A Clinical Study of Acute Kidney Injury on using Antituberculosis Drugs in Geriatrics

 

Syed Safiullah Ghori, Mohammed Abdul Quddus, Hafsa Khalid

Department of Hospital and Clinical Pharmacy, Anwar-ul-Uloom College of Pharmacy, New Mallepally, Hyderabad 500016, Telangana, India

 

ABSTRACT:

Patients on anti-tuberculosis treatment develop acute kidney injury (AKI) especially in an aging population. This study aimed to calculate the incidence of AKI due to anti-TB drugs and to analyse the outcomes and predictors of renal recovery. Patients on anti-TB treatment during the year 2015 and 2016 were identified and their medical records were reviewed. Acute kidney injury was identified according to the criteria established by the AKI Network, while renal recovery was calculated as a return of serum creatinine to baseline. Predictors of renal recovery were analysed by Cox regression analysis. 61 patients of the age 68 years on anti-TB treatment had AKI with male predominance. 43 (71%) developed AKI within two months of anti-TB treatment, including 3 (5%) with a prior history of rifampin exposure. 30 (26%) had co-morbid chronic kidney disease or end-stage renal disease. The median time of renal recovery was 39.6 days. Factors predicting renal recovery were, presence of fever, rash, and gastro-intestinal disturbance at the onset of AKI. 51 of the 60 patients who recovered from AKI had successful re-introduction or continuation of rifampin. The present study suggests that acute kidney injury is caused by anti-tuberculosis drugs mainly in geriatrics. Some of the patients with acute kidney injury recovered and some of them had permanent renal impairment. Patients with predictable factors of fever, rash, and gastrointestinal disturbance at the onset of acute kidney injury had better renal recovery. Further research efforts should be directed towards better findings related to association of anti-tuberculosis drugs with acute kidney injury and increasing systematic strategies for prevention.

 

 

 

 

INTRODUCTION:

Tuberculosis is a fatal contagious disease which can affect almost any part of the body but is mainly an infection of the lungs. It is caused by a bacterial microorganism, the tubercle bacillus or Mycobacterium tuberculosis[1]^. It can be treated and can also be prevented if persons at risk take certain drugs. It is a global disease affecting one third of world’s population.

 

The World Health Organization statistics for 2015 gives an estimated incidence of 2.2 million cases of TB for India out of a global incidence of 9.6 million. Anti-tuberculosis treatment remains the most important and effective intervention for controlling spread, but adverse events from first-line antitubercular drugs are common. Acute kidney injury is an abrupt decline in renal function, clinically manifesting as a reversible acute increase in nitrogen waste products measured by blood urea nitrogen and serum creatinine levels over the course of hours to weeks. Acute kidney injury has three main causes, a sudden serious drop in blood flow to the kidneys, heavy blood loss or a bad infection called sepsis which can reduce blood flow to the kidneys leading to ischemia[2]. Because the elderly are more vulnerable to drug-induced AKI and usually have poor renal recovery, AKI during anti-TB treatment may be more common and serious

 

Drugs commonly used to treat tuberculosis include isoniazid (INH, Lanizid, Nydrazid) rifampicin (rifadin, rimactane) pyrazinamide (tebrazid) streptomycin and ethambutol. Long term use of anti-tubercular drugs may lead to complex conditions such as renal failure, acute kidney injury, chronic kidney disease etc[3] Although isoniazid and ethambutol have been associated with AKI, rifampicin is the most common anti-TB drug responsible for AKI identified by most studies. It is common in patients receiving anti-tuberculosis drugs. Identifying risk and prognostic factors of acute kidney injury is important in the management of tuberculosis. Rifampicin is excreted especially over hepatobiliary path, 30% of the drug is excreted unmodified in urine. Pyrazinamide excretion is primary hepatic, but its metabolites can be partially excreted through the renal path. In elderly patients, elevated concentrations achieve toxic levels which first causes acute kidney injury ^[5].People who have experienced AKI may have an increased risk of chronic kidney disease in the future. Management includes treatment of the underlying cause and supportive care, such as renal replacement therapy. The present study aimed at Determination of the onset of acute kidney injury and assessing the status of renal recovery in patients on anti-tuberculosis drugs which in turn helps in preventing acute kidney injury or further progression of nephrotoxicity.

 

MATERIAL AND METHODS

This was a prospective study observed at Om Sai Hospital. The study was approved by Hospitals Research Ethics Committee with approval number (2007/16). Patients were included if they met the following criteria: age ≥18 years, clinical diagnosis or suspicion of tuberculosis, under rifampicin-containing anti-tubercular treatment and had onset of acute kidney injury during anti-tubercular treatment[4-5]. Acute kidney injury was determined according to the criteria established by the Acute Kidney Injury Network and was classified into three stages (Stages 1 to 3) based on serial changes in serum creatinine level. Stage 1 was regarded as an increase in serum creatinine ≥26.52 μmol/L or by 1.5-fold but less than twice the baseline level. Stage 2 was a two-fold increase but less than three-fold increase from baseline, while Stage 3 was a three-fold increase from the baseline level.

 

All the tuberculosis patients received a standard anti-Tuberculosis treatment of daily Isoniazid, Rifampicin, Ethambutol, and pyrazinamide for the first two months, and daily Isoniazid and Rifampicin for the next four months. For patients with an estimated creatinine clearance of < 30 ml/minute, the frequencies of Ethambutol and Pyrazinamide were changed to once every two days with the unit dose unchanged[6]. The regimen was modified by the primary care physician if necessary, e.g. when there were adverse drug effects. Demographic data, including sex, age, smoking status, excessive alcohol consumption (defined according to a single-question alcohol screening test), co-morbidities, results of sputum acid-fast bacilli (AFB) smear and mycobacterial culture, anti-TB regimen, laboratory results, onset, and management of Acute kidney injury, were collected[7].

 

The patients were classified into two groups based on haemoglobin < or ≥100 g/L, leukocyte > or ≤10×109/L, eosinophil count > or ≤0.5×109/L, and platelet < or ≥100×109/L. Tuberculosis laboratory tests were repeated every two weeks in the first two months and every eight weeks thereafter, or when the primary care physician deemed it necessary. If renal recovery was not achieved after 180 days from the onset of acute kidney injury, the acute kidney injury was considered “unrecovered”.

 

Patients were included on basis of inclusion and exclusion criteria. The inclusion criteria included male and female geriatrics with clinical diagnosis or suspicion of tuberculosis, under rifampicin-containing anti-Tuberculosis treatment, onset of acute kidney injury during anti-tuberculosis treatment. Patients were excluded if they had shock or urinary tract infection, and under potentially nephrotoxic drugs other than rifampicin at the onset of acute kidney injury. Patients who had other conditions possibly resulting in acute kidney injury, such as hypercalcemia and nephrotic syndrome, end-stage renal disease, under renal replacement therapy and who had non-tuberculosis mycobacteria infection were also excluded. The most common underlying co-morbidities were pre-existing chronic kidney disease, diabetes mellitus, and malignancy. Outcomes included were sputum culture conversion, treatment failure, recurrence and adverse events, including hepatotoxicity and flu-like syndrome.

 

All data was expressed as either mean ± standard deviation or median [inter-quartile range]. Inter-group difference was compared using the t-test or Mann–Whitney U-test for continuous variables based on their normality, and the chi-square test or Fisher’s exact test for categorical variables, as appropriate. Time for renal recovery for each variable was compared.

 

RESULTS:

Results of Patient Characteristics:

In terms of severity, 43 (84%) patients were in AKIN Stage 1, 15(10%) in Stage 2, and 2(6%) in Stage 3. The patients’ median age was 68 years (56–76 years), and there was a male predominance (71%). The diagnosis of Tuberculosis was culture-confirmed in 11 Of the 60 acute kidney injury patients, 16 had regular alcohol intake and 39 were smokers (Table 1). The most common underlying co-morbidities were pre-existing chronic kidney disease, diabetes mellitus, and malignancy.

 

Results of Onset of AKI:

Within six months after anti-TB treatment, there was a continuous probability of developing acute kidney injury (Figure 1). The median interval in all of the study subjects between the start of anti-TB treatment and the onset of acute kidney injury was 44 days. Moreover, 61% of acute kidney injury episodes happened in the first two months of treatment. In all patients taking rifampicin at the onset of acute kidney injury, some were also taking isoniazid, ethambutol, and pyrazinamide.

 

 

Table No.1: Patient characteristics based on recovery status of acute kidney injury.

Variables	Overall (n=60)	Aki recovered (n=51)	Aki un-recovered (n=9)
Male	42	38	4
Age<68	47	43	4
Smoking	39	19	20
Alcoholism	16	13	3
Malnutrition	32	23	9
Old Tb History	3	2	1
Re-treatment Of Tb	13	11	2
CKD	16	13	3
DM	19	15	4
Malignancy	15	12	3
Gout	4	3	1
Autoimmune Disease	6	4	2
HIV	1	1	0
Afb-Positive	12	9	3
Culture-Positive	47	37	10
Rash	19	16	3
Gastro-Intestinal Upset	26	19	7
Fever	9	9	0
Arthralgia	6	5	1
Stage 1	43	40	3
Stage 2	15	10	5
Stage 3	2	1	1
Onset of AKI after ATT	37(0-120)	29 (15-104)	40(27-90)
Hold Rifampicin	24	20	4
Hold Pyrazinamide	16	13	3
Re-Challenge Rifampicin	10	8	2

AFB acid-fast bacilli smear, AKI acute kidney injury, ATT anti-TB treatment, TB tuberculosis.

Note:

Data are either number or median. There was no statistically significant difference between the AKI-recovered and -unrecovered groups.

*Re-treatment meant that AKI recurred after re-exposure to rifampicin.

Only 35 patients received pyrazinamide-containing anti-TB regimen at the onset of AKI.

 

Figure No.1: Interval between the start of anti-tuberculous treatment and onset of acute kidney injury.

 

 

The most common laboratory findings were hypoalbuminemia, increased eosinophil count (>0.5×10⁹/L), and anemia (hemoglobin < 100 g/L) (Table 2). Urinalysis showed proteinuria in 20%, sterile leukocyturia in 17%, and hematuria in 5%. Aside from elevated serum creatinine level, serum uric acid level was also elevated during Acute kidney injury compared to baseline (p < 0.001) (Table 2).

 

Table No. 2: Laboratory data of patients recovered and unrecovered from acute kidney injury.

Note: Data are either median [inter-quartile range] or number (%) unless otherwise stated.

*Significantly different (p < 0.05) between the AKI-recovered and –unrecovered groups.

**p = 0.064.

 

Results of Modifications of anti-TB treatment during Acute kidney injury:

Rifampicin was successfully re-introduced or continued without interruption in 51 of the 60 acute kidney injury-recovered patients and in of the 9 acute kidney injury-unrecovered patients (Figure No: 1). Pyrazinamide was discontinued in some patients after the onset of acute kidney injury. Anti-Tuberculosis drugs were interrupted in some, including few who failed to show compliance one patient died. In the remaining few patients, the median duration of treatment interruption was 14 days (IQR, 7–28 days).

 

Outcome and prognostic factors of acute kidney injury:

Within a follow-up period of 180 days since the onset of acute kidney injury, Nine patients did not recover from acute kidney injury (AKI-unrecovered group), (median age, 68.5 years [IQR 59–81.5 years]) who required long-term renal replacement therapy. Very few had hypoalbuminemia.

 

Among the 51 patients who recovered from Acute kidney injury (AKI-recovered group), 44 recovered within 100 days. Serum BUN level (p = 0.005) and the prevalence of haematuria (p = 0.033) and proteinuria (p = 0.048) at the onset of Acute kidney injury were significantly higher in the AKI-unrecovered group, whereas thrombocytopenia was less common (p = 0.064) (Tables 1 and 2). The Acute kidney injury recovery rate was not different among the different Acute kidney injury network stages (p = 0.061) (Table no: 1).

 

 

Table No. 3: Predictive factors of recovery from acute kidney injury, by multivariate Cox proportional hazard reanalysis

 

DISCUSSION:

Acute kidney injury is a rare complication in patients on anti-TB therapy. Several reports, summarized in some review articles, address this rare event and most reveal rifampicin as the most common responsible drug[8] By retrospective analysis of 60 TB patients, this study has several important findings. First, the incidence of AKI in patients on anti-TB therapy is [9] much higher (7.1%) than in previous reports (0.05%), with a recovery rate of 73%. Second, rifampicin is successfully re-introduced or continued without interruption in 87% of TB patients with AKI recovered. Third, factors predicting recovery from AKI are clinical symptoms at the onset of AKI, including fever, skin rash, and GI disturbance, but not AKI stage, age, and co-morbidities.

 

Within six months after anti-TB treatment, there was a continuous probability of developing acute kidney injury. The median interval in all of the study subjects between the start of anti-TB treatment and the onset of acute kidney injury was 44 days. Moreover, 61% of acute kidney injury episodes happened in the first two months of treatment. In all patients taking rifampicin at the onset of acute kidney injury, some were also taking isoniazid, ethambutol, and pyrazinamide[10-11]

 

In this study, the diagnosis of AKI is not confirmed because renal biopsy was not performed. However, the results of previous studies suggest that even without histology studies, the diagnosis of rifampicin-induced AKI can be made based on the typical time course and by excluding other etiologies. In the present study, the medical records were reviewed extensively to exclude other possible causes of AKI like sepsis, hypotension, or use of other nephrotoxic medication. Seven patients had a second AKI episode after rifampicin re-challenge, further confirming that rifampicin may be the leading cause of AKI.

 

CONCLUSION:

Anti-tuberculosis drug-induced acute kidney injury is regular in geriatrics. It usually develops within two months of treatment and resolves within three months after onset. Though some of the patients with acute kidney injury will recover and some have permanent renal impairment. Patients with three predictable factors like fever, rash, and gastrointestinal disturbance at the onset of acute kidney injury have better renal recovery. 51 patients who had recovered from AKI was successfully continued with rifampicin.

 

REFERENCES:

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2.       De Vriese AS, Robbrecht DL, Vanholder RC, Vogelaers DP, Lameire NH: Rifampicin-associated acute renal failure: pathophysiologic, immunologic, and clinical features. Am J Kidney Dis: Off J Nat Kidney Found 1998, 31(1):108–115.

3.       Kumar S, Mehta JA, Trivedi HL: Light-chain proteinuria and reversible renal failure in rifampin-treated patients with tuberculosis. Chest 1976, 70(4):564–565.

4.       World Health Organization: Global Tuberculosis Report 2012. Geneva; 2012.

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6.       Kruger B, Benck U, Singer T, Kramer BK: Drug-induced impairment of renal function. Deutsche medizinische Wochenschrift (1946) 2012, 137(38):1873–1877.

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8.       Covic A, Goldsmith DJ, Segall L, Stoicescu C, Lungu S, Volovat C, Covic M: Rifampicin-induced acute renal failure: a series of 60 patients. Nephrol Dial Transpl: Off Publ European Dial Transpl Assoc European Renal Assoc 1998, 13(4):924–929.

9.       Muthukumar T, Jayakumar M, Fernando EM, Muthusethupathi MA: Acute renal failure due to rifampicin: a study of 25 patients. Am J kidney Dis: Off J Nat Kidney Found 2002, 40(4):690–696.

10.     Schubert C, Bates WD, Moosa MR: Acute tubulointerstitial nephritis related to antituberculous drug therapy. Clin Nephrol 2010, 73(6):413–419.

11.     Kruger B, Benck U, Singer T, Kramer BK: Drug-induced impairment of renal function. Deutsche medizinische Wochenschrift (1946) 2012, 137(38):1873–1877.

 

 

 

 

 

Accepted on 23.05.2017        © RJPT All right reserved