concentration (P less than 0.05). However, for S. pneumoniae type 6, these two tests correlated poorly (P greater than 0.05). This poor correlation suggests that concentrations of antibody to type 6A polysaccharide which are achieved after immunization may not be opsonically active in vitro against S. pneumoniae type 6B.     

Association between viral infections and post-transplant malignancies in renal transplant recipients

Immunosuppressive treatment is associated with an increased incidence of different malignant diseases. The etiology of posttransplant malignancies is multifactorial and includes decreased immune response to different viral infections, inappropriate removal of damaged cells, and impaired ability to repair DNA. EBV, HHV-8, Merkel cell virus, hepatitis B virus, hepatitis C virus and BK virus are all considered to be involved in the etiology of post-transplant malignancies. CMV has been considered as a potential causative factor in the development of colon cancer. However, current knowledge is mainly based on case reports. Further studies are needed to establish the causative role of different viruses in the etiology and pathogenesis of different malignant diseases in renal transplant population.     

Timing of mTORI usage and outcomes in kidney transplant recipients

The introduction of mammalian target of rapamycin inhibitors (mTORi) as immunosuppressive agents has changed the landscape of calcineurin inhibitor-based immunosuppressive regimens. However, the timing of mTORi conversion and its associated outcomes in kidney transplantation have conflicting results. This study investigated the effect of early or late mTORi post-transplant initiation on major transplant outcomes, including post-transplant malignancy, in kidney transplant recipients in our center. We enrolled 201 kidney transplant recipients with surviving function grafts of >3 months between 1983 and 2016. Patients were divided into three groups: early mTORi (initiated within 6 months of kidney transplantation), late mTORi, (mTORi initiation >6 months after kidney transplantation) and no mTORi. The mean creatinine at conversion was 1.46 ± 0.48 mg/dL and 1.30 ± 0.53 mg/dL for the early and late mTORi groups, respectively. During the study period, 10.5% of mTORi users and 19.2% of mTORi nonusers developed malignancy, mainly urothelial carcinoma. After adjustment for confounding factors, mTORi users were found to have a lower incidence of post-transplant malignancy than did nonusers (adjusted OR: 0.28, P = 0.04). No significant difference was observed between early and late mTORi users. Our results verified the potential advantages of mTORi usage in reducing cancer incidence after kidney transplantation. However, no significant result was found related to the timing of mTORi introduction. Future studies should include a longer observation period with a larger cohort.     

Cutaneous infections from viral sources in solid organ transplant recipients

Although there is an abundance of information on cutaneous malignancies in transplant recipients, information on cutaneous infections in solid organ transplant recipients is underrepresented in dermatologic and transplant literature. Our paper provides a comprehensive review of viral cutaneous infections within the solid organ transplant population. We compiled literature specific to the solid organ transplant population, reviewing cutaneous manifestations secondary to viral infections. Furthermore, we discuss the diagnosis and treatment of such infections. The following is a list of the viruses that we will discuss:

• -Human papillomavirus
• -Human herpesvirus type 1,2
• -Varicella-Zoster virus
• -Cytomegalovirus
• -Epstein-Barr virus
• -Human herpesvirus type 6 variant A
• -Human herpesvirus type 6 variant B
• -Human herpesvirus type 7
• -Human herpesvirus 8
• -Trichodysplasia spinulosa polyomavirus
• -Human polyomavirus 7
• -Merkel cell polyomavirus
• -Molluscum contagiosum

     

西罗莫司在肾移植受者中的转换治疗

背景：传统的钙调磷酸酶抑制剂能导致慢性移植肾肾病的发生,新型免疫抑制剂西罗莫司的出现就为替换这一治疗方案提供了可能。 目的：验证西罗莫司在肾移植后受者中转换治疗的临床效果及其安全性。 方法：对同种异体肾移植后以口服钙调磷酸酶抑制剂为主的60例受者,进行以西罗莫司为主的转换治疗,观察转换后6个月内临床效果、安全性和不良反应。 结果与结论：西罗莫司转换治疗后6个月内急性排斥反应发生率为13.3%。因慢性移植肾肾病进行药物转换的受者,转换后肾功能改善;其他转换后移植后肝损害及高血糖有所改善。结果提示西罗莫司在转换治疗时疗效优于钙调磷酸酶抑制剂。     

Effect of delayed graft function in hypersensitized kidney transplant recipients

There is increased evidence about the deleterious effect of delayed graft function (DGF) in both short- and long-term kidney graft outcome. Among the mechanisms involved in the production of DGF, immune factors play a role, especially in the level of hypersensitization. From the 1389 patients transplanted at our hospital until November 2004, it has been found that the presence of moderate and high levels of sensitization, as measured by panel-reactive antibodies, is a risk factor for suffering from DGF. Further, DGF was associated with poor graft survival, and the risk was even higher when DGF was combined with moderate/high panel-reactive antibodies. Recent data demonstrate the usefulness of intravenous immunoglobulins in the management of hypersensitized patients in terms of short-term outcome. It remains to be demonstrated whether this therapy is able to ameliorate the higher ischemic injury that kidneys undergo from these immunologically high-risk patients.     

Analysis of the peripheral T-cell repertoire in kidney transplant patients

The long-term stability of renal grafts depends on the absence of chronic rejection. As T cells play a key role in rejection processes, analyzing the T-cell repertoire may be useful for understanding graft function outcomes. We have therefore investigated the power of a new statistical tool, used to analyze the peripheral blood TCR repertoire, for determining immunological differences in a group of 229 stable renal transplant patients undergoing immunosuppression. Despite selecting the patients according to stringent criteria, the patients displayed heterogeneous T-cell repertoire usage, ranging from unbiased to highly selected TCR repertoires; a skewed TCR repertoire correlating with an increase in the CD8(+) /CD4(+) T-cell ratio. T-cell repertoire patterns were compared in patients with clinically opposing outcomes i.e. stable drug-free operationally tolerant recipients and patients with the "suspicious" form of humoral chronic rejection and were found significantly different, from polyclonal to highly selected TCR repertoires, respectively. Moreover, a selected TCR repertoire was found to positively correlate with the Banff score grade. Collectively, these data suggest that TCR repertoire categorization might be included in the calculation of a composite score for the follow-up of patients after kidney transplantation.     

B-Cell crossmatching and kidney allograft outcome in 9031 United States transplant recipients

The predictive power of a positive B-cell crossmatch remains controversial due to the presence of cofactors, such as sensitization and human leukocyte antigen (HLA) mismatch levels. UNOS OPTN/Scientific Registry data were analyzed on 9031 cadaveric kidney graft recipients who were B-cell crossmatched during 1994 and 1995 for graft outcome. This 2-year time period was chosen so that most US transplant recipients in this study would have had a similar regimen of immunosuppression consisting of prednisone, Sandimmune, and azathioprine The two patient groups that were analyzed were B-pos (n = 336) and B-neg (n = 8,695). All T-cell crossmatches were negative. Data analyzed included donor-recipient demographics, sensitization levels, B-cell crossmatch techniques, histocompatibility mismatching, graft rejection incidence, early graft loss, cause of graft failure, and statistical analyses (univariate and multivariate) in primary and repeat graft recipients. Significant factors in both crossmatch groups included pretransplant transfusions, peak and most recent class I PRA levels, a previous kidney graft, histocompatibility mismatching at HLA-A plus -B, urine in first 24 h, and rejection incidence between discharge and 6 months post-transplantation. Class II antibody specificities and panel reactive antibody (PRA) levels were not available from the UNOS database. Fifty-seven percent of 15,896 (1994-1995) transplant recipients (n 9031) were B-cell crossmatched, and 336 of 9031 recipients (3.7%) were transplanted with a B-pos crossmatch. Sixteen percent of B-pos recipients experienced early graft loss (< 6 months) compared with 11% of B-neg recipients (p < 0.001). Both primary and repeat grafts with B-pos crossmatches experienced an increase in rejection incidence (p = 0.023) and early graft loss (p < 0.001). In the sensitized (PRA > 10%) recipient subset (n = 2,789), both primary (n = 93) and regraft (n = 52) recipients with B-pos crossmatches had a higher incidence of early graft loss at 3 months, p < 0.001 and p = 0.016, respectively. HLA-DR mismatch levels in both patient groups were not different (p = 0.109). There was a 68% increase in the odds of 3-month graft loss in B-pos versus B-neg recipients (multivariate logistic regression analysis p = 0.054, 95% confidence interval 0.99-2.85). In conclusion, a B-pos crossmatch in primary and regraft recipients, including a sensitized subset, is predictive of inferior kidney graft outcome.     

CMV antigenemia and quantitative viral load assessments in hematopoietic stem cell transplant recipients

BackgroundSensitive and reliable diagnostic tests are essential for the prevention of cytomegalovirus (CMV) disease after hematopoietic stem cell transplantation (HSCT). pp65 antigenemia and polymerase chain reaction (PCR) assays are commonly used to monitor CMV in HSCT recipients. However, there is considerable intra- and inter-laboratory variability in the results, which impact comparability and clinical practice.Objectives/study designUsing 380 samples from 135 HSCT recipients, we compared the new FDA approved quantitative PCR assay, COBAS^® AmpliPrep/COBAS^® TaqMan^® CMV test (CAP/CTM CMV test) developed and standardized using the 1st WHO International Standard for CMV with pp65 antigenemia and COBAS^® AMPLICOR MONITOR CMV tests.ResultsThe median time between transplantation and testing samples was 57 days (range, 0–207 days). The median CMV load (log₁₀) was 3.17 IU/mL (3.21 copies/mL). Among samples with detectable CMV load, 52% were negative by pp65 antigenemia. CMV loads were higher in pp65 antigenemia-positive than in negative samples. One pp65-antigenemia-positive cell per 100,000 leukocytes corresponded to a median CMV load of 1200 IU/mL. CMV loads determined by the CAP/CTM CMV test were slightly lower than the ones by the AMPLICOR MONITOR CMV test (?0.15 [95% CI, ?0.18 to ?0.13] copies/mL), but slope differences indicated only limited co-linearity.ConclusionsThe CAP/CTM CMV test is more sensitive than pp65 antigenemia and the AMPLICOR MONITOR CMV test in HSCT recipients. The lower limit of quantification and co-linearity with the international WHO standard renders the CAP/CTM CMV test suitable for future clinical trials defining viral load thresholds of CMV therapy.