Cytomegalovirus in renal transplantation

Cytomegalovirus (CMV) was first isolated from the salivary gland and kidney of two dying infants with cytomegalic inclusion bodies and reported in 1956 (1). Two other laboratories isolated CMV at approximately the same time. Thus, CMV was initially called "salivary gland virus" or "salivary gland inclusion disease virus". In 1960, Weller et al. (2) proposed the use of the term cytomegalovirus. Klemola and Kaarianinen (3) first described CMV mononucleosis, the principal presentation of previously healthy individuals, in 1965. CMV was first isolated in a renal transplant patient in 1965,     

Cytomegalovirus infection after renal transplantation: selective prophylaxis and treatment

We have reviewed our experience in selective cytomegalovirus (CMV) infection prophylaxis and treatment in our renal transplant population. Between 1996 and 2001, 263 cadaveric renal transplant recipients had at least 6 months follow up. Immunosuppression was based on cyclosporine Neoral (n=108) or tacrolimus (n=155). CMV infection prophylaxis (oral acyclovir or gancyclovir at half usual doses) was only prescribed in recipients receiving a CMV positive ve kidney and in recipients treated with OKT3. CMV infection was diagnosed by a positive pp65 antigenemia upon appearance of CMV-related symptoms, leading to specific treatment (IV ganciclovir) only if symptoms were intense or there was visceral involvement. Thus, no preemptive treatment or programmed or periodic antigenemia was performed in any case. Nineteen episodes of symptomatic CMV infection were diagnosed (prevalence 7.2%). The frequency was similar for all immunosuppressive regimens. Only 9 of 19 (47%) of patients were given IV ganciclovir; the others were not treated. All patients survived without apparent complications, relapses, or recurrences. No oral gancyclovir was delivered after IV treatment. Our CMV prophylaxis protocol was limited to high-risk patients, using lower gancyclovir dosages than those usually advocated. It does not include programmed or scheduled search for CMV antigenemia in asymptomatic renal transplant patients. Despite these factors, our CMV infection rate and severity were similar to those reported with more aggressive protocols, with extended prophylaxis, preemptive therapy, or intense surveillance.     

肾移植术后远期急性排斥反应与巨细胞病毒感染

目的探讨肾移植术后远期急性排斥反应与巨细胞病毒感染的关系。方法检测４５例移植肾有功能存活１年以上后发生急性排斥反应者外周血白细胞中巨细胞病毒ＤＮＡ（ＣＭＶＤＮＡ）,并给予激素冲击治疗,对激素冲击无效的部分患者给予更昔洛韦抗病毒治疗。结果３２例激素冲击有效,１３例无效。无效者外周血白细胞内可测到ＣＭＶＤＮＡ,８例用更昔洛韦治疗后ＣＭＶＤＮＡ转阴,２例肾功能好转,６例恢复正常,另５例未用更昔洛韦者ＣＭＶＤＮＡ持续阳性,肾功能损害加重。结论部分肾移植受者发生的远期急性排斥反应与ＣＭＶ感染有一定关系;临床上对用激素冲击治疗无效的远期急性排斥可给予抗病毒治疗     

Cytokine gene polymorphisms predict acute graft rejection following renal transplantation.

BACKGROUND: The proinflammatory cytokine tumor necrosis factor-alpha (TNF-alpha) has been implicated in the pathogenesis of acute rejection, while animal models suggest a role for interleukin-10 (IL-10) in promoting graft survival. It has also been shown that polymorphisms in the TNFA gene promoter (position -308) and in the IL-10 gene promoter (position -1082) correlate with differential production of these cytokines in vitro. The aim of this study was to determine whether TNF-alpha and IL-10 gene polymorphisms influence the incidence and severity of acute rejection in the first six months following renal transplantation. METHODS: The cytokine genotypes of 115 consecutive first cadaveric kidney allograft recipients and their donors were screened. The rejection episodes (REs) were defined clinically and confirmed histologically where possible and further classified according to severity (RS), namely steroid-resistant or responsive REs. The genotypes were then correlated with the REs and RS. RESULTS: The recipient TNF-alpha high producer genotype and IL-10 high producer genotype were significantly associated with multiple REs (>/=2) in human leukocyte antigen (HLA)-DR mismatched transplants (P = 0.0047 and P = 0.045, respectively), whereas only the TNF-alpha high producer genotype was associated with steroid-resistant REs (P = 0.025). When recipient cytokines were analyzed together, the TNF-alpha high/IL-10 high producer genotype had the worst prognosis, whereas TNF-alpha low/IL-10 low producer genotype was protective. CONCLUSIONS: We conclude that recipient TNF-alpha and IL-10 gene polymorphisms are determinants of REs and RS following kidney transplantation. Routine screening of these gene polymorphisms may have a clinical role in identifying patients at risk of multiple REs and severe rejections.     

Influence of time of rejection on long-term graft survival in renal transplantation

BACKGROUND: The aim of this analysis was to investigate the relationship of acute rejection episodes (ARE) at different times posttransplantation with reversibility of graft dysfunction and long-term graft failure using data from the Collaborative Transplant Study database. METHODS: A total of 28,867 patients receiving their graft between 1995 and 2005 from deceased donors were included in the analysis. The time from renal transplantation to first treated ARE was divided into intervals up to 3 years. Long-term graft survival and half-life rates were calculated and hazard ratios (HR) for failure were computed using multivariate Cox regression analysis. RESULTS: Compared with patients who did not receive rejection treatment during the first posttransplant year, HR for graft survival increased to 1.35 for patients with rejection 0 to 90 days (P<0.001), 2.05 with rejection 91 to 180 days (P<0.001), and 2.74 with rejection 181 to 365 days of posttransplantion (P<0.001). First rejections occurring during the second year were associated with HR 3.35 (P<0.001) and rejections during the third year with HR 3.17 (P<0.001). In addition to the time of rejection, the degree of functional recovery after rejection treatment was found to be important for subsequent graft survival. CONCLUSION: The time point of occurrence and the degree of functional recovery after rejection treatment were found to significantly influence the impact of ARE on long-term graft survival, and we were able to quantify the associated risks.     

Cytomegalovirus infection of the graft duodenum and urinary bladder after simultaneous pancreas-kidney transplantation

Cytomegalovirus (CMV) is an important cause of morbidity after solid organ transplantation. We report a case of CMV infection involving the transplanted duodenum that developed after simultaneous pancreas-kidney transplantation. The patient, a 30-year-old woman with insulin-dependent diabetes undergoing hemodialysis due to chronic renal failure, received a simultaneous cadaveric pancreas-kidney transplantation. The exocrine secretion was diverted using bladder drainage. Immunosuppression was maintained by a combination of tacrolimus, mycophenolate mofetil, and steroids together with OKT3 induction. Both the donor and the recipient were serologically positive for CMV IgG CMV prophylaxis consisted of a short course of parenteral gancyclovir. The patient was discharged on postoperative day 39 with normal pancreas and kidney function. She presented 2 months after transplantation with hematuria. Cystoscopic pancreas allograft biopsy specimens showed evidence of tissue invasive CMV infection in the graft duodenum and bladder. The CMV antigenemia test was positive. At 4 months after transplantation, the patient underwent surgery with the diagnosis of acute abdomen. The surgical findings consisted of a diffuse acute purulent peritonitis due to perforation of the duodenal graft. We sutured the perforation with nonreabsorbable material. The CMV antigenemia test was negative. Eight days later, the patient developed massive hematuria. At surgery, the graft was removed. The patient was discharged from the hospital with normal renal function. Pathological study of the removed graft showed the duodenal segment to have multiple wide ulcers with CMV inclusions in epithelial cells.     

Cytomegalovirus infection following renal transplantation in patients administered low-dose rituximab induction therapy

Anti-CD20 antibody (rituximab) is recently being used as a B cell-depleting agent in renal transplantation (RTx). However, the incidence of infectious complications associated with rituximab therapy remains uncertain. We evaluated the incidence of cytomegalovirus (CMV) infection associated with rituximab therapy in RTx. A total of 83 patients were enrolled. The immunosuppressive regimen consisted of tacrolimus or cyclosporin, mycophenolate mofetil, methylprednisolone and basiliximab. In 54 patients, only one dose of rituximab (200 or 500 mg/kg body weight) was given before RTx. A total of 25 of 43 (58.1%) recipients who were CMV seropositive prior to RTx and who received rituximab induction therapy developed CMV infection, compared to 18 of 24 (75%) CMV seropositive recipients who did not receive rituximab therapy ( P  = 0.1676). A total of 8 of 11 patients who were CMV seronegative prior to RTx and who received rituximab developed CMV infection. However, CMV seroconversion was seen in all 8 of these infected patients. Low-dose rituximab induction therapy in renal transplant recipients appears to have no influence on the incidence of CMV infection and CMV seroconversion. However, we have to consider anti-CMV prophylaxis therapy, because of high incidents of CMV infection, especially for CMV seronegative recipients who received rituximab.     

Cytomegalovirus infection complicating renal transplantation and its relationship to acute transplant glomerulopathy

The incidence of cytomegalovirus (CMV) infection was established, using laboratory criteria, in 298 patients receiving 362 renal allografts (164/298 = 55%). The incidence of CMV infection did not differ between azathioprine/prednisolone-treated and cyclosporine-treated patients (55% vs. 57% NS). The use of antithymocyte globulin (ATG) increased the incidence of CMV infection (78% vs. 51%: P less than 0.01). Donor and recipient CMV status, known for 116 allografts, did not correlate with the incidence of CMV infection (recipient CMV-positive = 50%; recipient CMV-negative = 54%: NS). CMV infection was responsible for 8 patients' deaths (2.7% mortality). Thirty-three patients with acute transplant glomerulopathy were identified (11%). There was no correlation between acute transplant glomerulopathy and CMV infection. Glomerulopathy was associated with poor graft survival (22/33 patients with a graft survival of less than 6 months). Thus CMV infection, although a common complication of renal transplantation with significant morbidity and mortality, is not closely associated with acute transplant glomerulopathy. Further, the lack of correlation of donor-recipient CMV serologic status with graft outcome limits the usefulness of pretransplantation donor screening.     

Chronic rejection in renal transplantation

With renal transplantation, chronic rejection is currently the most prevalent cause of late transplant failure. Clinically, chronic rejection presents as chronic transplant dysfunction, characterized by a slow loss of function, often in combination with hypertension and proteinuria. Transplant glomerulopathy and multilayering of the peritubular capillaries are highly characteristic for chronic rejection. Risk factors have been identified and include young recipient age, black race, presensitization, histoincompatibility, and acute rejection episodes, especially vascular rejection episodes and rejections that occur late after transplantation. Chronic rejection develops in grafts that undergo intermittent or persistent damage from cellular and humoral immune responses resulting from indirect recognition of alloantigens. Progression factors such as advanced donor age, renal dysfunction, hypertension, proteinuria, hyperlipidemia, and smoking play an important role. At the tissue level, senescence conditioned by ischemia/reperfusion may contribute to the development of chronic rejection. The most effective option to prevent renal failure from chronic rejection is to avoid graft injury from both immune and nonimmune mechanism together with nonnephrotoxic maintenance immunosuppression.     

Chronic rejection in renal transplantation

Chronic rejection in renal transplantation is an alloantigen-dependent immune process ultimately leading to graft failure. We reviewed the literature on the basis of the case history of a patient who lost her renal allograft apparently from chronic interstitial rejection. Chronic rejection presents clinically as chronic transplant dysfunction starting at various intervals after transplantation. The histopathologic features consist of chronic allograft nephropathy with or without transplant vasculopathy or glomerulopathy. Chronic rejection should be differentiated from chronic toxicity of calcineurin inhibitors, de novo or recurrent glomerulonephritis, polyoma (BK) virus nephropathy, transplant renal artery stenosis, and nephrosclerosis. Young recipient age, black race, presensitization, histoincompatibility, and acute, especially vascular, and late acute rejection episodes are dominant risk factors, compatible with immunologic mechanisms. Cellular and humoral responses resulting from indirect recognition of alloantigens with subsequent fibrotic sequelae play a central role in the pathogenesis. Circulating donor-specific antibodies and staining for C4d can detect humoral chronic rejection. The prognosis depends on alloreactivity and the presence of progression factors such as old donor age, renal dysfunction, proteinuria, hyperlipidemia, and smoking. A multifactorial approach directed to the risk and progression factors is needed to prevent premature graft loss from chronic rejection.     

Cytomegalovirus infection in orthotopic liver transplantation

We retrospectively studied 175 orthotopic liver transplants in 151 patients. Of the 151 patients, 59 (39.1%) were diagnosed as having cytomegalovirus (CMV) infection. The rate of infection in patients treated for rejection was 48.8% as compared to 26.2% in patients without rejection (P less than 0.01). Antirejection therapy was associated with culture-positive cases in 33 out of 43 patients as compared to 9 out of 16 patients who had CMV antibody titer elevations. Patients were treated with gancyclovir if they had simultaneous positive cultures from multiple sites and were seriously ill. Eighteen of the 19 patients thus treated had side effects, one of which was serious (bone marrow hypoplasia). Cultures became negative in 15 out of 17 (88%) of the surviving patients. Patient survival was similar to our overall survival rate of 87%.     

KIR gene and KIR ligand analysis to predict graft rejection after renal transplantation

BACKGROUND: The identification of transplant patients at high risk for rejection after reduction of immunosuppression would allow minimization of immunosuppression and avoidance of side effects in low-risk patients. Next to T cells, innate natural killer (NK) cells may contribute to graft rejection. NK cell activation depends on the balance between activating and inhibitory signals, delivered by self-human leukocyte antigens (HLA) through binding of killer-cell immunoglobulin receptors (KIR). In transplantation, KIR and/or HLA mismatching may lead to NK cell activation. METHODS: In this study, we have evaluated whether acute rejection after reduction of immunosuppression after renal transplantation was associated with peripheral blood NK cell frequencies or with predicted NK cell alloreactivity based on KIR gene and ligand analysis. HLA and KIR genotyping was used to analyze the presence of single KIR genes and haplotypes, and to predict NK cell alloreactivity based on the "missing self" and "missing ligand" hypothesis. NK cell frequencies were analyzed using flow cytometry. RESULTS: No association was found between NK cell alloreactivity based on KIR gene analysis or peripheral blood NK cell subset frequencies and the occurrence of acute rejection after reduction of immunosuppression. CONCLUSIONS: Our data suggest that in a setting where immunosuppression is reduced, prior analysis of NK cell reactivity cannot identify patients at risk for subsequent graft rejection.