Tuberculosis (TB) is the leading cause of infectious mortality and morbidity in the world, second only to coronavirus disease 2019. Patients with chronic kidney disease and kidney transplant recipients are at a higher risk of developing TB than the general population. Active TB is difficult to diagnose in this population due to close mimics. All transplant candidates should be screened for latent TB infection and given TB prophylaxis. Patients who develop active TB pre- or post-transplantation should receive multidrug combination therapy of antitubercular therapy for the recommended duration with optimal dose modification as per glomerular filtration rate.

Tuberculosis (TB) is a common infection in chronic kidney disease. The prolonged therapy of TB can delay kidney transplantation in patients on antitubercular therapy (ATT).

This was a retrospective single-center study to analyze the safety of kidney transplantation and its outcomes in patients undergoing transplantation while on the continuation phase of ATT.

Between 2013 and 2022, 30 patients underwent kidney transplantation while on ATT. Median age was 38 years and 70% were males. Majority of the patients (86.7%) had extrapulmonary tuberculosis, most common site of involvement being tubercular lymphadenitis. 14/30 patients had microbiological/histopathological diagnosis of TB and the rest were diagnosed by ancillary tests. Patients were treated with 4 drug ATT (isoniazid, rifampicin, pyrazinamide, ethambutol) before transplantation for aminimum of 2 months. Post-transplantation fluoroquinolone-based non-rifamycin ATT was used (median duration 11 months). All patients completed therapy. At 2 years, there was 100% patient survival and 96.7% graft survival. Median eGFR at 6, 12, and 24 months post-transplantation was 71.9, 64.7, and 67 mL/min/1.73m2, respectively. The percentage of patients suffering a biopsy proven acute rejection at 6, 12, and 24 months was 3.3%, 6.7%, and 6.7%.

Kidney transplantation can be done in patients with TB who have a satisfactory response to the intensive phase of the ATT. The decision for transplantation while on the continuation phase of ATT should be individualized. In our experience, there is excellent patient and graft survival in these patients with a low risk of failure of ATT or relapse of TB.

Solid organ transplant recipients have an increased risk of tuberculosis (TB). Due to the use of immunosuppressants, the incidence of TB among solid organ transplant recipients has been consistently reported to be higher than that among the general population. TB frequently develops within the first year after transplantation when a high level of immunosuppression is maintained. Extrapulmonary TB and disseminated TB account for a substantial proportion of TB among solid organ transplant recipients. Treatment of TB among recipients is complicated by the drug-drug interactions between anti-TB drugs and immunosuppressants. TB is associated with an increased risk of graft rejection, graft failure and mortality. Detection and management of latent TB infection among solid organ transplant candidates and recipients have been recommended. However, strategy to mitigate the risk of TB among solid organ transplant recipients has not yet been established in Taiwan. To address the challenges of TB among solid organ transplant recipients, a working group of the Transplantation Society of Taiwan was established. The working group searched literatures on TB among solid organ transplant recipients as well as guidelines and recommendations, and proposed interventions to strengthen TB prevention and care among solid organ transplant recipients.

Little is known about the change in drug level and the need for dose adjustment of calcineurin inhibitor when it is used with rifabutin in solid organ transplant (SOT) recipients. We aimed to analyze whether the drug level of tacrolimus significantly reduced after the use of rifabutin and to assess optimal adjustment of tacrolimus dose in SOT recipients.

Of the SOT recipients in a tertiary referral center in South Korea in 2000-2019, 50 patients who maintained an unchanged dose of tacrolimus after the use of rifabutin for treating mycobacterial disease were enrolled. Their medical records were reviewed retrospectively.

The mean age of the patients was 53.9 ± 11.5 years. The most commonly transplanted organ was the liver (66.0%). The most common indication of rifabutin use was for treating active tuberculosis (78.0%). After rifabutin initiation, the trough level of tacrolimus decreased significantly to the subtherapeutic range in 38 (76.0%) patients. The drug levels of these 38 patients dropped from 7.2 to 3.8 ng/mL (p < 0.001) after rifabutin treatment. In these patients, the median 1.5-fold increase in the tacrolimus dose was required to restore the drug level to the within-therapeutic range.

These findings indicate that careful tacrolimus drug-level monitoring and dose adjustment are necessary for most SOT recipients when rifabutin is administered for the treatment of mycobacterial disease. This article is protected by copyright. All rights reserved.

TB remains a major challenge in transplantation, particularly in endemic countries. This study aimed to describe the incidence, clinical presentation and outcomes of TB in paediatric kidney transplant recipients and to assess the impact of INH prophylaxis.

Single-centre retrospective descriptive analysis of children who received kidney transplants from 1995 to 2019 was carried out. The cohort was stratified according to receipt of INH prophylaxis which began in 2005.

A total of 212 children received a kidney transplant during the study period. Median age at transplantation was 11.2 years (IQR: 2.2-17.9), and 56% were males. TB was diagnosed in 20 (9%) children, with almost two-thirds (n = 12) occurring within the first year. Most infections were pulmonary. The main presenting symptoms included fever (n = 13/20), weight loss (n = 12/20) and cough (n = 10/20). TST was positive in four of 20 children. Coinfection with EBV, CMV or Staph was found in five children. Due to drug interactions, an up to threefold increase in calcineurin inhibitor dose was required to maintain therapeutic blood levels. INH prophylaxis was protective against development of TB (p = .04). Gender, age and type of allograft were not significant risk factors. Graft and patient survival was 100% upon completion of TB treatment.

Kidney transplant recipients in endemic countries have a high risk of developing TB. Diagnosis remains a challenge. Frequent and meticulous monitoring of immunosuppression drug levels during treatment of TB is required to avoid loss of patient or graft. INH prophylaxis protects against development of TB in this population.

Tuberculosis (TB) is a frequent infectious complication in patients on renal replacement therapy, as a result of immunosuppression from uremia and drugs in the post-transplantation period. A retrospective study of all renal transplantation patients from 1989 to date was conducted. This study tried to examine the prevalence, course, and outcome of TB in renal transplant recipients. A comparison with the occurrence of TB in other modalities of renal replacement therapy was also made. We also discussed the treatment protocols for TB in this group of patients. No difference in the prevalence, age, or male/female ratio of TB was seen among the 3 modes of renal replacement therapy. TB of the lung was the more favored site of infection in patients on hemodialysis (77.3%), when compared with those on CAPD (30%) and renal transplant recipients (33.3%). In renal transplant recipients, no deaths occurred due to TB. In 7 patients there was co-infection with cytomegalovirus and in 3 patients there was Aspergillus lung infection.

We describe a pediatric renal transplant patient with Mycobacterium bovis disease who was successfully treated using an antituberculosis regimen that included rifampin. We discuss the history of M. bovis and the diagnosis and management of M. bovis infection in renal transplant patients.

To assess the influence of the CYP3A4 enzyme inducer rifampin on the pharmacokinetics of the immunosuppressant everolimus to provide guidance for their coadministration.

In this open-label, single-sequence, crossover study, 12 healthy subjects received a single oral 4-mg dose of everolimus alone and again after an 8-day pretreatment with rifampin 600 mg/d. Urinary excretion of 6beta-hydroxycortisol was measured at various time points during rifampin treatment as a marker of CYP3A4 induction.

Urine excretion of 6beta-hydroxycortisol was significantly elevated during treatment with rifampin compared with prestudy, indicating enzyme induction. When everolimus was coadministered during rifampin treatment, the apparent clearance of everolimus was significantly increased, on average by 172%. This was manifested as a decrease in maximum concentration in all subjects, on average by 58% (range 14-73%). The AUC remained unaffected in 1 subject (although 6beta-hydroxycortisol indicated enzyme induction) and decreased in the other 11 subjects. The average decrease in AUC in the full study population was 63% (range 0-82%). Everolimus half-life was reduced significantly, from an average of 32 hours to 24 hours.

In everolimus-treated patients for whom rifampin is indicated, alternative agents with less enzyme induction potential than rifampin could be considered. Alternatively, the dose of everolimus could be individually titrated based on everolimus therapeutic drug monitoring during rifampin therapy.

Pharmacokinetic interactions involving anti-infective drugs may be important in the intensive care unit (ICU). Although some interactions involve absorption or distribution, the most clinically relevant interactions during anti-infective treatment involve the elimination phase. Cytochrome P450 (CYP) 1A2, 2C9, 2C19, 2D6 and 3A4 are the major isoforms responsible for oxidative metabolism of drugs. Macrolides (especially troleandomycin and erythromycin versus CYP3A4), fluoroquinolones (especially enoxacin, ciprofloxacin and norfloxacin versus CYP1A2) and azole antifungals (especially fluconazole versus CYP2C9 and CYP2C19, and ketoconazole and itraconazole versus CYP3A4) are all inhibitors of CYP-mediated metabolism and may therefore be responsible for toxicity of other coadministered drugs by decreasing their clearance. On the other hand, rifampicin is a nonspecific inducer of CYP-mediated metabolism (especially of CYP2C9, CYP2C19 and CYP3A4) and may therefore cause therapeutic failure of other coadministered drugs by increasing their clearance. Drugs frequently used in the ICU that are at risk of clinically relevant pharrmacokinetic interactions with anti-infective agents include some benzodiazepines (especially midazolam and triazolam), immunosuppressive agents (cyclosporin, tacrolimus), antiasthmatic agents (theophylline), opioid analgesics (alfentanil), anticonvulsants (phenytoin, carbamazepine), calcium antagonists (verapamil, nifedipine, felodipine) and anticoagulants (warfarin). Some lipophilic anti-infective agents inhibit (clarithromycin, itraconazole) or induce (rifampicin) the transmembrane transporter P-glycoprotein, which promotes excretion from renal tubular and intestinal cells. This results in a decrease or increase, respectively, in the clearance of P-glycoprotein substrates at the renal level and an increase or decrease, respectively, of their oral bioavailability at the intestinal level. Hydrophilic anti-infective agents are often eliminated unchanged by renal glomerular filtration and tubular secretion, and are therefore involved in competition for excretion. Beta-lactams are known to compete with other drugs for renal tubular secretion mediated by the organic anion transport system, but this is frequently not of major concern, given their wide therapeutic index. However, there is a risk of nephrotoxicity and neurotoxicity with some cephalosporins and carbapenems. Therapeutic failure with these hydrophilic compounds may be due to haemodynamically active coadministered drugs, such as dopamine, dobutamine and furosemide, which increase their renal clearance by means of enhanced cardiac output and/or renal blood flow. Therefore, coadministration of some drugs should be avoided, or at least careful therapeutic drug monitoring should be performed when available. Monitoring may be especially helpful when there is some coexisting pathophysiological condition affecting drug disposition, for example malabsorption or marked instability of the systemic circulation or of renal or hepatic function.

A 10-year-old girl with chronic myelogenous leukemia began receiving cyclosporine the day before bone marrow transplant surgery Three days after the transplant, she developed fever and neutropenia due to a Staphylococcus aureus bacteremia. Despite treatment with various antibiotics, the patient's fever persisted over the next 4 days. Intravenous rifampin was added to her antibiotic regimen of piperacillin, tobramycin, cloxacillin, and amphotericin. On day 12, the patient's blood cultures were negative and her fever had resolved; rifampin was discontinued. On day 16, the patient engrafted; she subsequently developed a grade II graft-versus-host disease of the skin and gastrointestinal tract, which responded to methylprednisolone. Her cyclosporine blood levels, which had been subtherapeutic since day 5 despite increasing intravenous dosages, were within the therapeutic range on day 21, and she was discharged 12 days later. To our knowledge, this is the first documented case of an intravenous cyclosporine-rifampin interaction that resulted in subtherapeutic cyclosporine concentrations in a child receiving a bone marrow transplant who subsequently developed acute graft-versus-host disease.

In this article, the authors have provided a comprehensive review of TB and MOTT infections in patients on renal dialysis and receiving kidney transplants. Because most published series are small retrospective studies or case reports, there are several uncertainties still involved in the diagnosis and treatment of such patients. Unanswered questions include selection of optimal dosage and duration of therapeutic agents; the best tests for screening and diagnosis, especially in high prevalence areas; and the best management of MOTT infections because of unavailability of highly effective therapy.

The objective of this section is to evaluate the contributions of hepatic metabolism, intestinal metabolism and intestinal p-glycoprotein to the pharmacokinetics of orally administered cyclosporine and tacrolimus. Cyclosporine and tacrolimus are metabolized primarily by cytochrome P450 3A4 (CYP3A4) in the liver and small intestine. There is also evidence that cyclosporine is metabolized to a lesser extent by cytochrome P450 3A5 (CYP3A5). Cyclosporine and tacrolimus are also substrates for p-glycoprotein, which acts as a counter-transport pump, actively transporting cyclosporine and tacrolimus back into the intestinal lumen. Traditional teaching of clinical drug metabolism has been that hepatic metabolism is of primary importance, and other sites of metabolism play a relatively minor role. It appears as though intestinal metabolism plays a much greater role in the pharmacokinetics of orally administered drugs than previously thought. Intestinal metabolism may account for as much as 50% of oral cyclosporine metabolism. There are at least two components of intestinal metabolism for cyclosporine and tacrolimus, intestinal CYP3A4/CYP3A5 and intestinal p-glycoprotein activities. The quantity of intestinal enzymes, although highly variable, do not appear to be the key to explaining the variability of oral cyclosporine pharmacokinetics in kidney transplant patients. However, the quantity of intestinal p-glycoprotein accounts for approximately 17% of the variability in oral cyclosporine pharmacokinetics. It may be that p-glycoprotein maximizes drug exposure to intestinal enzymes, thus decreasing the importance of enzyme quantity. Since cyclosporine's FDA approval in 1983, there have been many reports of clinically significant drug interactions of other agents when given concomitantly with cyclosporine. With the FDA approval of tacrolimus in 1994, a similar pattern of clinically significant drug interactions appears to be emerging. It seems that compounds that alter (either induce or inhibit) CYP3A4 and/or p-glycoprotein will alter the oral pharmacokinetics of cyclosporine and tacrolimus. It should be expected that, until further data are available, the drugs which interact with cyclosporine will also interact with tacrolimus.

Tuberculosis is unusual in transplant recipients. The incidence, clinical manifestations, and optimal treatment of this disease in this population has not been adequately defined. The present study was undertaken to assess the incidence, clinical features, and response to therapy of Mycobacterium tuberculosis infection in solid-organ transplant recipients.

We evaluated retrospectively the incidence, clinical characteristics, diagnostic procedures, antituberculous treatment, clinical course, and factors influencing mortality in 51 solid-organ transplant recipients who developed tuberculosis after transplantation. We also reviewed the world literature on tuberculosis in solid-organ transplantation.

The overall incidence of tuberculosis was 0.8%. The localization was pulmonary in 63% of the cases, disseminated in 25%, and extrapulmonary in 12%. Tuberculosis developed from 15 days to 13 years after surgery (mean, 23 months). In one third of the cases, diagnosis was not suspected initially, and in three cases, diagnosis was made at necropsy. Fever was the most frequent symptom, followed by constitutional symptoms, cough, respiratory insufficiency, and pleuritic pain. Fifteen patients (33%) developed hepatotoxicity during treatment; hepatotoxicity was severe in seven cases. Hepatotoxicity was higher in patients receiving four or more antituberculous drugs (50%) than in patients receiving three drugs (21%; P=0.03). Serum levels of cyclosporine decreased in the 26 patients under the simultaneous use of rifampin. Nine of them (35%) developed acute rejection, and five (56%) died, in comparison with 3 of 17 patients (18%) who did not develop rejection after the use of cyclosporine and rifampin (P=0.03). Although microbiological response was favorable in 94% of the 35 patients who completed 6 or more months of treatment, 16 other patients (31%) died before diagnosis or in the course of treatment. None of the patients treated for more than 9 months died as a consequence of tuberculosis, whereas the mortality rate was 33% among those treated for 6 to 9 months (P=0.03). Use of antilymphocyte antibodies or high doses of steroids for acute rejection before tuberculosis was associated with a higher mortality rate.

M tuberculosis causes serious and potentially life-threatening disease in solid-organ transplant recipients. Treatment with at least three drugs during 9 months or more, avoiding the use of rifampin, appears to be appropriate.

In vitro models are being used increasingly during all phases of the drug development process in concert with the more traditional in vivo toxicological and pharmacokinetic evaluations. These in vitro models may be classified empirically as either validated in vitro screens, value-added screens or 'ad-hoc' mechanistic screens. The application of these screens is discussed with respect to their level of validation, standardization, uses of human tissue, level of iteration with in vivo studies, regulatory position and utility in the drug discovery and development process. The predictability and reproducibility of these screens is discussed, as well as future trends in regard to emerging technology and its application.

To determine the prevalence and presentation of mycobacterial infection as well as the influence on outcome in graft function and patient survival in renal transplant recipients at our institution.

A retrospective review of case records of all renal transplant recipients from 1980 to 1992.

Groote Schuur Hospital, a large teaching hospital and regional tertiary referral center in Cape Town, South Africa.

During the period reviewed, 857 transplants were performed. The records of 487 patients who had remained in Cape Town were examined.

There were 22 cases of mycobacterial infection (21 confirmed or presumed Mycobacterium tuberculosis and 1 unidentified Mycobacterium other than tuberculosis). In seven cases, immunosuppression had been intensified within 3 months of diagnosis. The median time from transplantation to diagnosis was 14 months (range, 2 to 74). Chest radiograph findings included consolidation (14), miliary pattern (4), pleural effusion (3), tuberculoma (2), cavitation (2), and hilar lymphadenopathy (1). Diagnosis of tuberculosis was made on sputum smears (eight), pleural biopsy specimen (two), fine-needle aspiration (one), and fiberoptic bronchoscopy in ten cases (brushings, eight; transbronchial biopsy specimen, three). Extrapulmonary tuberculosis (in addition to pulmonary tuberculosis) occurred in five patients (tuberculous meningitis, one; renal tuberculosis, one; and dissemminated infection, four). Five of the seven patients in whom immunosuppression had been intensified had concurrent infections; two of these died and the remainder returned to dialysis within 6 months. All but one patient received three antituberculosis drugs, including rifampin and isoniazid, for between 6 and 18 months. At the end of the period of review, 12 (59 percent) patients were alive, 10 with functioning grafts and 2 receiving dialysis. Four patients died while receiving antituberculosis treatment, but death was only directly related to tuberculosis in one case.

Tuberculosis is an important infection in renal transplant recipients in Cape Town, but disseminated disease is less common than reported elsewhere.

Cyclosporin A is an essential immunosuppressive drug, but it is potentially toxic to the kidney and liver. Ursodeoxycholic acid, a hydrophilic bile acid, has been reported to improve cholestasis in liver disease in man. The purpose of this work was to examine whether tauroursodeoxycholate could reduce cyclosporin A-induced hepatic or renal injuries in the rat. After randomization into three groups (N = 8), rats received daily for 17 days: cyclosporin A intraperitoneally alone (30 mg/kg) or cyclosporin A intraperitoneally and tauroursodeoxycholate (60 mg/kg) by gavage; control received the cyclosporin A excipient. Under tauroursodeoxycholate, cholestatic parameters (bile flow, bile salt secretion, serum bile salts, serum bilirubin) improved significantly without affecting cyclosporin A blood levels, and excretion of the drug and its metabolites in bile increased by 47%. Serum creatinine levels were better preserved, although not significantly. These results show that tauroursodeoxycholate prevents cyclosporin A-induced cholestasis in long-term treatment in rats, possibly by facilitating the drug elimination in bile.

Rifampicin, an antituberculosis drug, is usually administered for 4 to 12 months with other antituberculosis drugs or medications from other classes. A potential for drug interactions often exists because rifampicin is a potent inducer of hepatic drug metabolism, as evidenced by a proliferation of smooth endoplasmic reticulum and an increase in the cytochrome P450 content in the liver. The induction is a highly selective process and not every drug metabolised via oxidation is affected. Case reports and studies have demonstrated enhanced metabolism of several drugs; most of these interactions are clinically important. At the start of rifampicin treatment, and again at the end, clinicians must check the dosages of any accompanying medications with which rifampicin may potentially interact. Monitoring of clinical response and blood drug concentrations is essential to adjust the drug dosage during rifampicin therapy. Rifampicin also interacts with cholephils such as bilirubin and bromosulphthalein. Its pharmacokinetics are reported to be altered by ethambutol, p-aminosalicylic acid (through its excipient component), ketoconazole, cyclosporin, clofazimine, probenecid and phenobarbital through one or other of the following mechanisms--impaired absorption of rifampicin, competition between the drug and rifampicin for hepatic uptake and altered hepatic metabolism of rifampicin. Most interactions affecting rifampicin have been relatively minor or are not expected to alter its therapeutic efficacy.

Part I of this article, which appeared in the previous issue of the Journal, considered the potential mechanisms of drug interactions with cyclosporin, and divided the interacting drugs into 2 categories. Drugs that decrease cyclosporin concentrations (e.g. anti-convulsants, rifampicin, etc.) were dealt with first; the authors then moved on to consider the second category, those that increase cyclosporin concentration (macrolide antibiotics, azole antifungal drugs). Part II continues the survey of this category.

Cyclosporine (CyA) is commonly prescribed as an immunosuppressive to prevent rejection of organ transplants. Numerous pharmacokinetic drug interactions of potential clinical significance exist because other drugs may induce or inhibit the metabolism of CyA. Case reports and studies demonstrate that rifampin, phenytoin, phenobarbital, and carbamazepine may induce the hepatic metabolism of CyA, causing decreased CyA concentrations. Graft rejection through inadequate immunosuppression may be associated with subtherapeutic or decreased CyA levels. Erythromycin, ketoconazole, calcium channel blockers, and sex hormones appear to inhibit CyA metabolism, causing increased CyA concentrations. Signs and symptoms of renal, hepatic, or neurotoxicity may be evident with increased or toxic CyA levels. Mutual inhibition of metabolism occurs between CyA and corticosteroids. Intravenous sulphadimidine and trimethoprim may cause decreased CyA concentrations by an unknown mechanism.