The impact on incident tuberculosis by kidney function impairment status: analysis of severity relationship

Background The risk of tuberculosis (TB) in patients with impaired kidney function remains unclear by different stages of renal function impairment. Methods We retrospectively recruited all patients with kidney function in a tertiary-care referral center from January 2008 to December 2013 and followed them till December 2016. We defined the primary outcome as active TB development and analyzed the impact of kidney function impairment. Results During the study period, a total of 289,579 patients were enrolled for analysis, and of them, 1012 patients had active TB events in an average of 4.13 years of follow-up. According to kidney function impairment, the incidence rate of TB was similar in patients with no chronic kidney disease (CKD) or stage 1 and stage 2, and it increased apparently at stage 3a (167.68 per 100,000 person-years) to stage 3b, stage 4 and stage 5 (229.25, 304.95 and 349.29 per 100,000 person-years, respectively). In a Cox proportional hazard regression model, the dose response of TB risk among different stages of kidney function impairment increased significantly from CKD stage 3a to stage 5. Patients with long-term dialysis had a hazard ratio of 2.041 (1.092–3.815, p = 0.0254), which is similar to that of stage 4 CKD but lower than that of stage 5. Conclusion In patients with impaired kidney function, the risk of TB increases from CKD stage 3, and in stage 5, the risk is even higher than that of those receiving dialysis. Further strategies of TB control need to consider this high-risk group.

decline in kidney function is a risk factor for infection [10] and has reportedly been correlated with infection associated mortality [11,12]. Due to changes in the immune system due to deterioration of kidney function, active TB is an infectious complication that may develop or reactivate from LTBI.
In fact, few studies have examined TB risk in patients with kidney function impairment [13]. Only a previous cohort study reports that an adjusted hazard ratio of pulmonary TB was 1.45-fold higher in the CKD group than the non-CKD group [14]. But there is no study shows the TB risk according to the different stages of kidney function impairment [13], therefore, we cannot pick out which sub-population with kidney function impairment for implementation of LTBI strategy. Hence, we conducted this retrospective cohort study to analyze the correlation between kidney function and the incidence of TB in Taiwan, an intermediate TB country with incidence of 38.9 per 100,000 person-years in 2018 [15], using a large hospital-based cohort.

Participant enrollment
This retrospective study was conducted in a tertiary-care referral center in northern Taiwan under the approval of the Institutional Review Board of Research Ethics Committee of National Taiwan University Hospital (NO. 201510009RINB). From January 2008 to December 2013, patients aged ≥20 years were identified. We included patients with data of serum creatinine and excluded those having follow-up periods at the study hospital of less than 6 months and 3 months, respectively, before and after the index data of initial kidney function. In addition, we excluded those who had active tuberculosis before recruitment and within 3 months right after the index data of the kidney function.

Definitions of kidney function, active tuberculosis and comorbidity
We retrieved the participants' clinical information such as age, gender, body mass index, and underlying disease from the hospital's electronic record database within a total 12 months (6 months before and after the index date). We used an abbreviated Modification of Diet in Renal Disease (MDRD) equation to estimate the glomerular filtration rate (eGFR) [16] and classified the patient's initial kidney function according to the guidelines of the National Kidney Foundation [17]. The eGFR of ≥90, < 90~≥ 60, < 60~≥ 45, < 45~≥ 30, < 30~≥ 15, and < 15 ml/min/1.73m 2 stood for no CKD or stage 1, stage 2, stage 3a, stage 3b, stage 4, and stage 5, respectively. We defined active TB by positive culture result for Mycobacterium tuberculosis. For the diagnosis without microbiological evidence, we could define active TB by the unique diagnosis code in electronic chart record, because active TB is a certifiable infectious disease that needs to report to the Taiwan Centers for Disease Control. We used one time of admission diagnosis, or at least two outpatient clinic diagnoses plus prescription of anti-tuberculous agents for TB diagnosis. Co-morbidity of long-term dialysis, transplantation, pneumoconiosis, idiopathic pulmonary fibrosis, cirrhosis of the liver, cancer, lupus erythematous, rheumatoid arthritis, polymyositis, and dermatomyositis were defined by a record of a catastrophic illness card. Other underlying diseases were categorized by one admission diagnosis or more than 2 outpatient clinic diagnoses.

Outcome and statistical analysis
We followed up all enrolled participants till December 2016 and defined occurrence of active TB as the primary outcome. The incidence of TB was calculated as the average number per 100,000 person-years. Inter-group differences were compared using t test or one-way ANOVA for continuous variables, where appropriate, and chi squared test for categorical variables. We used Cox proportional hazard regression for time to TB event analysis. Once the patients with CKD at the initial received long-term dialysis or kidney transplantation in the follow-up or were lost to follow-up, they were censored in the time dependent analysis. We combined no CKD or stage 1 and stage 2 as a reference group (≥ 60 min/ml per 1.73m 2 ) in Cox regression analysis because their TB incidence were similar [18]. We calculated the correlations between the kidney function of eGFR and the univariate hazard ratio for TB by Spline Cox proportional regression. We investigated the risk factors for active TB using multivariate Cox proportional hazard regression analysis with possible associated variables from univariate analysis. Only variables with a two-sided p < 0.05 were retained in the final model. All analyses were performed in SAS version 9.4 (SAS Institute Inc., Cary, NC, USA).

Demographics of patients with different stages of kidney function impairment
During the study period, a total of 485,190 patients in the study hospital were eligible, and 289,579 were enrolled for analysis after excluding 124,274 for short follow-up (< 90 days), 69,912 for short previous data (< 6 months) and 1425 for having TB within 90 days (Fig. 1 Many underlying comorbidities significantly increased in advanced CKD stage included CHF, stroke, DM and SLE. By contrast, obesity was less frequently in in patients with worse kidney function than those with no CKD or stage 1 and 2. In comparison with patients without TB (Additional file 1: Table S1), those who developed TB during follow-up were older and predominantly male. In addition, they had lower eGFR and more advanced renal disease, dialysis, and kidney transplant. The proportion of patients with active TB development was lower in no CKD or stage 1 and 2, but it became higher in advanced CKD stage 3 to 5 in comparing with those without TB (p < 0.0001). The underlying diseases of pulmonary disease, gastroesophageal reflux disease, cancer, heart failure, cirrhosis, diabetes mellitus and autoimmune disease were higher in patients with TB development. By contrast, obesity was higher in patients without TB development.

TB incidence for different kidney functions
According to kidney function, the incidence rate of TB was similar in no CKD or stage 1 and stage 2 (70.06 and 71.08 per 100,000 person-years, respectively), and increased apparently from stage 3a ( For confirming that the case exclusion criteria of follow-up period ≤90 days did not influence the results of TB incidence, we used different follow-up period as exclusion criteria, including ≤30 days or ≤ 180 days and analyzed the TB incidence by different kidney function status. We found that the trends of TB incidence in the different CKD subgroups were similar (Additional file 1: Table S2 and S3).

Risk factors and the hazard ratio for TB development
In a Cox proportional hazard regression model (Table 3), we analyzed the hazard ratio (HR) of TB development for kidney function and other clinically relevant factors. In univariate analysis, patients had similar TB risk in no CKD or stages 1 vs stage 2 (HR: 1.024 [95% C.I.: 0.888-1.182], p = 0.7408, compared with no CKD or stage 1), so we used them as the reference group for those with deteriorated kidney function in Cox regression analysis. In univariate analysis, the dose response of TB risk among different kidney functions increased significantly from CKD stage 3a to stage 5. When we evaluated the univariate HR of TB risk at every eGFR below 90 ml/ min/1.73m 2 using spline Cox regression, the correlation actually increased slowly in stage 2 and obviously from stage 3a. A plateau was noticed around the beginning of stage 3b and a mild decline at late stage 5. However, the outcome number was small in stage 5, and the 95% confidence interval became large (Fig. 2). In multivariate Cox regression (

Discussion
In the present study, patients with decline in kidney function of CKD stage 3 and worse had increasing incidences and HR for TB development. The incidence and HR of TB in CKD stage 5 seemed around two-fold and 1.4-fold, respectively, relative to those with long-term dialysis although the 95% C.I.s were overlapped. Decline in kidney function is assumed to influence immune function [10] and is associated with oxidative stress and inflammation due to the decrease of renal clearance of toxins [13]. In addition, Vitamin D insufficiency is not uncommon among patients with CKD or dialysis and might lead to immune dysfunction [19]. Many immune cells such as T cells and B cells, as well as natural killer cells, will be attenuated when renal function has deteriorated [20][21][22]. Previously, many studies focus on the TB risk in dialysis population [23,24], but few studies report increasing TB incidence in patients with CKD [14,25]. Cheng et al. reported the adjusted HR of pulmonary TB was 1.45-fold higher in the CKD group than in the non-CKD group. The effect of TB susceptibility due to differences in kidney function has scarcely been reported before [13]. Cho et al. analyzed a community-based cohort and showed that stage 1-4 CKD had a 25% increase in TB hazard than those without CKD [25]. The present study was conducted based on a large hospital cohort and report the association between TB risk and different stages of impaired kidney function. The incidence and HR of developing active TB rise significantly from CKD stage 3 to stage 5. This finding is compatible with a previous assumption [13] that the decline of immunity begins and wastes accumulate significantly in stage 3 CKD. The risk of TB worsens in advanced stages of CKD and is highest at CKD stage 5 (incidence of 349.29 per 100,000 person-years), where it is around 7.0-fold that of the 55-65 year-old general population [26]. But the rate of increase in the adjusted HR begins to slow from stage 4 to stage 5. However, the unadjusted HR within stage 5 slightly declines as eGFR decreases (Fig. 2).
For patients receiving long-term dialysis, the TB incidence is similar to that of patients with CKD stage 3, and the adjusted HR resembles that of patients with stage 4 CKD (175.6 per 100,000 person-years; adjusted HR: 2.041). The possible explanation is that the dialysis remove partial uremic toxin and might decrease the uremia related immune suppression [27]. Therefore, the TB risk of advanced CKD might be much higher than that of our previous consideration. Because the WHO suggests active LTBI screening in patients with dialysis, those with stage 3 CKD or higher should also be targeted for TB prevention [6,8]. Such screening needs to be incorporated into a CKD care bundle to counter their higher infection risk. On the other hand, patients with kidney transplants still have very high risk of TB development. The incidence of 1429.33 per 100,000 person-years is around 48-fold that of the same-aged general population [26]. This result is much higher than those in a previous report [28] and might have been influenced by the small case number in this cohort. It might also be due to the higher proportion of corticosteroid and immune-suppressants use that may be correlated with increasing TB incidence [29]. However, the influences by corticosteroid and immunosuppressants need to be analyzed in further study specially designed for drug dose, duration and equivalent effect.
In addition to the stage of kidney impairment, TB development was also significantly associated with old age, male gender, and underlying co-morbidities such as underlying airway and immunocompromised diseases in the multivariate Cox regression analysis. They are all well known risk factors for TB [30][31][32][33] and might play a role in developing TB. In the future, we might integrate the risk factors to validate this model and form a prediction score model. There are several limitations in this study. First, this was a hospital-based study design. Although we only enrolled patients who were regularly followed up at the study hospital, there was a risk of outcome underestimation bias. In addition, the retrospective design might have missed some data in the record review, such as TB contact history and BCG vaccination. Third, because the study hospital is a tertiary referral center, selection bias existed and TB incidence as well as underlying comorbidities might have been higher than those in the general population.

Conclusions
Patients with impaired kidney function, eGFR ≤60 ml/ min/1.73m 2 , had increasing risk for TB development. The risk reached 2.877-fold and 2.041-fold HR of TB risk in patients with stage 5 CKD and in those with long-term dialysis, respectively, in comparison with those with CKD ≤ stages 2. The results indicate that patients with advanced CKD are susceptible to TB and have a higher risk than patients receiving dialysis. In the development of LTBI prevention strategies for patients with long-term dialysis, those with advanced CKD should also be considered.
Additional file 1 Table S1. Demographics of study population according to development of tuberculosis (TB). Table S2. Incidence rates of tuberculosis (TB) if we excluded patients lost to follow up < 30 days.