Authors’ reply

We are grateful to Dr. Marcin Skowroński for his insightful comments on our manuscript1 and for raising additional questions. Due to word limit constraints, we were forced to omit certain details from our article. Here, we will try to clarify the remaining issues.

As noted by Dr. Skowroński, organ tuberculosis can be attributed to infection caused by various members of the genus Mycobacterium. In this particular case, M. tuberculosis was the identified pathogen, and the diagnosis was confirmed by microbiological examination of a sample taken from a focal lesion in the transplanted kidney. Regarding the diagnostic tests used, both the Ziehl-Neelsen–stained Acid Fast Bacilli Smear and the Bactec MGIT 960 system yielded positive results for M. tuberculosis. Susceptibility testing showed high susceptibility to pyrazinamide, ethambutol, isoniazid, rifampicin, and streptomycin. In addition, the Xpert MTB/RIF (Cepheid GeneXpert, Sunnyvale, California, United States) assay confirmed the presence of M. tuberculosis complex DNA and susceptibility to rifampicin, with no mutations found in the rpoB gene.

Regarding the search for tuberculosis in other organs, we would like to emphasize that according to the transplantation guidelines in force at that time, chest X-ray was performed 9 months before the transplantation and showed no abnormalities. The patient reported no respiratory complaints or known exposure to tuberculosis. To investigate the cause of recurrent fever of unknown origin, the patient underwent 2 computed tomography (CT) scans of the chest, at 4 and 9 months after the renal transplant. Both scans showed small, nonspecific pulmonary nodules ranging in size from 1 to 4 mm, predominantly in the right upper lobe (Figure 1A). There was no evidence of inflammation or lymph node enlargement. Based on a pulmonologist’s evaluation, there was no evidence of active pulmonary tuberculosis, and no further pulmonary testing was required. The lesions were characterized as post-inflammatory in origin.

Figure 1. A – computed tomography (CT) scan of the chest showing nonspecific pulmonary nodules, mostly in the right upper lobe (arrow); B – CT scan showing focal lesions in the patient’s kidneys (arrows), subsequently confirmed as bilateral renal cell carcinoma

In addition, abdominal CT scan was performed 4 months after the transplant as part of the diagnostic workup of fever. It revealed bilateral focal lesions in the patient’s kidneys (Figure 1B), which raised a suspicion of malignancy. Consequently, the patient underwent bilateral nephrectomy 8 months after the transplantation, which confirmed the presence of renal cell carcinoma (RCC) foci in both kidneys. Given the patient’s history of RCC, 18F-choline positron emission tomography / CT scan was performed. It showed no significant uptake of the radioactive tracer, with the exception of small accumulation in the left hilar and subcarinal lymph nodes.

Due to the absence of respiratory symptoms and nondiagnostic imaging results, after a pulmonary consultation, we decided not to pursue sputum or bronchial washings for microbiological analysis. All urine cultures were sterile.

To justify our therapeutic protocol, it is important to underscore that solid organ transplant recipients are at an increased risk of mortality and graft loss due to tuberculosis. Statistically, the risk is increased 10-fold, as compared with patients who are not immunocompromised.2 While randomized control trials are lacking, the optimal duration and regimen of therapy for renal allograft tuberculosis remains controversial.3 According to the available literature, prolonged treatment may be warranted in transplant recipients.4 In our patient, the treatment was extended due to ongoing immunosuppression and persistence of residual renal lesions on ultrasonography. The intensive phase of antituberculosis treatment with 4 antituberculosis drugs (pyrazinamide, ethambutol, isoniazid, and rifampicin) was administered for 12 months, followed by a 12-month continuation phase with isoniazid and rifampicin.

As pointed out by the author of the commentary, antituberculosis therapy can be associated with a variety of side effects, often necessitating changes in the treatment protocol.5 Our patient experienced transiently elevated levels of aminotransferases, with peak levels not exceeding 3 times the upper limit of normal (alanine aminotransferase, 102 IU/l; reference range [RR], 10–35 IU/l; aspartate aminotransferase, 90 IU/l; RR, 10–35 IU/l), in the absence of clinical hepatitis. After a hepatology consultation, adjustment of the antituberculosis drug dosages was deemed unnecessary. Early in the course of the treatment, tacrolimus dose adjustment was a challenge due to its pharmacokinetic interaction with rifampicin. However, during the treatment, we did not observe any graft rejection or tacrolimus-related nephrotoxicity.

The duration of antituberculosis therapy in this patient, although significantly prolonged, was carefully considered under the circumstances. Given the good graft function, concomitant need for immunosuppression, residual lesions in the transplanted kidney observed on ultrasound, and the patient’s excellent tolerance of the treatment, a prolonged course was considered a prudent strategy to increase the likelihood of durable disease remission and to prevent recurrence of allograft tuberculosis that might necessitate graftectomy.

We hope that the above details comprehensively address any uncertainties regarding this case. Should there be additional questions, we welcome further discussion.