Chronic kidney disease with genitourinary tuberculosis: old disease but ongoing complication

We conducted this retrospective study at the Severance Hospital, a 2400-bed university-affiliated teaching hospital and tertiary care referral hospital in Seoul, South Korea. We enrolled participants older than 18 years of age diagnosed with GUTB. We identified patients with ICD-10 codes A18.1, B90.1 and N33.0 from January 2005 to July 2016 from electronic medical records and enrolled only those who started and completed the treatment during the study period. Clinical and laboratory data at the time of GUTB diagnosis, including age, sex, medical history, follow-up duration and symptoms, were collected. To assess renal function, serum creatinine levels were reported before treatment and at the 6- and 12-month post-treatment follow-ups. Body mass index (BMI) was calculated as weight divided by height squared (kg/m²). We also investigated the diagnostic methods, treatment modalities and outcomes of GUTB patients during a recent 10-year period in one centre in Korea to identify risk factors for CKD developing after ending treatment. All surgical techniques were investigated included all ablative surgery and reconstructive surgery between diagnosis and during medical treatment. We excluded patients with a follow-up duration of <1 year, unfulfilled GUTB diagnostic criteria, pre-existing CKD and insufficient data. This study was approved by the Institutional Review Board of the Yonsei University Health System Clinical Trial Center.

The diagnosis of GUTB was defined as the presence of any clinical finding plus a positive result for one of the following: (1) acid-fast bacilli (AFB) in urine, (2) urine culture of Mycobacterium tuberculosis (M. tuberculosis), (3) polymerase chain reaction (PCR) for M. tuberculosis in urine or (4) histopathological evidence of TB in any GU tissue specimen. A histological diagnosis of TB was confirmed by identifying caseating necrosis, loose aggregates of epithelioid histiocytes and Langerhans giant cells in tissue specimens [6, 10]. Immunosuppressant use was defined as a daily dose of ≥20 mg prednisolone-equivalent steroid, monoclonal antibodies, antimetabolite drugs or T-cell inhibitors within 30 days prior to diagnosis of GUTB. Pre-TB (pre-existing) CKD was defined as an estimated glomerular filtration rate (eGFR) of <60 mL/min/1.73m² for more than 3 months before diagnosis of GUTB or a self-reported history. Acute renal failure (ARF) was defined according to the KDIGO (Kidney Disease: Improving Global Outcomes) criteria (increased serum creatinine level ≥ 1.5-fold compared with baseline or by ≥0.3 mg/dL). We used the serum creatinine level to investigate the presence of ARF at the time of GUTB diagnosis. The eGFR was calculated from the serum creatinine level using the Modification of Diet in Renal Diseases (MDRD) equation [11]. Microscopic haematuria was defined as the excretion of more than two red blood cells per high-power field in a centrifuged urine specimen and pyuria as the excretion of more than five white blood cells. Proteinuria was defined as more than one positive urine dipstick test. Anaemia was defined as a haemoglobin level <11 g/dL according to the KDIGO guidelines based on the target for renal anaemia therapy [12].

CKD group was defined as an eGFR <60 mL/min/1.73m² after completing GUTB treatment. We used the serum creatinine level between 6 months and 1 year after completion of GUTB treatment to investigate the presence of CKD. Patients with a history of CKD at the time of GUTB diagnosis (pre-TB CKD) were excluded. To assess kidney function, serum creatinine levels were determined before treatment and at the 6- and 12-month post-treatment follow-ups. After the treatment was completed, any surgical treatment, recurrence, ESRD development, and all cause mortality were investigated.

All statistical analyses were performed using the Statistical Package for the Social Sciences for Windows (ver. 23.0, SPSS Inc., Chicago, IL, USA). To identify risk factors for CKD, parameters were compared between patients who did and those who did not develop CKD. Continuous variables are expressed as means ± standard deviation and categorical variables as numbers (percentages). The Kolmogorov–Smirnov test was used to analyse the normality of the data distribution. Non-normally distributed data are expressed as medians and interquartile ranges (IQRs). We used Student’s t-test or Mann–Whitney U-test and the χ² test or Fisher’s exact test to compare continuous and categorical variables, respectively, in univariate analyses. Variables with p-values <0.05 by the Wald test in the univariate analyses were included in a multivariate logistic regression analysis to identify risk factors for CKD. The multivariate analysis results are expressed as odds ratios (ORs) and 95% confidence intervals (CIs). A two-sided p value <0.05 was considered to indicate significance.

During a 10-year period, 56 patients were diagnosed with GUTB, of whom 11 (19.6%) developed CKD after treatment for GUTB (Fig. 1). The mean age of these patients was 52.8 years, and 24 (42.9%) patients had a history of TB, most frequently pulmonary TB (21/24). Three patients were taking immunosuppressants, and two had a history of gastrectomy. No patient had HIV or multi-drug resistant TB. The most frequent symptom was abdominal pain (42.9%), and gross haematuria was present in 33% of the patients (Table 1).

The diagnosis was confirmed most frequently by histopathology (30/56, 53.6%). Urine AFB staining was positive in six of the 56 patients (10.7%). A TB interferon-gamma evaluation was performed in 5/56 patients, all of whom showed a positive result.

Almost all of the patients (53/56, 94.6%) underwent a 6- or 9-month course of chemotherapy with isoniazid, rifampicin, and ethambutol with or without pyrazinamide; the median treatment duration was 9 months. In addition, 42 of the 56 patients (75.0%) underwent surgical treatment. All surgical techniques included all ablative surgery and reconstructive surgery from the time of diagnosis to completion of medical treatment. During an average 40-month observation period, CKD developed in 11 (19.6%) and ESRD in 4 (7.1%) of the patients. Of the patients, 26.8% required additional surgical treatment after completion of medical TB treatment, and recurrence was observed in 4 (7.1%) patients. The all-cause mortality rate was 7.1% (4/56).

CKD occurred in 11 (19.6%) patients during the follow-up period. In univariate analyses, patients with CKD were older (50.1 ± 15.1 vs. 63.9 ± 18.5 years; p = 0.012) and had higher creatinine levels at the time of diagnosis (0.9 [IQR 0.8–1.0] vs. 1.4 [IQR 1.1–1.8] mg/dL; p = 0.002). ARF occurred in 10 of the 56 patients (17.9%), of whom three recovered and seven progressed to CKD due to persistent renal insufficiency.

There were significantly lower rates of microscopic haematuria (42.2% vs. 81.8%; p = 0.019) and proteinuria (13.3% vs. 45.5%; p = 0.029) in the non-CKD group compared with the CKD group in the univariate analyses. There was also a significantly higher rate of positive urine TB PCR results in the CKD group (72.7% vs. 37.8%; p = 0.030) (Table 2). In the CKD group, five patients had both microscopic haematuria and proteinuria, four had only microscopic haematuria, and two patients had neither microscopic haematuria nor proteinuria. Microscopic haematuria and proteinuria were significant (microscopic haematuria, p = 0.019; proteinuria, p = 0.029) in the univariate analyses but not in the multivariate analysis.

The sex ratio and BMI did not show significant differences between the two groups. The site of TB infection, previous TB history and comorbidities were not significant independent factors. Treatment modality and duration did not differ significantly between the two groups. Surgical treatment including nephrectomy may be performed during medical treatment, so it does not affect creatinine at the time of diagnosis but may affect CKD development. Of the patients, 15/56 (26.8%) had total or partial nephrectomy; there were no significant differences between the two groups according to kidney function (p = 0.674). But, the rate of ESRD development (0.0% vs. 36.4%; p = 0.001) and the rate of surgical treatment (20.0% vs. 54.5%; p = 0.005) after completion of treatment were significantly higher in the CKD group than in the non-CKD group (Table 3).

In the multivariate analysis, ARF (OR, 54.305; 95% CI, 1.517–1944.002; p = 0.032) and old age (OR, 54.255; 95% CI, 1.523–1932.905; p = 0.028) were independent risk factors for CKD in GUTB patients (Table 4).