Ketoconazole inhibits cytochrome P 3A4, leading to a 10-fold increase in sirolimus blood levels. Although it has not been reported in the clinical setting so far, sirolimus and ketoconazole co-prescription can lead to cost saving by reducing the dose of sirolimus administered. After informed consent was obtained, sirolimus and ketoconazole co-prescription was studied in six patients who could not afford the current recommended doses. Patients received one-eighth to one-fourth of the recommended dose of sirolimus (0.25-0.5 mg) with 100 to 200 mg of ketoconazole. Sirolimus levels were monitored, and the dose of ketoconazole was increased to achieve target levels of sirolimus. The loading dose was 3 mg of sirolimus with 100 mg of ketoconazole. After sirolimus rescue therapy was started, serum creatinine decreased in five patients. The mean serum creatinine for the group decreased from 2.6 +/- 0.3 mg/dL at the initiation of rescue therapy to 2.2 +/- 0.5 mg/dL on the last follow-up. Sirolimus ketoconazole co-prescription with monitoring of sirolimus levels is possible and safe and needs to be explored further.

We assessed the bioavailability of cyclosporine (CyA) in the test formulation (Cap Arpimune ME) relative to the reference formulation (Cap Sandimmune Neoral) to ascertain the switchability between the two formulations in patients. The study population included 30 patients on maintenance hemodialysis awaiting renal transplantation. The study adopted a randomized open-label, two-way, two-period, two-sequence crossover design. The dose administered was 8 mg/kg/d in two divided doses for 5 days in each study period with a washout period of 1 week between the two periods. A five-point blood sampling (at 0, 1, 2, 3, and 4 hours postdose) was done on the last day of each study period for CyA level monitoring. The study measures included C(max) (maximum blood concentration), AUC (area under the blood CyA concentration versus time curve, 0 to 4 hours) and actual time concentrations at individual sampling times. The differences in mean values for all parameters and the least significant differences were less than 20% of reference mean. Assessment of bioequivalence using log-transformed data showed that the point estimate (ratio test: reference) for C(max) was 0.9717 with a 90% confidence interval (CI) of 0.88 to 1.06 and that for AUC was 1.0053 with a 90% CI of 0.90 to 1.12. The bioequivalence obtained suggests that the test formulation can replace the reference formulation in patients who require CyA therapy.

AIM: To study spectrum of biopsy proven renal disease (BPRD) and to look for any changing trends in renal disease in comparison to a previous study from this centre and other studies. MATERIALS AND METHODS: Retrospective analysis of the histopathological reports of all native kidney biopsies performed from 1990 – 2001 at this centre is presented (n=5258). Incomplete records (n=92) and inadequate biopsies (n=150) were excluded. Reports of the remaining biopsies 928 from children (<15 years) and 4035 from adults (15 and above) were analyzed and categorized into major histological patterns as proliferative glomerulonephritis (PGN), minimal Change Disease (MCD), focal and segmental glomerulosclerosis (FSGS), membranous nephropathy (MN), IgA nephropathy (IgAN), diabetic glomerulosclerosis (DG) and benign arteriolar nephrosclerosis (BANS). RESULTS: Most BPRD showed male preponderance except in systemic lupus erythematosus (17.5%) and cortical necrosis (40%). BPRD in children showed MCD (47.2%), FSGS (12.5%), mesangial PGN (11.3%), endocapillary proliferative GN (8.8%) and lupus nephritis (3.5%). The incidence of MPGN has declined to 2.6% in this study when compared to 7.2% between 1970 and 1985. Non-diabetic renal disease (NDRD) was seen in 72% diabetics who underwent a biopsy. PGN was seen in 40.7%, MCD 8.7%, FSGS 22%, MN 11%, BANS 6.8% and interstitial nephritis 6.8% respectively. Comparison of primary glomerulonephritis from the Italian registry of renal biopsies with the present study showed an increased incidence of IgAN, MN and MPGN in Italy, whereas MCD, FSGS, mesangial PGN and post infectious GN were significantly more common in the present study. CONCLUSION: This study provides descriptive epidemiological biopsy data and highlights some important trends in changing prevalence of renal disease.

Background. Systemic mycoses have a high impact on tropical renal-transplant recipients. Methods. Data from 1,476 primary renal-transplant recipients was prospectively recorded from 1986 to 2000 at a single center. Cumulative incidence of systemic mycoses, its time of occurrence, risk factors, outcome, and postmortem findings in 30 patients with systemic mycoses were analyzed. Results. A total of 110 episodes of systemic mycoses occurred in 98 patients. The fungal genera Aspergillus, Cryptococcus, and Candida constituted 61% of pathogens, 45% localizing to the lungs. Cytomegalovirus (CMV) disease caused a 5-fold and chronic liver disease a 2-fold increase in systemic mycoses. Tuberculosis (TB) with or without nocardiosis was a significant coinfection. Cyclosporine (CsA) was associated with nearly a 4-fold risk of systemic mycoses less than 6 months from the time of transplantation as compared with prednisolone+azathioprine (PRED+AZA) therapy. Overall, the probability of survival with systemic mycoses was 73.4%, 60.8%, 39.5%, and 25.6% and was 92.5%, 87.5%, 80.0%, and 75.5% without systemic mycoses at 1, 2, 5, and 10 years, respectively (P <0.0001). An extended Cox model with time-independent and dependent covariates showed greater than 15 times the risk of death among those who develop systemic mycoses. Similarly, Posttransplantation (postTX) TB±Nocardiosis, preTX TB, CMV disease, diabetes mellitus, PTDM, chronic liver disease (>40 months), and Pred+AZA immunosuppression (>2 years) had 3.5, 1.5, 2.9, 1.9, 1.4, 1.6, 2.3 times the risk for death, respectively, as compared with those who did not have those risk factors. Conclusions. There is a recent predominance of Aspergillus among the transplant recipients. The risk factors for systemic mycoses are CMV disease, chronic liver disease, and hyperglycemia, and TB is an important coinfection. Systemic mycoses increased in the early postTX period with CsA. The risk factors for death are systemic mycoses, CMV disease, chronic liver disease (>40 months), diabetes mellitus, and Pred+AZA immunosuppression (>2 years). Overall, the probability of survival with systemic mycoses was poor; however, survival has recently improved.

The availability of a microemulsion formulation (ME) of cyclosporin (CyA) displays improved bioavailability and reduced inter and intra-patient variability, resulting in improved long-term outcomes. Recent developments in therapeutic drug monitoring stress the need to optimize peak drug levels during the early posttransplant period to obtain long-term benefit.Method: We studied early CyA-ME pharmacokinetics, comparing pre- versus immediate posttransplant values, to assess predictability of pre-transplant profiles in 22 patients including 3 diabetics. An 8 mg/kg per day amount in two divided doses was administered, for 5 days pretransplant and 10-14 days posttransplant before performing the pharmacokinetic studies. Drugs interacting with CyA metabolism/absorption were withdrawn and patients with liver disease were excluded the CyA level monitoring used a 5-point blood sampling (at 0 hours, 1 hours, 2 hours, 3 hours, and 4 hours post-dose) The study compared actual concentrations at each individual time and the limited 0-4 hour AUC.Results: The paired values at each point pre- and posttransplant were: C0 = 171 +/- 63 and 215 +/- 112, C1 = 723.86 +/- 345 and 1239.95 +/- 415, C2 = 972 +/- 185 and 1249.95 +/- 336, C3 822 +/- 242 and 942.7 +/- 286, and C4 601.54 +/- 190 and 670.5 +/- 208 ng/mL respectively. The C1 and C2 values were significantly higher posttransplant (P = .008 and 0.0045 respectively), suggesting a steeper absorption phase, a conclusion consistent with the higher 0-4 hour AUC posttransplant (P = .0089). However, linear regression analysis of pre- versus posttransplant values showed poor correlations.Conclusion: CyA absorption is significantly lower among patients on maintenance hemodialysis and showed no predictive correlation with posttransplant levels. The possible role of uremia in retarding absorption which may have clinical significance for primary graft dysfunction, needs further evaluation.

BACKGROUND:GB virus C/hepatitis G virus (GBV-C/HGV) and TT virus (TTV) have been widely reported in patients with high parenteral risk such as haemodialysis and renal transplant recipients. The occurrence of these agents in association with hepatitis B virus (HBV) and hepatitis C virus (HCV), in Indian renal transplant recipients, is yet unreported. STUDY DESIGN:Molecular and serological markers of GBV-C/HGV and TTV were examined in addition to those for HBV, HCV and hepatitis D virus (HDV) in a selected group of seventy renal transplant recipients. HGV RNA detection was achieved using primers specific for the 5'NCR and NS5a regions of the genome. Anti-GBV-C/HGV antibody was detected using the mu plate anti-HG env kit (Roche, Germany). TTV DNA PCR was performed using primers specific for the coding region (method A) of the genome. In 50% of patients, TTV DNA was also tested for using primers specific for the non-coding region (method B). Host related factors such as age, alanine aminotransferase (ALT) levels, number of transfusions, haemodialysis sessions, and months following transplantation were also studied. RESULTS:Exposure rates to GBV-C/HGV, TTV (method A), HBV, HCV and HDV were 58.6, 32.9, 52.9, 54.3 and 2.9%, respectively. 'Active' infection as measured by viraemia and/or virus-specific antigenaemia for GBV-C/HGV, TTV, HBV and HCV was 52.9, 32.9, 15.7 and 52.9%, respectively. The majority of GBV-C/HGV and TTV infections were seen as co-infections with other hepatitis viruses. Single infection with GBV-C/HGV and TTV was seen in ten (14.2%) and eight (11.4%) patients, and was not associated with ALT elevation when compared to uninfected blood donors. Using univariate analysis, GBV-C/HGV RNA was significantly associated with > or =20 haemodialysis sessions. TTV DNA occurrence was not associated with any risk factors. CONCLUSIONS:There is a high occurrence of GBV-C/HGV and TTV in this select group of renal transplant recipients in India. These viruses mostly occurred in the context of co-infections with other hepatitis viruses. Long term effects of multiple hepatotropic viral infections need to be carefully documented in such transplant populations.

Background: The usefulness of serum cystatin C and serum β2-microglobulin (B2M) as markers of glomerular filtration rate (GFR) were compared in kidney donors before and after nephrectomy. Methods: Blood samples were taken from 28 donors (15 women and 13 men) for serum creatinine, urea, cystatin C and B2M estimation a median of 7 days before and 10 days after nephrectomy. Results: Estimated GFR decreased from a median of 86.2 mL/min/1.73 m2 to 60.3 mL/min/1.73 m2, a median decrease of 28.6%. Serum creatinine increased by 40% and urea by 30.4%; serum cystatin C increased by 31.2% and serum B2M increased by 65.6%. Using published data on biological variation, critical values were calculated. An increase in serum creatinine above 18 µmol/L detected the decline in renal function in 26/28 (92.9%) subjects. Increases in serum B2M greater than a critical value of 0.94 mg/L detected 24/28 (85.7%) of these subjects, but the critical value of 0.59 mg/L for cystatin C detected only 8/28 (28.6%). Conclusion: Using critical values, serial measurement of serum creatinine was better than serum B2M in detecting reduced renal function. Because of its large intraindividual variation, serial serum cystatin C estimation was very poor in detecting reduced renal function.

Background: The epidemiology of nocardiosis in the tropics among renal transplant recipients has not been reported.Methods: An evaluation of nocardiosis for 30 yr in one of the large transplant centres in South Asian region.Results: Of the 1968 patients who received primary renal allografts at Christian Medical College & Hospital, 27 patients developed nocardiosis over 30 yr. Early nocardiosis (less than or equal to 2 yr) was associated with chronic liver disease and the use of cyclosporin (CsA) as compared with its later occurrence (>2 yr). Seventeen patients (63%) had two or more associated post-transplant infections, of whom 10 had tuberculosis. Mortality in these patients was associated with chronic liver disease.Conclusions: Nocardiosis manifests earlier (<2 yr) in CsA treated patients who have chronic liver disease. Among renal transplant recipients of the tropics nocardiosis is a marker of a high susceptibility to tuberculosis and other infections, the association with tuberculosis is stronger in those developing early nocardiosis (<2 yr). Chronic liver disease is a risk factor for death in patients with nocardiosis especially when associated with tuberculosis. This report constitutes the largest single centre experience among renal transplant recipients.

Background & objectives Cytomegalovirus (CMV) disease in seroendemic transplant populations is due to reactivation of the virus, or reinfection. In this context, the antibody response is likely to influence presentation, clinical severity and outcome of the disease, and may provide a diagnostic and prognostic marker. This study was carried out in Indian renal transplant patients and healthy adults to characterize the antibody response to cytomegalovirus.Methods: Thirty three transplant recipients with CMV illness (symptomatology with IgM and/or nPCR positive status), 20 recipients who were asymptomatic in the 6 months of follow up after transplantation and 62 healthy controls were investigated for markers of CMV infection. These individuals were tested for IgG avidity and neutralizing antibody by ELISA techniques.Results: All 53 transplant recipients were found to have an IgG avidity index of > 50 per cent. Antibody to a CMV envelope glycoprotein gB/AD-1 (putative neutralizing antibody) was expressed as S/N ratio and was greater than or equal to5 in asymptomatic (65%) and symptomatic (27%) immunosuppressed renal transplant recipients. However, none of the 53 CMV IgG positive healthy controls were positive for neutralizing antibodies S/N ratio greater than or equal to5 (S/N ratio = sample mean OD/mean OD of 3 negative controls in each run). We observed the simultaneous presence of CMV PCR signal in leukocytes and neutralizing antibody (S/N ratio greater than or equal to5) in the plasma in 22 (41.5%) of the 53 renal transplant recipients.Interpretation & conclusions: In this study among the immunosuppressed transplant patients we observed an association between symptomatic disease and the relative absence of neutralizing antibodies. The neutralizing antibodies are less frequently demonstrable among controls; while appearance in a higher proportion of asymptomatic recipients especially in association with high IgG avidity (> 90%) is suggestive of its role in control of CMV disease despite reactivation as evidenced by DNAemia while on immunosuppressive therapy.

BACKGROUND:Post-transplant tuberculosis (post-TxTB) occurs in 12 to 20% of patients in India and results in the death of 20 to 25% of those patients. Prospective studies on post-TxTB are few. METHODS:Renal allograft recipients were studied prospectively for 3.1 (0 to 13.9) median (range) years for incidence, manifestations, risk factors, and prognosis for post-TxTB. Kaplan-Meier analysis was used to study the survival rates. The extended Cox proportional model for time-dependent covariates was used to measure the risk factors when the hazard was nonuniform. RESULTS:Of the 1414 patients considered for inclusion, multiple-transplant subjects (N = 37) and patients who developed pre-transplant TB (pre-TxTB; N = 126) were excluded from the study. The prevalence of post-TxTB was 13.3% (N = 166). The risk of post-TxTB when on cyclosporine (CsA) therapy was 2.5 (P = 0.0311) and 1.9 (P = 0.0430) times at < or =6 and < or =12 months, respectively, compared with patients on prednisolone plus azathioprine (PRED + AZA). The risk of post-TxTB in the presence of diabetes mellitus, chronic liver disease, and other co-existing infections [including deep mycoses, cytomegalovirus (CMV), Pneumocystis carinii pneumonia (PCP), nocardia] was 2.2 (P = 0.0011), 1.7 (P = 0.0010) and 2.4 (P < 0.0001) times, respectively. Of the 166 patients with post-TxTB, 53 patients died, and of those deaths, 17 (32%) were due to post-TxTB; 11 (65%) of the 17 had co-existing infections. The factors associated with death were HLA mismatches, PRED + AZA immunosuppression, pre- and post-TxTB, diabetes mellitus, post-transplant diabetes (PTDM), and other co-existing infections. The extended Cox model for death as the outcome variable showed the following to be significant risk factors: post-TxTB> 2 years (P = 0.0036), chronic liver disease> 6 years (P = 0.0457), PTDM> 5 years (P = 0.0729), diabetes mellitus (P = 0.0091), human lymphocyte antigen match < or =1 antigen (P = 0.0134), two to three antigens (P = 0.0448), and the presence of other co-existing infections (P < 0.0001). CONCLUSIONS:Cyclosporine therapy is associated with early post-TxTB. Diabetes mellitus and chronic liver disease are risk factors for post-TxTB. The occurrence of both pre-TxTB and post-TxTB (>2 years) along with hyperglycemia, liver disease, and other co-existing infections are important risk factors for death.

Background/Aims: The detection of viremia by polymerase chain reaction (PCR) in cytomegalovirus (CMV) infection in renal allograft recipients has been shown to have a predictive value for disease. However, its diagnostic utility in a population with high background seropositivity has not been defined. This prospective study was undertaken to assess the relationship of CMV DNAemia, and/or IgM seropositivity to CMV disease in a seroendemic transplant population. Methods: Consecutive patients undergoing renal transplantation between August 1997 and February 1998 were enrolled. Blood was sampled before transplantation from the donors and recipients for CMV serology and nested PCR for CMV DNA, and after transplantation from the recipients only at monthly intervals until 6 months. Patients were observed for the development of any CMV-like illness during follow-up. CMV DNA was quantitated using limiting dilution PCR on samples obtained from symptomatic patients at the time of illness and from asymptomatic patients at the end of their 6-month follow-up. Results: A total of 57 recipient-donor pairs were recruited. Immunosuppression was cyclosporine-based in 55 of 57 (95.6%). The CMV serologic status was D+R+ in 55 of 57 and D+R– in 2 of 57 pairs. PCR positivity indicating viremia increased from 5% before transplantation to 95% at 6 months after transplantation. Similarly IgM positivity reached 80% at 3 months and thereafter; positivity for any marker was 100% by 6 months. Viremia was sustained in over half the patients. The incidence of CMV-attributable disease peaked at 3 months, and was predominantly mild and self-limiting. Tissue-invasive disease appeared later in 4 patients (7%). Asymptomatic viremia was seen in 60–70% of patients at each sampling point. The positive predictive value (PPV) of PCR positivity for disease was 35–40%, and the negative predictive value (NPV), 90–100%. However, the high NPV was of use only in the early post-transplant period, negativity for markers declining rapidly with time. Quantitative assay showed significantly higher levels of CMV DNA in symptomatic patients (p = 0.01). A cutoff of 0.001 µg had a specificity of 95% and a PPV of 92.3% for symptomatic CMV disease. Conclusion: Qualitative tests to detect CMV DNAemia and IgM, although useful markers of viremia and active infection, have limited utility for the diagnosis of disease in a seroendemic transplant population. Quantitation of CMV DNAemia may play an important role in diagnosis in such a setting.

Although infection is the commonest central nervous system complication following renal transplantation, brain abscess is uncommon. Over the last 11 years, five renal transplant recipients who had brain abscesses were treated by computed tomography (CT)-guided stereotactic aspiration. Three patients had a fungal abscess, one a tuberculous abscess and the other had a methicillin-resistant Staphylococcus aureus abscess. One patient required a craniotomy for the excision of a fungal abscess which was persistent after two CT-guided stereotactic aspirations. The survivors in this group are the patient with a tuberculous abscess who is alive and well 5 years after diagnosis, and another with a dematiaceous fungal abscess (phaeohyphomycosis). CT-guided stereotactic surgery is minimally invasive, and can safely be performed in these patients. It often leads to an aetiological diagnosis in renal transplant recipients with brain abscesses. Specific antibiotic management directed towards the causative organism rather than empirical treatment can be instituted following the procedure. Although the ultimate prognosis in these patients is bleak even with specific antibiotic therapy, an occasional patient might have a good outcome with prompt and appropriate therapy.