A Time Table for Infections After Renal Transplantation in the Tropics

Infections are a major cause for mortality and morbidity in renal transplant recipients all over the world. In the tropics, infections account for the majority of deaths in the transplant population (1). Published accounts on the chronological appearance of various infections have helped physicians target investigative protocols and empirical treatment based on the probability of disease at varying intervals after transplantation. Risk of infection is determined by epidemiologic exposure to the infective agents and the net state of immunosuppression (2, 3). Even though the immunosuppressive protocols at this center are similar to those in the developed western countries, the added immunosuppression caused by concomitant infections, undernutrition, and organ dysfunction are different, as is the environmental exposure to various infective agents. The sequence of infections encountered after transplantation in this center is reported. From 1986 to 1994, 920 patients received living-related renal allografts. Low-dose prednisolone and azathioprine were employed initially, and cyclosporine-based immunosuppression was used since 1989 (4). Prednisolone-azathioprine-cyclosporine schedule consisted of oral prednisolone 20 mg/day from days 0 to 90. Azathioprine 1-1.5 mg/kg from days 0-5 was adjusted as per leukocyte response. Oral cyclosporine was initiated at a dose of 8 mg/kg on day 0 and tapered to 2 mg/kg by the 180th day. For the prednisolone-cyclosporine group 20 mg of prednisolone was given from days 0 to 90. Then it was tapered to a maintenance dose of 10 mg by the 180th day. Oral cyclosporine was initiated at 12 mg/kg on day 0 and reduced to 10 mg/kg by day 15. It was tapered to 3 mg/kg by the 180th day. Cyclosporine doses were modified as per cyclosporine blood levels (whole blood Enzyme Immuno Assay Syva, San Jose, Ca) in association with clinical features. The conventional immunosuppression consisted of azathioprine 2-2.5 mg/kg/day started on days 0-5 and modified by leukocyte response; 100 mg of prednisolone was started on day 0, reduced to 20 mg/day by the 28th day, and tapered to 10 mg by the 180th day. Acute rejections were treated with i.v. methylprednisolone 1 g on 3 consecutive days. Acute vascular rejections in patients receiving conventional therapy were treated with cyclosporine (5). Cyclosporine was added at a dose of 5 mg/kg/day, reduced to 4 mg/kg/day by 4 weeks and 3 mg/kg/day by 8 weeks. All patients were seen frequently for the first 6 months, then at the 9th month and 12th month. Thereafter, yearly followup was advised with earlier visits in case of complications. Our patients originate from all the states of India and neighboring countries like Nepal, Bhutan, Bangladesh, and Srilanka. Because communications were difficult and distances vast, all our transplant recipients stayed at Vellore for 6 months after surgery. Our policy was to discontinue cyclosporine at the end of 1 year. Hence, the followup at 6 months was 100%, 9th month about 80%, and 12th month 95%. Subsequent followup falls to about 40%; however, patients communicate with us or come to the center in case of major medical problems. Patients with fever of unknown origin or features of organ involvement had appropriate tests. The transplant-disease interval in 9 important infective syndromes is presented in Table 1 and charted (Fig. 1). Rubin categorized infections as those occurring within 1 month, 2-6 months, and thereafter. The first group included urinary infections, vascular access, catheter, and surgery related infections. In our patients also, urinary tract infections clustered around the first month, which was free from opportunistic infections. Pneumocystis carinii pneumonia was first seen in 1991 (6). Of the 12 cases a later report indicated that 9 manifested the disease within 6 months of transplantation (7). Cryptococcal infections occurred after 6 months of transplantation in all but one case who had received added immunosuppression (8). All the above findings fit into Rubin's schema. Thirty cases of deep mycoses encountered included candida (13), zygomycetes (11), aspergillus (10), and one each of histoplasma, T. bigelii, C. globosum(9), individually or in various combinations. There were 17 cases of nocardiosis. There was no significant difference in the number or type of risk factors like renal failure, liver disease, hyperglycemia, extra immunosuppression, or leucopenia contributing to the development of these two infections before or after 6 months. The sixth month marks the beginning of maintenance immunosuppression but does not influence the occurrence of these two groups of infections. The environmental exposure factor was highlighted by the large number of patients with posttransplant tuberculosis. This appears to occur earlier in cyclosporine-treated patients as compared with those receiving azathioprine and prednisolone immunosuppression (4)(Table 1). HBsAq positivity in our hemodialysis population is 40-50% (10), and in the absence of cirrhosis or portal hypertension was not considered, as a contraindication for transplantation, hence this was a risk factor even in the early posttransplant period. The overall risk of posttransplant tuberculosis increased 4-fold in patients with chronic liver disease and 2-fold in those with hyperglycemia. Varicella-zoster was seen 24.5±15.7 months after surgery and is an endemic disease in southern India with a bimodal peak incidence annually among staff and students of this hospital (11). Despite these epidemiologic features only one was infected during the first 6 months. Five patients without clinical leprosy at transplantation had the disease from 3.5 years after transplantation. Leprosy can occur 5 years after transplantation as has been reported from Brazil (12). In summary our experience validates Rubin's observations and provides further information on tuberculosis, M. leprae, and varicella-zoster infections prevalent in the tropics. We found that the 6th month milestone did not demarcate the onset and susceptibility in our patients, which appeared as a continuum from the first month. This may reflect an altered balance between the compromised host and the environmental risks.