| Abstract|| |
The objective is to study the clinical profile of tuberculosis (TB) in chronic kidney disease (CKD). This is retrospective study of CKD patients who were diagnosed to have TB over a period of seven years at a tertiary care hospital. TB was diagnosed in 115 patients with an incidence of 4200/100,000. Mean age of the patients was 46.9 ± 16 years. Sixty-two patients (53.9%) were male. Causes of CKD were diabetic nephropathy and hypertension in 11.3% each, chronic glomerulonephritis in 31.3%, chronic tubulointerstitial nephritis in 39.1%, autosomal dominant polycystic kidney disease, and post-renal transplant CKD in 3.5% each. About 68.7% of patients with TB had advanced CKD stage of 4–5D, whereas 31.3% of patients had early CKD stage 1–3. Twenty percent of patients were on dialysis. Three-fourths of the patients had extrapulmonary TB. Pleuropulmonary (41.8%), kidney and urinary tract (20%), and abdomen and lymph node (13% each) were the most common sites for TB. The main clinical presentation of TB was: fever/pyrexia of unknown origin in 24.3%, constitutional symptoms of anorexia, fever, night sweats, and weight loss in 27.8%, abnormal chest radiograph in 31.2%, ascites/peritonitis in 13.9%, pleural effusion in 25.2%, lymphadenopathy in 20%, and sterile pyuria/hematuria/chronic pyelonephritis in 13%. Microbiological and/or histopathological diagnoses were made in 45.2% and in the other 54.8%, diagnosis of TB was made on clinical grounds. Adverse effects of anti-TB drugs were seen in 9.6% of patients. Ninety-three percent completed the treatment and survived. Eight patients (7%), all in CKD stage 5D, died. The incidence of TB was high among CKD stages 4 and 5 and in those receiving dialysis. Extrapulmonary disease such as pleuropulmonary, renal, peritoneal, and lymph node were the common forms of TB.
|How to cite this article:|
Vikrant S. Clinical profile of tuberculosis in patients with chronic kidney disease: A report from an endemic Country. Saudi J Kidney Dis Transpl 2019;30:470-7
|How to cite this URL:|
Vikrant S. Clinical profile of tuberculosis in patients with chronic kidney disease: A report from an endemic Country. Saudi J Kidney Dis Transpl [serial online] 2019 [cited 2019 Sep 21];30:470-7. Available from: http://www.sjkdt.org/text.asp?2019/30/2/470/256854
| Introduction|| |
Tuberculosis (TB) is a major public health problem and a leading cause of infectious morbidity and mortality worldwide. It was estimated that 10.4 million people developed TB and 16% of them died due to TB during the year 2016. India and China are experiencing rapid increases in the prevalence of chronic kidney disease (CKD) and account for more than one-third of global prevalence of TB. The pathophysiology of CKD-related immunodeficiency would suggest that early stage of CKD could also be a risk factor for TB. Immunodeficiency associated with CKD appears to be multifactorial in etiology. Advanced CKD is associated with oxidative stress and inflammation, 25-hydroxyvitamin D deficiency, and malnutrition, with evidence of functional abnormalities in a variety of immune cells, including B and T cells, neutrophils, monocytes, and natural killer cells. Changes in immunity begin as early as stage 3 CKD (defined as a glomerular filtration rate <60 mL/min/1.73 m2) and worsen in later stages as kidney function deteriorates and waste products accumulate. Active TB is an infectious complication that may develop and result from progression of Mycobacterium tuberculosis infection after recent exposure or reactivation of latent TB infection (LTBI) from a distant exposure, often years before the disease develops. The presentation of TB in uremic patients is often quite unusual and insidious, and diagnosis and management provide the treating physician with many special challenges.
TB has been reported in dialysis patients,,, but no study has described TB across the spectrum of CKD. Therefore, a clinical spectrum of TB among CKD patients was studied at, the Indira Gandhi Medical College Hospital, Shimla, which is the only tertiary care hospital in Himachal Pradesh, a mountainous state in north India having a population of six million.
| Materials and Methods|| |
This was a retrospective study of CKD patients who were diagnosed to have TB over seven years (January 2010 to December 2016) at a tertiary care hospital in India. CKD was defined and classified as per the Kidney Disease Outcomes Quality Initiative criteria. The estimated glomerular filtration rates were calculated from the serum creatinine level using the Cockcroft–Gault equation. The diagnosis of underlying basic kidney disease was made on clinical evidence.
We analyzed the clinical and laboratory features at the time of TB diagnosis including epidemiological characteristics and signs suggestive of pulmonary or extrapulmonary involvement. Diagnosis of TB was based on the following criteria: (a) positive direct microscopy or culture of any specimen or a tissue for M. tuberculosis and (b) histopathological evidence of M. tuberculosis (granulomatous with caseating necrosis). In cases without bacteriological or pathological confirmation, TB was defined as clinical (unexplained fever, impaired general condition), biological (high C-reactive protein, hypoalbuminemia, lymphocyte predominance, and exudative effusion of peritoneal, pericardial, and pleural fluid), imaging (pleural lesions, pulmonary lesions) and/or histopathological (noncaseating granulomas), and/or positive tuberculin skin test (TST) and/or history of active TB, and the exclusion of other disease. Anti-TB drugs, adverse effects of therapy, and outcome were noted. All patients who had either completed the treatment and were alive till the end of the study period or died after the diagnosis of TB during the study period were included in the study. Institute ethical committee approved this work.
| Results|| |
The total CKD patients registered over the study period of seven years were 2757. TB was diagnosed in 115 patients with an incidence of 4200/100,000. Mean age of the patients with TB was 46.9 ± 16 years (range 18–86). Sixty-two patients (53.9%) were male and 53 were female (46.1%). Causes of CKD included: diabetic nephropathy and hypertension in 13 each (11.3%), chronic glomerulonephritis in 36 (31.3%), chronic tubulointerstitial nephritis in 45 (39.1%), autosomal dominant polycystic kidney disease, and postrenal transplant CKD in four (3.5%) each. Seventy-nine patients (68.7%) with TB had advanced CKD stage of 4–5D. Of these 55 (69.6%) were of CKD stage 5 and 5D. Thirty-six patients (31.3%) had early CKD stage 1–3 and majority (69.4%) of those were CKD stage 3. Among dialysis patients, 18 (15.7%) were on hemodialysis (HD) and five (4.3%) on peritoneal dialysis (PD) [Table 1].
|Table 1: Demographic and clinical characteristics of the study patients (n=115).|
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[Table 2] shows the site of TB in these patients. Three-fourth of the patients had extrapulmonary TB. Pleuropulmonary (48; 41.8%), kidney and urinary tract (23; 20%), abdomen and lymph node (15; 13 %), were the most common sites for TB. Six patients (5.2%) were diagnosed to have disseminated TB.
|Table 2: Site of tuberculosis in patients with chronic kidney disease (n = 115).|
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In CKD stage 2, renal TB was the most common (62.5%). Pleuropulmonary (32%), peritoneal, and renal (12% each) were the main sites for TB in CKD stage 3. Common sites of TB in CKD stage 4 were pleuropulmonary (29.2%) and renal and urinary tract (25% each). In CKD stage 5, pleuropulmonary (59.4%), lymph nodal (15.6%) and disseminated (9.4%) were the main types of TB seen. In CKD stage 5D, pleuropulmonary (47.8%) and peritoneal (30.4%) were the main types of TB. [Table 3] shows the site of TB in the two modalities of dialysis. Among PD patients, 60% had pleuropulmonary involvement and 40% had peritoneal TB (46.7%). Pleuropulmonary (38.9%) followed by peritoneal (27.8%) and lymph nodal (22.2%) were the main types of TB among HD patients. One HD patient had disseminated TB with central nervous system (CNS) involvement. Median duration on dialysis at diagnosis was 12 months with a range of 1–50 months. One patient with renal TB had kidney failure at diagnosis and required dialysis. The remaining patients with renal TB belonged to CKD stage 2–4. Patients with TB of the urinary tract were in CKD stage 3 and 4.
The clinical presentation of TB was: fever/ pyrexia of unknown origin in 28 (24.3%), constitutional symptoms of anorexia, fever, night sweats, and weight loss in 32 (27.8%), abnormal chest radiograph in 36 (31.2%), ascites/peritonitis in 16 (13.9%), pleural effusion in 29 (25.2%), lymph nodal enlargement in 23 (20%), and urinary manifestations (sterile pyuria/hematuria/chronic pyelonephritis) in 15 patients (13%) [Table 4]. Peritoneal TB in PD patients had presentation as a nonresolving peritonitis, whereas in HD patients, it presented as ascites. Ten patients had a history of TB in the past. Mean erythrocyte sedimentation rate was 76 ± 32 (range 2–160) mm 1st h. Out of 29 patients with pleural effusion, 13 (44.8%) had right sided, 12 (41.4%) left sided and four (13.8%) had bilateral pleural effusion.
The mean level of adenosine deaminase (ADA) in pleural fluid was 48 ± 32 IU/L and in peritoneal fluid 55 ± 27 IU/L. TST was performed in 30 patients with suspected TB, most in CKD stage 5 and 5D, and was positive in 14 patients (47%). Microbiological and/or histopathological diagnoses were achieved in 52 patients (45.2%) and in the other 63 patients (54.8%), the diagnosis of TB was made on clinical grounds.
All patients were treated with four drug standard regimen of anti-TB therapy (ATT) consisting of rifampicin, isoniazid, ethambutol, and pyrazinamide. Rifampicin and isoniazid were administered daily for six months along with pyridoxine. Ethambutol and pyrazinamide were administered every alternate day in CKD stage 4, 5, and 5D for the initial two months and in others, a daily regimen was followed. Eleven patients (9.6%) had adverse effects of anti-TB drugs. Three patients with TB peritonitis had a poor gastrointestinal tolerance to the ATT and defaulted on the treatment. They experienced gastrointestinal side effects in the form of recurrent nausea and vomiting related to intake of anti-TB drugs. This led them to stop the anti-TB drugs. Two patients developed severe hepatitis requiring temporary stoppage of ATT and three patients experienced an asymptomatic rise of liver enzymes. One CKD 5D patient developed recurrent hepatitis and succumbed to it. Cutaneous manifestations of drug allergy and hypersensitivity occurred in two patients; all drugs were stopped and restarted gradually with good tolerance. One CKD 5D patient developed neuropsychiatric symptoms which resolved after temporary stoppage of isoniazid and increasing pyridoxine to 100 mg/day.
One hundred and seven patients (93%) completed the treatment and recovered. None had relapse of TB on follow-up. Eight patients, all CKD stage 5D, died during the treatment. The mortality in CKD 5D was 34.8%, whereas overall mortality was 7%. Three PD patients died due to multi-organ failure. The cause of death in five HD patients was cardiovascular in two, cerebrovascular, acute liver failure, and sepsis-induced multi-organ failure in one patient each.
| Discussion|| |
Host resistance to infection is primarily mediated by cellular immunity which is deficient in patients with CKD. The occurrence of infections including TB is, therefore, high in such patients. Various studies have reported the incidence of TB in patients with CKD and on maintenance HD to be 6–52.5 times that of the general population.,,, Estimated TB incidence in the general population in India is 211/100,000. Therefore, the observed incidence of TB in CKD in our study is 20 times that of the general population. Impaired cellular immunity suppresses the mitogenic response of lymphocytes. Protein malnutrition, zinc and pyridoxine deficiency, and defects in leukocyte function following exposure to dialysis membranes increase the susceptibility of dialysis patients to TB., There is an inverse association between renal function and TB; the worse the renal function, higher is the incidence of TB. The study results suggest that with increasing severity of CKD there is a progressive increase in the risk of TB. About one-third of TB patients in our study had early CKD stage 1–3, whereas above two-third of TB patients had advance CKD stage 4–5D.
Pleuropulmonary (41.8%), renal (20%), peritoneum and lymph node (13% each) were the most common sites for TB in our patients. Three-fourth of the patients had extrapulmonary TB in our study. In ESRD, the diagnosis of TB disease is often difficult because of prevailing extrapulmonary involvement and nonspecific symptoms. Extra-pulmonary TB has been reported in as many as 60%–80% of cases, either alone or in association with pulmonary TB. The most common forms of presentation are lymphadenitis, gastrointestinal, bone, genitourinary, peritonitis, pleural effusion, pericardial effusion, miliary TB, and pyrexia of unknown origin.,,,
Renal TB is the second-most common form of extrapulmonary TB after lymph node TB., The genitourinary system is often affected in TB resulting from hematogenous spread from primary pulmonary TB. The manifestations of renal TB include hematuria, sterile pyuria, colic, and renal failure. Constitutional symptoms, such as fever, weight loss, and fatigue, are less common. Renal TB is suspected, particularly with sterile pyuria., Renal dysfunction may result from direct infection of the kidney parenchyma or ureteral obstruction with resultant hydronephrosis. In this study, renal TB was the most common form of extrapulmonary TB, but none among them had associated with genital involvement.
Among CKD stage 5D, pleuropulmonary (47.8%) and peritoneal (30.4%) were the common form TB in our patients. Sixty percent had pleuropulmonary involvement and 40% had peritoneal (46.7%) TB in PD patients, whereas pleuropulmonary (38.9%) followed by peritoneal (27.8%) and lymph nodal (22.2%) was the main types of TB among HD patients. The presentation of TB may be different in PD patients than in HD patients. Pulmonary involvement is still in first place but tuberculous peritonitis has a special place in PD. Presentation of peritoneal TB can differ between PD and HD as was observed in this study.
The clinical and laboratory findings of peritoneal TB are nonspecific, and the diagnosis requires a high index of suspicion. The hardest cases to diagnose are those with culturenegative peritonitis or culture-positive peritonitis resistant to appropriate antibiotics without any additional clues suggesting TB. The sensitivity of smears and cultures can be enhanced by centrifuging 50–150 mL of a dialysate sample. A fluid culture medium reduces the time required for the growth of mycobacteria. Laparoscopy with biopsy should be considered at an early stage when peritoneal TB is suspected.
TB is a common cause of pleural effusion in CKD as was observed in a quarter of our patients. TB and uremia are the leading cause of exudative pleural effusion among CKD patients. Differentiating TB from uremic effusion requires a combined clinicopathological approach and this differentiation is absolutely necessary for proper management. In high-burden settings, the diagnosis is frequently inferred in patients who present with a lymphocytic predominant exudate and a high ADA level, which is a valuable adjunct in the diagnostic evaluation.
Among CKD patients, lymph node TB was a common cause of TB after pleural and renal TB. Recent studies place lymph node TB in the second position in frequency after pleural TB among HIV-negative patients, whereas in patients with HIV/AIDS, it has been determined to be at first position of extrapulmonary TB.
In majority of our patients, TB diagnosis was made on clinical grounds. TB diagnosis is more complex and difficult in CKD patients because of an increased frequency of extrapulmonary TB, atypical clinical presentation, and nonspecific symptoms and findings. This atypical presentation may often lead to a delay in accurate diagnosis and therapy, sometimes resulting in patients’ death. In addition to this, patients on PD who are at risk of intraabdominal infection also require special consideration. Therefore, physicians should always have a high degree of suspicion and consider the possibility of TB whenever confronted with CKD patient presenting with general symptoms such as fever, weight loss, and/or lymphadenopathy. The diagnosis would then require the isolation of acid-fast bacilli, the finding of typical caseating granuloma on biopsy, or the recovery of tubercle bacilli from the culture of the biopsy material. TST is unreliable in patients with advanced CKD and in those on immunosuppressive agents. A positive test may be useful, but a negative result cannot be assumed to be a true negative. However, it is well known that this test lacks sensitivity, especially in patients on dialysis, with reported anergy rates of up to 50%. Therefore, a negative test result cannot be assumed to be true negative, whereas a positive test result should prompt further investigation in these patients. Another limitation of the TST is false-positive TST results in the context of previous Bacille Calmette-Guérin vaccination. Newer interferon interferongamma release assays have been reported to be more sensitive than TSTs for the detection of infected individuals in dialysis patients. However, these assays have become available for commercial use only recently and were not used in our patient. Therefore, the current strategy in dialysis patients should use these tests instead of TST for the diagnosis of LTBI screening and as an aid in the diagnosis of active TB.
TB in dialysis is associated with a poor prognosis and high mortality due to delay in diagnosis, and adverse effects of anti-TB drugs., The adverse effects of anti-TB drugs were seen 9.6% of our patients. A lower incidence observed in our study was because the patients were treated with due dose modification of the anti-TB drugs. We also observed high mortality in CKD 5D, whereas all patients in other CKD stages completed the treatment and survived.
Our study is a large series on the clinical profile of TB across a spectrum of CKD stages from an endemic country. It has certain limitations. First, due to the retrospective nature of this study, we could not gather more information regarding risk factors, additional comorbidities, or diagnostic procedures. Second, pediatric patients were excluded. Finally, we had a higher proportion of presumptive or clinical TB diagnosis due to nonavailability of the new molecular diagnostic tests such as IGRA or nucleic acid amplification tests during the study period.
In conclusion, majority of patients at the diagnosis of TB were at advanced CKD stage. Pleuropulmonary, renal, peritoneal, and lymph node were the common forms of TB. Extra-pulmonary disease was the most common in all CKD stages. Fever, constitutional symptoms, abnormal chest radiograph, pleural effusion, ascites/peritonitis, urinary symptoms of pyuria/hematuria/chronic pyelonephritis, and lymph node enlargement were the main clinical manifestations. TB in dialysis carries a high mortality. Early diagnosis and timely treatment are important to reduce the high morbidity and mortality due to TB in CKD.
Conflict of interest: None declared.
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Department of Nephrology, Indira Gandhi Medical College, Shimla - 171 001,Himachal Pradesh
[Table 1], [Table 2], [Table 3], [Table 4]