Analysis of the clinical characteristics of patients who developed tuberculosis after renal transplantation

doi:10.21203/rs.3.rs-5299322/v1

Background

The early clinical diagnosis of tuberculosis (TB) in kidney transplant recipients is difficult, and TB is a major factor contributing to transplant failure and mortality in these patients. This study is to analyze the characteristics of patients who developed TB after renal transplantation in an effort to improve the diagnosis and treatment of such patients.

Methods

This retrospective study examined 100 patients who received kidney transplants and subsequently developed TB, and were then treated at the Hunan Chest Hospital from January 2014 to January 2024. The clinical characteristics of patients were examined, including general condition, time of TB onset, clinical manifestations, site of TB, immunological indicators, method of etiological detection, imaging findings, treatment, and outcome.

Results

Secondary pulmonary TB was the most common diagnosis overall (n = 76), and abdominal TB was the most common type of extrapulmonary TB (n = 8). Eighty-eight patients were tested by the interferon-gamma release assay (IGRA); 72 (81.8%) had positive results, 13 (14.8%) had negative results, and 3 (3.4%) had uncertain results. Twenty-six patients received the tuberculin skin test (TST); 7 (26.9%) had positive results and 19 (73.1%) had negative results. The overall etiological detection rate was 58.0%. Analysis of factors affecting outcome showed that patients who received an isoniazid + rifamycin + ethambutol + moxifloxacin regimen were more likely to achieve cure than those treated with an isoniazid + rifamycin + ethambutol + pyrazinamide regimen (P < 0.05).

Conclusions

Patients who develop TB after renal transplantation have atypical symptoms and imaging findings. In addition to conventional detection methods, the IGRA, TST, and biopsy may aid in diagnosis. The anti-TB regimen of isoniazid + rifamycin + ethambutol + moxifloxacin appeared to provide a better outcome in this group of patients.

Renal transplantation

tuberculosis

clinical characteristics

moxifloxacin

outcome

China has a high incidence of tuberculosis (TB), and TB has always been among the most common Class B infectious diseases in China^[1]. TB is a particularly serious concern for organ transplant patients, because they typically need long-term treatment with immunosuppressive drugs to prevent organ rejection. Thus, the incidence of TB in organ transplant recipients ranges from 1.2–15%, depending on the population^[2], and this is about 20- to 74-times higher than in the general population^[3]. Among all transplant recipients, the incidence of TB in kidney transplant recipients ranges from 0.6–2.6%, second only to lung transplant recipients^[3]. The early clinical manifestations of TB in kidney transplant recipients are not typical, and these patients may have negative results in the tuberculin skin test (TST), gamma interferon release assay (IGRA), TB antibody test, and sputum culture. The early clinical diagnosis of TB in kidney transplant recipients is therefore difficult, and TB is a major factor contributing to transplant failure and mortality in these patients^[4].

The purpose of this study was to retrospectively analyze the clinical data of 100 kidney transplant recipients who subsequently developed TB and were admitted to the Hunan Chest Hospital from January 2014 to January 2024 in an effort to provide information that can be used to improve the diagnosis and treatment of TB in patients who are kidney transplant recipients.

Patients and methods

Patients were eligible if they were recipients of allograft kidney transplantation, diagnosed with pulmonary or extrapulmonary TB after transplantation, and admitted to Hunan Chest Hospital (Changsha) from January 2014 to January 2024. All patients received treatment with long-term immunosuppressants after transplantation. The clinical characteristics of patients were examined, including general condition, time of TB onset, clinical manifestations, site of TB, immunological indicators, method of etiological detection, imaging findings, treatment, and outcome. This retrospective study was approved by the Ethics Committee of Hunan Chest Hospital (approval number:LS2024100901).

Diagnostic criteria for TB

Etiological diagnosis, which uses the results of multiple tests to identify a causative disease, is considered the gold standard for diagnosis of TB. Thus, according to established standards^[5], a patient with 3 or more of the 5 following characteristics was diagnosed with TB: (i) clinical manifestations and imaging results supporting a diagnosis of TB; (ii) a positive laboratory result from a TST or IGRA; (iii) a positive result from a polymerase chain reaction (PCR) test for Mycobacterium tuberculosis; (iv) exclusion of infection by pathogens other than M. tuberculosis; and (v) effectiveness of standard anti-TB therapy. All 100 patients were diagnosed with TB based on these criteria.

Treatment

All patients received standard anti-TB treatment after diagnosis. This treatment was guided by the principles of early initiation, regular dose and dosing schedule, full course of treatment (6 to 12 months), and use of standard drug combinations^[6]. Timely adjustment of the treatment plan and course were performed according to the site of infection and reaction to the different drugs. Timely adjustment of the use and dose of anti-rejection drugs was also performed according to measurements of their blood concentrations.

Statistical Methods

SPSS version 25.0 was used for statistical analysis. Continuous data were expressed as mean ± standard deviation, and the independent sample t-test or Mann-Whitney U test was used for comparisons. Categorical data were expressed as number (percentage), and the Chi-square test or Fisher’s exact test was used for comparisons. A P value below 0.05 was considered significant.

Clinical characteristics of patients

One hundred patients who developed TB after kidney transplantation were admitted to the Hunan Chest Hospital from January 2014 to January 2024. There were 82 males and 18 females, the age range was 17 to 67 years, and the average age was 44 ± 11 years. Ninety-six patients had one kidney transplant and 4 patients had two or more kidney transplants. Six patients had a history of contact with TB patients. Twenty-one patients had onset of TB less than 1 year after transplantation, 38 patients at 1 to 5 years after transplantation, 26 patients at 6 to 10 years after transplantation, 7 patients at 11 to 15 years after transplantation, 7 patients at 16 to 20 years after transplantation, and 1 patient at more than 20 years after transplantation.

Types of TB

Pulmonary TB was more common than extrapulmonary TB (Table 1). There were 58 patients with infection at a single site, 42 patients with infections at multiple sites, and 158 total sites with infection. Secondary pulmonary TB (n = 76) was the most common diagnosis overall, and abdominal TB (n = 8) was the most common diagnosis in patients with extrapulmonary TB.

Clinical manifestations

Sixty-five patients had fever and 64 patients had cough or sputum production (Table 2). The other symptoms were less common, and included shortness of breath, poor appetite, fatigue, night sweats, chest pain, chest tightness, weight loss, digestive tract symptoms (abdominal pain, diarrhea, abdominal distension, etc.), limb or joint swelling, hemoptysis, and nervous system symptoms (dizziness, headache, etc.). Seven patients were asymptomatic.

Detection of TB

Eighty-eight patients were tested by the IGRA; 72 (81.8%) had positive results, 13 (14.8%) had negative results, and 3 (3.4%) had uncertain results. Twenty-six patients received the TST; 7 (26.9%) had positive results and 19 (73.1%) had negative results. Fifty-one patients were positive in M. tuberculosis culture tests (38 from sputum, 11 from puncture fluid at various sites, 7 from alveolar lavage fluid, 2 from stool specimens, and 1 from a urine specimen). Thirty-seven patients were positive in PCR tests (28 from sputum, 8 from alveolar lavage fluid, 7 from puncture fluid at various sites, 1 in a stool specimen, and 1 in a urine specimen). There were also 17 positive results from the acid-fact bacteria (AFB) smear test (15 from sputum, 1 from alveolar lavage fluid, and 1 from puncture fluid).

Biopsy results

Five of the 100 patients received puncture biopsy (Table 3). This included 2 patients who received percutaneous lung biopsy, 1 who received bronchial mucosal biopsy, 1 who received axillary lymph node biopsy, and 1 who received thoracoscopic pleural biopsy.

Pulmonary imaging of patients with secondary pulmonary TB

We analyzed the medical imaging results (chest X-rays or computed tomography [CT] scans) of the 76 patients who had secondary pulmonary TB. Among these patients, 65 (85.5%) had nodules, 60 (78.9%) had plaques, 40 (52.6%) had mycobacterial cords, 25 (32.9%) had lymph node enlargement or calcification, 20 (26.3%) had pleural fluid, 15 (19.7%) had cavitation, 4 (5.3%) had the tree-in-bud sign, and 3 (3.9%) had a consolidation. Nine patients had infection only in the left lung, 11 patients had infection only in the right lung, and 56 patients had infections in both lungs. The lesions were confined to a single lobe in 17 patients (22.4%) and were in multiple lobes in 59 patients (77.6%).

Treatment and outcome

Each patient received a standard and individualized anti-TB regimen. Overall, 32 patients were cured, 66 were lost to follow-up due to various reasons (such as excessive adverse reactions to anti-TB drugs, financial difficulties, poor compliance, insufficient understanding of the disease), and 2 were still receiving treatment as of August 2024. We compared patients in the cure group and the lost to follow-up group to identify factors associated with outcome (Table 4). Patients who received treatment with isoniazid + rifamycin + ethambutol + moxifloxacin were more likely to achieve cure than those treated with isoniazid + rifamycin + ethambutol + pyrazinamide (P < 0.05).

The probability of TB infection in patients who received kidney transplantation is significantly higher than in the general population^[7]. Most kidney recipients received long-term hemodialysis and had prolonged anemia, and this can lead to dysregulation of lymphocytes and cytokines and immune dysfunction. Moreover, the long-term use of immunosuppressive drugs after transplantation further weakens the immune response, making these patients more vulnerable to infection by M. tuberculosis and other pathogens. In addition, many anti-TB drugs can lead to liver and kidney toxicity, and their interactions with immunosuppressive drugs can greatly complicate TB treatment for these patients. All of these factors greatly increase the TB-associated mortality rate of kidney recipients, which can be as high as 12–24%^[8].

Solid organ recipients need to take higher doses of immunosuppressants during the first year after transplantation, and studies in China and elsewhere reported that most patients diagnosed with TB after transplantation were infected within 12 months after transplantation^[9]. Among our 100 transplant patients, 21 developed TB within 1 year after transplantation, 38 developed TB at 1 to 5 years after transplantation, and the incidence was lower for longer periods after transplantation. Thus, the somewhat discrepant results of our study may be because all of our patients were treated at a single center in Changsha. However, consistent with most literature reports^[10], we found that secondary pulmonary TB was the most common diagnosis in patients who developed TB after kidney transplantation. Currently, it is believed that the symptoms of patients who develop TB after kidney transplantation are not typical, which may reflect dysfunction of the immune system and various inflammatory responses. This means that these patients develop clinical manifestations different from the classic TB symptoms, and some patients may even have no symptoms^[11].

The IGRA and the TST can provide a diagnostic basis for treatment of TB in patients whose symptoms are not obvious and who lack definitive evidence from chest imaging. According to most reports, the IGRA has higher sensitivity and specificity than the TST in populations with normal immune function and in solid organ recipients^[12–14]. In our study, the positive rate of IGRA (80.4%) was significantly higher than that of TST (29.2%). The IGRA is more objective than the TST and is not affected by BCG vaccination and most non-tuberculous mycobacteria^[13]. However, presumably due to the suppressed immune function of patients after kidney transplantation, both tests led to false negatives, so a negative result in such patients should not necessarily exclude a diagnosis of TB.

Etiological detection, with the use of results from multiple tests to identify a causative disease, is standard for the diagnosis of TB, and the main methods are TB smear, TB bacillus culture, and molecular biological detection^[15]. The etiological detection rate of all cases in this study was 58.0%, significantly higher than 33.3% reported in literature^[9]. This may be related to the use of various invasive examinations, such as various puncture fluids, bronchoscopic alveolar lavage fluid, percutaneous lung puncture biopsy, bronchoscopic bronchial mucosa biopsy, and lymph node puncture pathological biopsy. Therefore, invasive examinations appear to improve the detection rate of M. tuberculosis in patients who develop pulmonary TB after kidney transplantation.

For patients with negative TB test results, a chest CT is still the main means of diagnosing TB^[16]. Our examination of the chest imaging features of 76 patients with secondary pulmonary TB indicated the main imaging findings were nodules, plaques, and mycobacterial cords. Cavitation and the tree-bud-sign were rare, even though these findings are common in TB patients who are not transplant recipients. Our findings are consistent with a previous study^[17]. Thus, when TB infection is suspected after solid organ transplantation, we suggest that the pulmonary imaging findings should be closely followed to avoid misdiagnosis or missed diagnosis.

We divided patients into a cured group and a lost to follow-up group, and then analyzed factors affecting outcome. These two groups had no significant differences in gender, age, number of transplants, time of TB onset, and single site vs. multiple site infections. However, our sample size was relatively small, and more data are needed for further analysis of this topic. Expert consensus recommends that the anti-TB treatment of transplant recipients should be similar to that of the general population, and the regimen of isoniazid + rifampicin + ethambutol + pyrazinamide should be adopted^[18–20]. Fluoroquinolones such as moxifloxacin also have a good anti-TB effect, and have little impact on liver and kidney function^[9]. Moreover, there is very little moxifloxacin metabolism in kidneys, so this drug could be considered a suitable alternative for kidney transplant recipients^[9]. In the present study, our comparison of the treatment regimens of the cured group and the lost to follow-up group, showed that the isoniazid + rifamycin + ethambutol + moxifloxacin regimen was superior to the isoniazid + rifampicin + ethambutol + pyrazinamide regimen (P = 0.028). We therefore suggest that this regimen should be considered for patients who develop TB after kidney transplantation.

In summary, the symptoms and imaging findings of patients who develop TB after kidney transplantation differ from those typical of TB patients. In addition to conventional detection methods, the IGRA, TST and invasive examination may aid in diagnosis. The anti-TB regimen of isoniazid + rifamycin + ethambutol + moxifloxacin appears to have certain advantages for treatment of TB patients who were kidney transplant recipients.

TB	tuberculosis
IGRA	interferon-gamma release assay
TST	tuberculin skin test
PCR	polymerase chain reaction
AFB	acid-fact bacteria
CT	computed tomography

Ethics approval and consent to participate

All the study protocols and ethics protocols used were approved by the Scientific Research Ethics Committee of Hunan Chest Hospital (approval number:LS2024100901), and all the patients enrolled in this study provided written informed consent. The final clinical diagnosis of patients completing the study was reviewed by certified medical practitioners and researchers (Qian Su). All the results and charts were reviewed and approved by Yingfeng Qiu.

Clinical trial number

Not applicable.

Consent for publication

Not applicable.

Availability of data and materials

All the data involved in this study were included in this published article. The original data can be reasonably obtained after consulting the corresponding author by email.

Competing interests

The authors declare that they have no competing interests.

Funding

Not applicable.

Authors' contributions

QS, JX, and YQ conceived the study; QS, JX, and ZP collected clinical information; QS, JX, ZP, LZ, and YQ analyzed the data; and QS, JX, ZP, LZ, and JW were major contributors to the writing of the manuscript. All the authors read and agreed with the content.

Acknowledgements

We thank Medjaden Inc. for scientific editing of this manuscript.

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Table 1. Locations of M. tuberculosis infections.^*

Location	N	Percentage
Pulmonary
Secondary pulmonary TB	76	76.0%
Tuberculous pleurisy	27	27.0%
Hematogenous disseminated TB	11	11.0%
Bronchial TB	10	12.5%
Extrapulmonary
Abdominal TB^**	8	8.0%
TB of lymph nodes	7	7.0%
TB of bone and joint	6	6.0%
Tuberculous pericarditis	4	4.0%
Tuberculous encephalitis	2	2.0%
Tuberculous meningitis	2	2.0%
Renal TB	2	2.0%
Pelvic TB	2	2.0%
Laryngeal TB	1	1.0%

*Some patients had infections at multiple locations.

**Includes intestinal TB, splenic TB, and tuberculous peritonitis.

Table 2. Clinical manifestations of patients with TB.

Clinical manifestation	N	Percentage
Fever	65	65.0%
Cough and/or phlegm production	64	64.0%
Dyspnea	30	30.0%
Poor appetite	22	22.0%
Night sweat	22	22.0%
Fatigue	19	19.0%
Thoracodynia	11	11.0%
Chest distress	9	9.0%
Weight loss	9	9.0%
Swollen or painful limbs or joints	9	9.0%
Gastrointestinal symptoms	7	7.0%
Hemoptysis	7	7.0%
Asymptomatic	7	7.0%
Neurological symptoms	3	3.0%

Table 3. Biopsy results of 5 patients.

Case	Biopsy Location and Results
1	Lower lobe of left lung. Widened pulmonary alveolar septum, fibrous tissue hyperplasia, infiltration of the interstitium by a small number of inflammatory cells.
2	Lower lobe left of lung. Microscopy showing large coagulated necrotic cells, epithelioid cell masses, and multinuclear giant cells. TB was considered. AFB staining (suspicious +). Microscopy with immunofluorescence monitoring showed AFB positivity, but no visible mycobacteria.
3	Left main bronchus. Small foci of granulomatous inflammation with necrosis, which was considered as TB. AFB staining (−), PAS staining (−), silver hexamide staining (−).
4	Right axillary lymph node (puncture biopsy). A small amount of fibrous tissue, more necrosis. AFB staining (−), PAS staining (−), GMS staining (−)
5	Right parietal pleura. AFB staining (− )

Table 4. Factors affecting the outcome of patients who developed TB after kidney transplantation.

Characteristic		Cured (n=32)	Lost to follow-up (n=66)	Test statistic^*	P
Gender	Male	25	56	0.679	0.410
Gender	Female	7	10
Age, years	≥50	13	23	0.309	0.578
Age, years	<50	19	43
Number of transplants	1	31	63	~	1.000
Number of transplants	≥2	1	3
Time of TB onset	<1 year	7	13	~	0.838
	1–5 years	14	24
	6–10 years	7	18
	11–15 years	1	6
	16–20 years	3	4
	>20 years	0	1
Sites of infection	1	20	39	0.105	0.746
Sites of infection	≥2	12	27
Drug regimen for intensive phase	Isoniazid + rifamycin + ethambutol + pyrazinamide	9	15	0.340	0.560
	Isoniazid + rifamycin + ethambutol + moxifloxacin	13	13	4.843	0.028^#
	Other individualized treatment	10	38	2.288	0.130

*from the χ² test, t-test, or Mann-Whitney U test.

^#significant difference (P < 0.05).

No competing interests reported.

Analysis of the clinical characteristics of patients who developed tuberculosis after renal transplantation

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Abstract

Background

Methods

Results

Conclusions

Introduction

Methods

Results

Discussion

Conclusions

Abbreviations

Declarations

References

Tables

Additional Declarations

Status:

Version 1