Paraquat Poisoning 101 for the Nephrologist

Paraquat (1,1′-dimethyl-4,4′-bipyridinium dichloride) is a highly potent nonselective contact herbicide that is inexpensive and widely used in Southeast Asia, the Americas, and the Pacific (1). Although short-term dermal contact is relatively safe, ingestion has a very high fatality case rate (up to 60%–80%) (2), with a lethal dose as low as 30 mg/kg (10–20 mL of 20% solution) (1, 2). Intoxication—either accidental or deliberate—primarily happens via ingestion or inhalation, and it is a significant health concern, especially in agricultural communities.

Following ingestion, the stomach absorbs 20% of the poison, which is rapidly distributed to tissues with high blood flow and energy requirements (lungs, kidneys, liver, and muscles). Peak tissue concentrations are reached in 6 hours. Intracellularly, paraquat is oxidized in the presence of nicotinamide adenine dinucleotide phosphate hydrogen (NADPH) cytochrome P450 reductase and nitric oxide synthase, generating superoxide, peroxynitrite, and hydroxyl radicals (3). These free radicals lead to increased expression of nuclear factor-κB and activation of nucleotide-binding oligomerization domain, leucine-rich repeat, and pyrin (NLRP) inflammasome, ultimately leading to the generation of cytokines, including interleukin-1β, interleukin-18, and tumor necrosis factor α. Paraquat also induces the intracellular activity of death-associated protein kinase, which is required to assemble the NLRP protein 3 (NLRP3) inflammasome. Ultimately, NADPH depletion and free radical generation cause mitochondrial and cell membrane damage, nuclear condensation, and DNA fragmentation, culminating in apoptosis.

Paraquat is excreted, primarily unchanged by the kidneys, within 24 hours in cases of minor poisoning. However, the half-life can exceed 100 hours in patients with acute kidney injury (AKI) (4); this increases systemic exposure and worsens its toxicity. The toxin is secreted in the proximal tubular epithelial cells in the kidneys, causing tubular injury and AKI. Although there is a rapid decline in the glomerular filtration rate following paraquat ingestion, the rise in creatinine is disproportionately high (attributed to oxidative stress). Acidosis seen in the context of paraquat poisoning also increases creatinine production. It has also been hypothesized that paraquat acts as a noncompetitive inhibitor of paraquat uptake at the level of the renal tubule. Hence, cystatin C is believed to be a better marker of kidney function in patients with AKI following paraquat ingestion (5). Unlike AKI, which occurs early and reduces over a few weeks (6), lung injury is usually a delayed complication that presents as progressive pulmonary fibrosis over weeks and leads to mortality due to respiratory failure. Acute hepatitis and pancreatitis are also reported.

Initial symptoms include severe corrosive oral burns, nausea, vomiting, and abdominal pain. A generalized burning skin sensation is a sign of systemic toxicity associated with mortality. Patients with hypoxia requiring oxygen therapy almost uniformly have fatal outcomes. Ages older than 50 years, the presence of underlying kidney diseases, and development of AKI are associated with mortality. The Severity Index of Paraquat Poisoning score is a significant predictor for the development of AKI and subsequent survival (likely with a score <10%) (7). It is calculated by multiplying the time from paraquat ingestion to intensive treatment and serum paraquat levels at admission. A urine or serum dithionite test and serum paraquat concentration remain the gold standards for diagnosis. Initially, alkalemia may be present due to excessive vomiting, which later becomes lactic acidosis and respiratory acidosis. Interestingly, some ecological studies have linked chronic exposure of paraquat to the development of chronic kidney disease; however, this needs further evaluation (8).

The treatment of paraquat poisoning is primarily supportive, and none of the treatment modalities shows benefit in later stages, even when used aggressively in combination. Decontamination with activated charcoal or Fuller's earth is recommended within 2–4 hours of ingestion. The latter is preferred, as clay inactivates paraquat. Gastric lavage is contraindicated (5). Resuscitation with large volumes of crystalloids may be required in patients with delayed presentation to avoid hypovolemia. Oxygen therapy must not be administered until hypoxia is confirmed, as it exacerbates free radical injury. Extracorporeal therapy (hemoperfusion or hemodialysis) for toxin removal is useful only within the first 4 hours of paraquat ingestion.

The efficacy of hemoperfusion in paraquat poisoning is also controversial, as it does not reduce uptake in the lungs, and the toxin may rebound from tissues after the procedure. Once AKI sets in, the hemodialysis indications are as per standard indications. Hemoperfusion reduces paraquat absorbed by the lungs by a negligible amount (9). Alveolar inflammation following paraquat ingestion has been treated by intravenous high-dose dexamethasone and cyclophosphamide in smaller studies with equivocal results (10).

Other experimental therapies include antioxidants (N-acetylcysteine, high-dose vitamin C), salicylic acid, deferoxamine, and vitamin E. Edaravone is being evaluated in paraquat poisoning, which, owing to its antioxidant and anti-inflammatory properties, can delay the development of AKI and pulmonary fibrosis (11).

Owing to its lethal nature, the use of paraquat has been banned in the European Union, Sri Lanka, Kuwait, South Korea, Indonesia, and the Philippines. However, it continues to be widely used throughout Mexico, the United States, Latin America, and Southeast Asia due to its low cost and effective results as an herbicide and pesticide (12). It is time to give a clarion call to authorities to either ban this toxin or restrict its availability to only licensed pesticide applicators in nonresidential areas to reduce fatal human exposures.

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