Kidney transplant: immunosuppression and the resurgence of viral infections
Monday, 6 April 2009- Prophylaxis decreases the rate of cytomegalovirus (CMV) disease, infections and global mortality whilst increasing long-term graft survival amongst kidney transplant patients. This was amongst the key messages given by Prof. Enrique Lledo-Garcia (Madrid, Spain) during a section meeting held under the auspices of the 24th Annual EAU Congress in Stockholm, Sweden.
"New drugs as valganciclovir offer better results and bioavailability for CMV infections," said Lledo-Garcia who spoke during the meeting of the EAU Section of Transplantation Urology (ESTU). Lledo-Garcia noted that infectious complications after kidney transplantation remain an important cause of morbidity and mortality.
"The introduction of more potent immunosuppressive agents including tacrolimus (Tac) and mycophenolate mofetil (MMF) may result in resurgence of certain infections," he said. "Viral ethiologies constitute the single most important class of infection in transplant recipients."
In his lecture he gave an overview on the main viral infections in the context of kidney transplantation such as CMV, BK virus , Epstein-Barr virus, HHV-6 and respiratory virus.
According to Lledo-Garcia, the incidence of cytomegalovirus (a herpes virus that causes infection in 30% -80% of transplant patients) and the presence of symptomatic disease vary depending on transplant type, the presence of associated risk factors and the prevention strategies used.
He added that the main risk factor for CMV disease in solid organ transplant is transplantation from a seropositive donor (D+) to a seronegative recipient (R-) (D+/R-) or so-called ‘mismatched’ transplantation. Secondary high-risk patients are those receiving antilymphocite antibodies (induce ractivation of infections: EBV, CMV) and patients who experience acute rejection episodes.
He noted that the use of syrolimus (OR 0.2) as immunosuppressor is the main protective measure, and said that the period with the highest risk of CMV infection is from the first to the sixth month, with peak at the third month. Furthermore in primary infection, the lack of specific immunity of the patient allows a significant replication of CMV and symptomatic infection.
Moreover, CMV infections have also indirect effects caused by inflammatory response which impairs the immune capacity of the host. CMV cases are also linked with other hospital acquired infections (bacterial-fungal) and opportunistic infections (including other virus: herpes simplex, varicella-zoster, Epstein-Barr, human-herpes) and the development of graft rejection.
Lledo-Garcia added there are two main ways to prevent CMV disease, namely: pre-emptive therapy which includes regular monitoring using CMV PCR to detect the presence of CMV and, when tests are positive based on a defined cut-point, antiviral treatment is started. Prophylaxis is another crucial preventive measure, with the use of an antiviral drug that is continuously administered during the period of greatest risk following the transplant.
In relation to the treatment of established disease, he said the most important concept in CMV is the introduction of new drugs.
"New drugs are being introduced as new alternatives to ganciclovir with similar efficacy. In fact combined treatment with Ganciclover ev followed by valganciclovir has been reported recently as effective with a 95% success compared to an 84%- 86% success in monotherapy schedules," Lledo-Garcia said.
Human polyomaviruses BK and JC infect 80-100% of individuals in childhood, establishing persistent-subclinical infection predominantly in the kidney. In compromised hosts, BK virus (BKV) primarily causes disease in the urinary tract. Furthermore, in kidney transplant patients BK virus has been associated with ureteral stenosis, hemorrhagic cystitis and most frequently, virus-associated nephropaty.
“There are no effective drugs to cure tBK virus disease…the best therapeutic option is the reduction in immunosupression,” said Lledo-Garcia, adding that pre-emptive reduction in inmunosupression is based on quantitative BKV PCR on plasma results
Epstein-Barr Virus (EBV)-positive transplant patients are particularly at risk of developing post-transplant lymphoproliferative disease (PTLD) related to intensive immunosuppressive treatment to prevent graft rejection
Around 1% to 10% of solid organ transplant recipients develop post-transplant lymphoproliferative disorders (PLTDs). Early identification of patients at high risk of developing PTLD allows the adoption of pre-emptive strategies. Moreover, timely diagnosis of PTLD may improve the outcome of patients.
HHV-6 Gastro-Intestinal disease
Regarding HHV-6 gastro-intestinal disease, Lledo-Garcia noted that HHV-6 is not a significant problem in kidney tranpslant patients in comparison to liver transplant patients
In his concluding remarks, Lledo-Garcia reiterated that the use of potent immunosupressors (TAC-MMF) result in resurgence of viral infections, and that BKV nephritis risk should be screened in kidney transplant patients by quantitation of BKV DNA-PCR in urine and plasma, underscoring that the only effective tool against BKV implies reduction in immunosupression
"Early identification of patients at risk of developing PTLD-EBV is of utmost importance, particularly those kidney transplant patients with high and maintained plasma EBV load," he added.