Rifampicin-associated intravascular haemolysis causing acute kidney injury

INTRODUCTION

Rifampicin is used for both active and latent tuberculosis (TB) and is generally a well-tolerated drug in the antituberculous therapy (ATT) regimen.¹ Gastrointestinal symptoms, hepatotoxicity and drug interactions are the common side-effects of rifampicin. Rarely, rifampicin can cause acute kidney injury (AKI) and multiple mechanisms have been proposed for rifampicin-induced AKI.² We present a patient who had multiple prior exposures to ATT over several years and abruptly developed AKI after re-introduction of rifampicin following a short drug-free interval of 20 days.

THE CASE

A 53-year-old male, who had diabetes, and took ATT for pulmonary TB 30 years ago, presented with sputum-positive, isoniazid mono-resistant pulmonary TB. He was started on modified ATT (levofloxacin 500 mg, rifampicin 450 mg, pyrazinamide 1000 mg and ethambutol 750 mg). His baseline creatinine before starting ATT was 0.9 mg/dl. On completion of a 9-month course of the modified ATT, he stopped his medication and presented 20 days later to his pulmonologist. He was advised to continue ATT for another month for residual lesions of TB. However, within 7 days of resuming ATT, he developed nausea, vomiting, loss of appetite and decreased urine output. Blood investigations showed a serum creatinine of 15.8 mg/dl (Table I). He was started on haemodialysis for uraemic symptoms and his ATT was withheld. His serum lactate dehydrogenase was elevated at 451 IU/L and a polyspecific direct antiglobulin test was positive. Ultrasound abdomen revealed normal-sized kidneys with maintained corticomedullary differentiation with no features of obstruction. A renal biopsy was done which showed tubules occluded with pigment casts that stained positive for haemoglobin on immunohistochemistry (Fig 1). Immunohistochemistry for myoglobin was negative (Fig 1). Light microscopy images showed acute tubular injury with pigment casts.

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FIG 1.

(a) Immunohistochemistry for haemoglobin is positive on the pigment casts, (b) immunohistochemistry for myoglobin is negative on the pigment casts, (c) haematoxylin and eosin staining, (d) periodic acid Schiff staining, (e) Masson trichrome staining and (f) periodic Schiff–methenamine staining

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His urine output gradually improved after 3 days, and dialysis was stopped after a total of 4 sessions. He had a full renal recovery, with a nadir creatinine of 0.9 mg/dl on day 14.

DISCUSSION

TB is a major public health challenge globally and an estimated 10.6 million incident cases of TB were reported in 2021.³ Drug-induced immune haemolytic anaemia (DIIHA) is a rare complication of ATT that results primarily due to drug-induced antibodies. These antibodies can be either drug dependent or drug independent. DIIHA is relatively rare with an estimated occurrence of 1 in a million people.⁴ In 1967 only 13 drugs were considered to cause DIIHA but in 2007 around 125 drugs were identified to cause DIIHA and the number keeps increasing.⁵ The most common class of drugs that can cause DIIHA are antimicrobials followed by anti-inflammatory drugs. AKI is a rare complication in patients taking ATT, and rifampicin is the drug most commonly associated with AKI.² The exact incidence of rifampicin-associated AKI is not known but <0.1% of patients with TB are reported to have this condition.²

Since these demographics are different from the Asian countries where the incidence of TB is high, the same data may not apply to the Indian population. In another study done at a tertiary care hospital in southern India in 3300 AKI patients over 6 years, 20 patients had biopsy-proven pigment cast nephropathy and 7 patients had rifampicin-associated AKI.⁶

The mechanism of rifampicin causing AKI is not clear and multiple possible mechanisms been proposed. Acute interstitial nephritis (AIN) is the most frequently associated pathological finding on biopsy, followed by acute tubular necrosis (ATN). Other patterns such as crescentic glomerulonephritis, mesangial proliferation, minimal change disease and acute interstitial nephritis with pigment cast nephropathy have been reported less frequently.⁷ The type of AKI depends on the treatment regimen and also whether it is taken regularly or intermittently. ATN seems to manifest more commonly after intermittent use, whereas AIN manifests with uninterrupted therapy.² On daily regimens, the continuous formation of antigen–antibody complexes prevents the rise in free antibody titre to dangerous levels. However, a rise in titre does occur with intermittent dosage regimens or prolonged discontinuation and subsequent reinstitution of treatment.⁸

Our patient who had already completed the ATT course twice, developed intravascular haemolysis-related AKI while restarting rifampicin after 20 days. Hence, acquiring a proper history of ATT intake in the past is important before restarting ATT, along with the careful monitoring of renal function tests. Since ATT-induced hepatitis is a well-known complication of ATT, liver function tests are monitored in most centres, but the same cannot be said for renal function tests. Although rare given that ATT drugs can cause AKI and sometimes severe requiring dialysis, proper monitoring of renal function test should be done while the patient is on ATT. Treatment is often as simple as stopping the offending drug and providing supportive care. This case highlights that those who develop AKI while on ATT, rifampicin-associated intravascular haemolysis has to be kept as a differential diagnosis.