Role of Renal Replacement Therapy in Managing Toluene-Induced Acidosis

Introduction

Toluene, found in paints, thinners, adhesives, and petrol, is released into the air, water, and soil during production and use. Its high volatility poses a risk of poisoning, mainly by inhalation, causing symptoms such as drowsiness, headache, and unconsciousness [1]. Repeated exposure may also cause cognitive impairment. Toluene exposure can cause kidney damage, such as renal tubular acidosis and ureteral stones, as well as hypokalemia, cardiac arrhythmias, liver damage, hormonal abnormalities, and gastrointestinal problems [1].

The exact mechanisms of toluene toxicity remain unclear. Therefore, treatment strategies are primarily based on symptomatic management. Toluene toxicity cannot be reversed by hemodialysis [2]. Despite the high protein binding and low dialyzability of hippuric acid, hemodialysis was employed to address persistent metabolic acidosis and prevent complications. This approach aimed to enhance renal excretion in the presence of oliguria, acute kidney injury, distal renal tubular acidosis (dRTA), and acidosis unresponsive to symptomatic treatment. This intervention is crucial for managing severe electrolyte imbalances and acid-base disturbances that are not responsive to conservative therapies. Here, we report a case of acute toluene toxicity complicated by prerenal kidney injury and reversible dRTA, and describe the usefulness of hemodialysis as part of the treatment regimen.

Case Report

A 52-year-old man with a history of hypertension presented with loss of consciousness after working in the painting industry under intense heat. He had a Glasgow Coma Scale score of 10 and was agitated. Vital signs included a temperature of 36.7°C, heart rate of 81 bpm, respiratory rate of 22 breaths per minute, blood pressure of 180/111 mmHg, and SpO2 of 99% on room air. Pupils were equal and reactive, and no other physical abnormalities were noted. His blood test results are shown in Table 1. Blood tests revealed impaired renal function, and venous blood gas analysis showed elevated anion gap (AG) metabolic acidosis. Urine tests showed normal levels of N-acetyl-β-D-glucosaminidase (NAG) and β2-microglobulin (β2MG) but elevated levels of neutrophil gelatinase-associated lipocalin (NGAL) and L-type fatty acid-binding protein (L-FABP). In addition, the urine had an AG >0 and a decreased urine osmolality gap, and tested positive for urinary hippuric acid.

Bacterial cultures of both blood and cerebrospinal fluid were negative. No abnormalities were noted on the head computerized tomography (CT) scan and head magnetic resonance imaging. A coral-like stone was also identified in the right kidney on the chest through a pelvic CT scan, but no abnormalities were detected elsewhere. The electrocardiogram showed normal findings. Electroencephalogram findings were unremarkable, with no evidence of slow waves or epileptiform discharges. We suspected toluene poisoning because he had a solvent-like odor on his breath, impaired consciousness, significant metabolic acidosis, urinary AG >0, and a urinary osmolality gap ≤40, which together indicate the possibility of dRTA. Symptomatic treatment was initiated, including fluid replacement and alkali supplementation. There was no increase in the blood osmolality gap, ruling out other toxicities involving osmotic formation. Later, an increase in urinary hippuric acid was confirmed, and the patient was diagnosed with toluene poisoning. He was admitted to the intensive care unit (ICU) due to agitation. While signs of renal tubular impairment were noted initially, there was no rise in urinary NAG or urinary β2MG levels. Hemodialysis was initiated on the second day of admission, as acidosis and renal function did not improve. Blood gas analysis after hemodialysis showed improved metabolic acidosis, and urinary hippuric acid excretion increased after dialysis. Urinary NAG and urinary β2MG also demonstrated an increasing trend, with markers of tubular injury rising later than serum creatinine. Additionally, both the urinary AG and osmolality gap showed improvement over the course of treatment (Figure 1). After treatment, we assessed whether dRTA persisted as a result of toluene poisoning.

On the third day following admission, renal function improved, and even without sedatives, he became unagitated. Subsequently, there was no recurrence of worsening symptoms. Rehabilitation was initiated at the bedside, and oral in-take resumed. There were no neurological symptoms, and he was transferred to a general ward on the sixth day of admission. After stabilization of his overall condition, a furosemide and fludrocortisone loading test was conducted. The initial pH was 7.0, and over the next 3 hours, it gradually decreased to 5.0, confirming normal acidification capacity (Figure 2).

He continued rehabilitation and was discharged to home without any residual symptoms on the 24th day of hospitalization. At the follow-up visit 1 month after discharge, there was no recurrence of symptoms.

Discussion

Toluene is employed in various products, including cosmetics, ink, adhesives, and paints. It is rapidly absorbed through the respiratory tract, with 1–2% exhaled from the lungs and the remainder absorbed into the bloodstream [1]. Once absorbed, toluene tends to accumulate in fatty tissue and central nervous system tissues, where it undergoes oxidation of side-chain methyl groups and glycine conjugation to form hippuric acid in the liver, which is then excreted by the kidneys [3]. There is no specific treatment for toluene poisoning; treatment is symptomatic only. Hemodialysis is not indicated for toluene poisoning itself. Toluene is also known to directly induce AG and non-AG metabolic acidosis because of the dRTA. Mechanisms include the inability to excrete hydrogen ions as ammonium due to excessive production of hippuric acid as a metabolic byproduct and the direct effects of hippuric acid itself [4]. Toluene is thought to cause glomerulonephritis and tubular impairment, leading to the onset of acute kidney injury [1]. In this case, dehydration and toluene poisoning contributed to both prerenal and acute renal injury. Although there was no early elevation in NAG or β2MG, NGAL and L-FABP are recognized as early markers of acute kidney injury and tubular damage. The delayed rise in NAG and β2MG suggests that tubular damage due to hippuric acid was present from the onset. The early detection of NGAL and L-FABP highlights their utility in identifying tubular injury before the elevation of traditional markers. Blood hippuric acid, the main metabolite accumulated by toluene poisoning, cannot be removed by dialysis, and approximately 80% of the blood hippuric acid is removed by the kidneys [5]. Therefore, improving renal function and increasing urine output was thought to indirectly increase hippuric acid in the urine and positively impact treatment.

Acute kidney injury, dehydration, psychiatric symptoms, and rhabdomyolysis associated with toluene poisoning are considered to have a poor prognosis. In our case, the acidosis was partially corrected through systemic management, including fluids, which helped improve renal clearance and promote the excretion of toxic substances. However, despite these efforts, the response to conservative treatment was insufficient, and persistent acidosis posed a risk of worsening prognosis. To correct the acidosis and stabilize the patient, hemodialysis was initiated, not to remove hippuric acid, but to address the metabolic acidosis associated with renal failure. Hemodialysis also provided temporary renal support until the toxic substance could be naturally excreted, thereby mitigating toxicity [6,7]. Due to the poor dialyzability of hippuric acid, effective elimination largely depends on the kidneys. However, metabolic acidosis can cause constriction of the afferent arterioles, which may impair kidney function further. Early correction of acidosis is critical to restore renal perfusion and improve the excretion of toxic substances [8]. Reports suggest a proportional relationship between creatinine clearance and blood concentration of hippuric acid, indicating that early restoration of renal function may lead to accelerated excretion from the body [9]. Toluene, being lipophilic, is absorbed into the body and accumulates in fat tissues [10]. With the improvement of renal function, toluene is excreted from the body, leading to an increase in urinary hippuric acid. Elevated urinary tubular markers such as urinary NAG and β2MG result from the direct impact of hippuric acid during excretion [11]. As a result, the increased urinary hippuric acid post-dialysis likely indicates improved kidney function and acidosis correction. Hippuric acid, with a half-life of 13–72 hours, was undetectable in urine by the fourth day, indicating that it had been predominantly cleared from the body by that time.

We analyzed metabolic acidosis using the Boston method [3]. Using the Boston method, we observed AG metabolic acidosis due to acute kidney injury and hippuric acid, but based on corrected HCO3−, there was no indication of concurrent non-AG metabolic acidosis. A decrease in NH4+ excretion was observed from urinary AG and urinary osmolality gap, raising suspicion of concurrent dRTA [12]. The dRTA in toluene toxicity is attributed to direct exposure to hippuric acid and indirect exposure through metabolic acidosis and renal dysfunction. The dRTA manifests as impaired acid excretion mechanisms in the urine. Acid excretion disorder was confirmed based on the results of the urinary AG and urinary osmolality gap in this case. A dRTA is often accompanied by renal and ureteral stones due to acid excretion impairment [13]. The dRTA could partly explain the presence of a ureteral stone in our case [13,14].

Whether dRTA caused by toluene poisoning is transient or persistent remains uncertain. After the half-life period, urinary hippuric acid becomes negative, and metabolic acidosis or electrolyte abnormalities are not observed, indicating the potential reversibility of incomplete dRTA [15]. A furosemide and hydrocortisone loading test was performed to verify whether incomplete dRTA persists after the half-life period, as NH4+ loading tests are difficult to conduct at our facility. In this case, the loading test indicated no impairment in urinary acidification [16]. It was negative for incomplete dRTA, suggesting that dRTA is reversible after exposure to toluene. The absence of urinary NAG and β2MG provides additional evidence that the tubular damage induced by toluene exposure is likely reversible. Although hemodialysis for non-AG metabolic acidosis, such as in dRTA, is supported primarily by case reports, it is commonly employed to manage acute kidney injury secondary to toxin exposure [17]. In toluene poisoning, early hemodialysis has been proposed in prospective studies when poor prognostic factors, such as altered consciousness or acute kidney injury, are present [9]. Some studies have reported long-term neurological complications, underscoring the need for early diagnosis and treatment to enhance long-term outcomes [18].

Conclusions

Treatment for toluene poisoning should focus on managing dRTA and electrolyte abnormalities, which often accompany the medical history. While hydration and electrolyte correction are common treatments, in cases where metabolic acidosis persists and consciousness disorders persist, hemodialysis may be necessary to improve kidney function early and facilitate the excretion of toluene and its metabolite, hippuric acid, from the body. However, the efficacy of hemodialysis for toluene poisoning remains unclear, and further research is needed to compare it with conservative treatments. Additionally, whether the reversibility of dRTA is due to hemodialysis or could follow a similar course with conservative treatment requires further investigation.