Infection and Cancer Following Renal Transplantation

Ever increasingly potent but non-specific immunosuppression has necessarily brought with it the continuing risk of opportunistic infections and virus-induced malignancies. The improvement in graft and patient survival rates from transplantation has depended to a certain extent on parallel improvements in the diagnosis and treatment of infectious complications. This review will highlight some of the current problems and progress. The risks of infection are largely related to the total burden of immunosuppression rather than any particular drug, although sirolimus and the anti CD25 antibodies may be an exception. Almost all the post-transplant infections are treatable; a precise microbiological diagnosis is essential so that specific therapy can be used. Newer molecular diagnostic techniques are increasingly widely available, e.g.quantitative polymerase chain reaction. The transplant community will inevitably be faced with highly resistant bacteria such as. Methicillin resistant Staphylococcus Aureus (MRSA) and will have to develop appropriate strategies. New infectious organisms continue to be identified [e.g. Burkitt′s Virus (BKV), West Nile virus and Avian influenza) and will continue to tax the ingenuity of transplant physicians and microbiologists

Prospective study of human betaherpesviruses after renal transplantation: Association of human herpesvirus 7 and cytomegalovirus co-infection with cytomegalovirus disease and rejection

Background. Human herpesvirus 6 (HHV-6) and HHV-7 are two lymphotropic herpesviruses, which, like cytomegalovirus (CMV), have the potential to be pathogenic in immunocompromised individuals. We have conducted a prospective investigation to compare the natural history of HHV-6 and HHV-7 infection with that of CMV after renal transplantation. Methods. Polymerase chain reaction was used to identify infections and quantify the viral load of CMV, HHV-6, and HHV-7 in peripheral blood samples from 52 renal transplant recipients. Betaherpesvirus infections were related to defined clinical criteria obtained by detailed examination of the clinical records of each patient for the immediate 120-day posttransplant period. Results. CMV was the most commonly detected virus after transplant (58% of patients), followed by HHV-7 (46%) and HHV-6 (23%). Examining the time to first polymerase chain reaction positivity, HHV-7 infection was detected earlier than CMV (P =0.05). The median maximum CMV viral load was significantly higher than those for HHV-6 (P =0.01) and HHV-7 (P <0.0001) and a trend for HHV-7 viral load to be greater than HHV-6 (P =0.08). Clinicopathological analyses revealed that, in those patients with rejection, HHV-7 was associated with more episodes of rejection (P =0.02). In addition, there was a significant increase in CMV disease occurring in patients with CMV and HHV-7 co-infection compared to those with CMV infection only (P =0.04). Conclusions. HHV-7 should be further investigated as a possible co-factor in the development of CMV disease in renal transplant patients and may potentially exacerbate graft rejection. No clear pathological role was observed for HHV-6

Extensive human cytomegalovirus (HCMV) genomic DNA in the renal tubular epithelium early after renal transplantation: Relationship with HCMV DNAemia and long-term graft function

Human cytomegalovirus (HCMV) infection is associated with a series of direct and indirect effects following renal transplantation. However, the presence of HCMV in the kidney and its relationship with acute rejection and long-term graft function remain to be fully elucidated. Sixty-two biopsies derived from 30 renal transplant recipients with signs of clinical rejection were analyzed for HCMV using a sensitive in situ DNA hybridization method. Biopsies were also subjected to staining with anti-C4d antibodies and an anti-caspase 3 antibody to detect humoral rejection and apoptosis, respectively. In 21 patients, serial serum creatinine levels over 5 years of follow-up were analyzed. HCMV DNA was detected in biopsies from 21/30 (70%) of the patients and 32/62 (52%) of the individual biopsies. HCMV DNA was detected early after transplant and was localized to renal tubule epithelial cells but not associated with apoptosis. HCMV DNAemia developed within 2 weeks of detecting HCMV DNA in the biopsy in 53% of patients. Ninety percent of patients experiencing HCMV disease had HCMV DNA in their biopsy. HCMV DNA was equally distributed between patients with or without histological evidence of acute rejection and was detected more frequently in patients with peritubular C4d deposits. Creatinine levels at 12 months post-transplant were significantly higher in patients with HCMV DNA and remained elevated over the 5 years of follow-up. HCMV DNA is frequently detected in renal tubular epithelial cells early after renal transplantation, precedes DNAemia and is associated with poor long-term graft function

Modelling cytomegalovirus replication patterns in the human host: factors important for pathogenesis

Human cytomegalovirus can cause a diverse range of diseases in different immunocompromised hosts. The pathogenic mechanisms underlying these diseases have not been fully elucidated, though the maximal viral load during infection is strongly correlated with the disease. However, concentrating on single viral load measures during infection ignores valuable information contained during the entire replication history up to the onset of disease. We use a statistical model that allows all viral load data sampled during infection to be analysed, and have applied it to four immunocompromised groups exhibiting five distinct cytomegalovirus-related diseases. The results show that for all diseases, peaks in viral load contribute less to disease progression than phases of low virus load with equal amount of viral turnover. The model accurately predicted the time of disease onset for fever, gastrointestinal disease and pneumonitis but not for hepatitis and retinitis, implying that other factors may be involved in the pathology of these diseases