Non-Oliguric Acute Renal Failure Secondary to a Potentially Lethal Dose of Caffeine With Acute Intoxication: A Case Report

doi:10.21203/rs.3.rs-4893177/v1

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Case Report

Non-Oliguric Acute Renal Failure Secondary to a Potentially Lethal Dose of Caffeine With Acute Intoxication: A Case Report

https://doi.org/10.21203/rs.3.rs-4893177/v1

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Background Recently, the incidence of caffeine intoxication has been on an upward trend, with severe outcomes. However, acute kidney injury (AKI) resulting from renal pathologies secondary to caffeine intoxication is rare, and the pathophysiological mechanisms underlying AKI are unclear.

Case presentation

A female patient in her 20s ingested an over-the-counter drug containing caffeine. The patient was diagnosed with secondary non oliguric AKI caused by acute intoxication due to ingestion of a lethal dose of caffeine. On day 19 of hospitalization, a renal biopsy was performed to determine the etiology of her prolonged renal dysfunction. Light microscopy revealed normal glomeruli, mild inflammatory cell infiltration, and acute tubular damage. Myoglobin staining was positive within the tubules, with scattered myoglobin columns. Electron microscopy revealed loss of glomerular epithelial foot processes and inflated tubular mitochondria. After undergoing hemodialysis and continuous hemodiafiltration, the patient's overall condition stabilized. After a consultation with a psychiatrist, on her 34th day of hospitalization, she was discharged home.

Conclusions Caffeine antagonizes adenosine receptors, stimulates ryanodine receptors, and elevates catecholamines. The onset of AKI is hypothesized to result from a combination of these mechanisms, resulting in tubular ischemia and injury, as well as renal artery constriction. The development of AKI was thought to be caused by the following factors: (1) disruption of the tubular oxygen supply-demand ratio and consequent ischemia due to adenosine receptor antagonism by caffeine, (2) tubular damage due to rhabdomyolysis and consequent ryanodine receptor stimulation, and (3) increased catecholamine levels and consequent renal artery constriction.

acute caffeine intoxication

acute kidney injury

renal biopsy

Energy drinks and non-drowsy medications are relatively inexpensive and readily available. As the market for these drugs has expanded, cases of suicidal attempts by consuming large quantities of caffeine have resulted in successful subsequent suicides¹. Some countries are concerned regarding the increase in caffeine addiction, enacting laws restricting the amount of caffeine purchased².

Acute kidney injury (AKI) resulting from renal pathologies secondary to caffeine intoxication is rare. Therefore, we investigated the pathophysiological mechanisms underlying AKI and the manifestations thereof, by presenting a near-fatal, novel case of non-oliguric acute renal failure from myoglobinuria secondary to acute caffeine intoxication. Furthermore, the underlying etiologies were elucidated from a renal biopsy.

A female patient, in her twenties did not have a pertinent past medical history. She was an occasional drinker and nonsmoker and was taking low-dose birth-control pills. She ingested an over-the-counter drug containing 9.8 g of caffeine, as a suicidal attempt.

Seven hours post-ingestion, she experienced dyspnea and was brought to our hospital. She was conscious, however was fairly agitated. Her initial vital signs were as follows: blood pressure, 140/69 mm Hg; heart rate (HR), 230 beats/min (bpm), and respiratory rate, 24 breaths/min. Physical examination revealed pronounced, generalized sweating. Electrocardiography revealed a sustained ventricular tachycardia of 243 bpm. An arterial blood gas analysis revealed the pH, 7.32; CO2, 20.8 mmHg; HCO3, 10.6 mmHg; and lactate (Lac), 13.43. Laboratory results were as follows: leukocytes, 27,000/µL; creatine kinase (CK), 31,446 U/L; myoglobin, 7,000 ng/mL; creatinine (Cr), 1.04 mg/dL; potassium (K), 2.9 mmol/L; and C-reactive protein (CRP), 1.03 mg/dL. Additionally, the adrenaline, noradrenaline, and dopamine levels were 8510 pg/mL (reference range: 0–100 pg/mL), 15 910 pg/mL (reference range: 100–500 pg/mL), and 1558 pg/mL (reference range: 0–30 pg/mL), respectively.

Abdominal ultrasonography revealed an increased cortical brightness of both kidneys, short-axis swelling, consistent with AKI. Echocardiography revealed a low ejection fraction of 18%. The discovery of a large emptied package resulted in the primary diagnosis of acute caffeine intoxication.

Given the presence of metabolic acidosis, the patient underwent emergency hemodialysis (HD). After β-blocker administration, the HR stabilized at 120 bpm; and veno-venous HD was initiated, with the addition of a potassium. However, the patient experienced pulseless electrical activity shortly before the completion of HD. After 5 min of chest compressions, intubation, and adrenaline administration, she was successfully resuscitated. Continuous hemodiafiltration (CHDF) was promptly initiated, resulting in the gradual improvement of the HR, metabolic acidosis, and levels of consciousness. On the fifth day of hospitalization, she was extubated and CHDF was terminated. The Cr levels were on an ascending trend, resulting in the re-administration of HD, on two occasions. By the 20th day of hospitalization, the Cr levels had improved to within the standard reference range. The CK level peaked at 158 500 U/L on the third day, however, gradually decreased to lie within the reference range by the 12th day of hospitalization. The levels of catecholamines were considerably elevated on presentation, which remained until the seventh day of hospitalization. Conversely, the urinary β2-microgroblin remained markedly elevated from admission until the 15th day of hospitalization.

On the 19th day of hospitalization, a renal biopsy was performed to investigate the etiology of the prolonged renal dysfunction (Fig. 1). Ten glomeruli didn’t reveal any significant finding. Notably, focal, inflammatory cell infiltration within the interstitium, in addition to tubular epithelium denaturation and detachment from the basement membrane were observed. Myoglobin staining revealed the presence of stained tubules and scattered myoglobin columns. Fluorescence staining yielded negative results. Electron microscopy revealed a mild loss of the epithelial foot processes of the glomeruli. The mitochondria in the proximal tubular cells exhibited uniform distension with obscure cristae. The patient's overall condition stabilized. After a consultation with a psychiatrist, on her 34th day of hospitalization, she was discharged home.

The caffeine concentration was subsequently assessed using liquid chromatography–tandem mass spectrometry. Pre-dialysis, the concentration measured 24.1 µg/mL, a value within the toxic range. After 4 hours of HD and subsequent CHDF, the concentration first decreased slightly and then notably to 19.4 µg/mL and 0.69 µg/mL, respectively.

Caffeine, or 1,3,7-trimethylxanthine is a natural alkaloid commonly found in substances, including tea, coffee, and chocolate; as well as in over-the-counter medications, such as cold remedies¹. The toxic dose of caffeine is 1–3 g, while the lethal dose is approximately 150–200 mg/kg³. This case involved the ingestion of 9.8 g, which is 198.4 mg/kg, deemed to be a lethal dose.

The development of AKI resulted from the following contributors: (1) perturbation of the tubular oxygen demand-to-supply ratio, with ensuing ischemia, due to caffeine-induced adenosine receptor antagonism; (2) tubular impairment arising from rhabdomyolysis, consequent to ryanodine receptor stimulation; and (3) elevated levels of catecholamines, precipitating renal arteriolar constriction.

The diverse symptoms of caffeine intoxication are attributable to the varying effects of certain receptors, dependent on the serum caffeine concentration. Adenosine receptor antagonism, phosphodiesterase (PDE) inhibition, gamma-aminobutyric acid (GABA) receptor suppression, and ryanodine receptor stimulation are the main underlying mechanisms⁴.

Adenosine receptor antagonism, which causes gastrointestinal symptoms, headaches, and dizziness manifests at low caffeine concentrations. As the caffeine concentration increases, PDE inhibition can result in ventricular fibrillation. Simultaneously, GABA receptor inhibition results in central nervous system symptoms, including convulsions. Ryanodine receptor stimulation induces metabolic acidosis and rhabdomyolysis⁴. Moreover, severe caffeine intoxication is correlated with AKI. Three primary mechanisms underlie renal dysfunction induced by caffeine intoxication: adenosine receptor antagonism, ryanodine receptor stimulation, and catecholamine increase (Fig. 2). Adenosine exerts its effects through four receptors: A1, A2A, A2B, and A3, which are expressed in the kidneys⁵. Adenosine considerably affects the regulation of glomerular hemodynamics, by contracting and dilating the afferent and efferent arterioles, via A1 and A2 receptor activation, respectively. Additionally, adenosine possesses potent endogenous anti-inflammatory properties, potentially inhibiting inflammatory cell infiltration, endothelial adhesion, and superoxide production, via A2A receptor activation ⁶. Through A2B receptor activation, anti-inflammation occurs, by suppressing the proliferation of macrophages and reducing the activation of nuclear factor kappa B ^6,7. Adenosine may stabilize the oxygen demand-to-supply ratio, in response to the metabolic state of the kidney⁵.

Caffeine is an adenosine receptor antagonist, causing the dilation and constriction of afferent and efferent arterioles, respectively. Thus, proteinuria occurs, due to elevated intraglomerular pressure. Caffeine attenuates the anti-inflammatory effects of adenosine, exacerbates glomerular and interstitial inflammation, and triggers fibrosis⁶. Furthermore, an imbalance in the oxygen demand-to-supply ratio may directly injure the tubular epithelium.

In this case, focal infiltration of inflammatory cells was observed in the interstitium. Degeneration of the tubular epithelium and detachment of the tubular basement membrane indicated tubular injury. Electron microscopy revealed proximal tubules with swollen mitochondria; however, mitochondrial injury, due to AKI results from various etiologies⁸. Tubular ischemia occurred quite considerably, because of a disruption in the oxygen demand-to-supply ratio, induced by caffeine.

Ryanodine receptors stimulation induces skeletal and cardiac muscular contraction⁹. Via this receptor, excessive caffeine intake causes an excessive contractile response within the skeletal muscles, ultimately culminating in rhabdomyolysis. AKI secondary to rhabdomyolysis stems from multiple mechanisms, including renal vasoconstriction-induced ischemia, myoglobin-induced tubular toxicity; and obstruction of the distal tubules, by the Tamm–Horsfall protein and myoglobin complex¹⁰. In this case, the CK levels surpassed of 150 000 U༏L, on the third day of hospitalization. A renal biopsy revealed myoglobin-stained distal tubules with scattered myoglobin columns. These findings suggest that tubular injury resulted from a direct consequence of adenosine receptor antagonism and an indirect outcome of ryanodine receptor stimulation.

Furthermore, caffeine can elevate catecholamine release, by affecting the adenosine A1 receptor and adrenal medulla¹¹. Notably, substantial quantities of catecholamines cause the constriction of afferent arterioles and a reduction in the glomerular filtration rate¹². Additionally, renin secretion is induced, activating the renin-angiotensin-aldosterone system (RAAS), thus intensifying vasoconstriction¹². This could be attributed to the potent catecholamine-induced vasoconstriction and RAAS activation, outweighing any potential vasodilation due to adenosine receptor antagonism. The extent of these effects is relatively dependent on caffeine concentration; nonetheless, post-mortem investigations of those who demised from a caffeine intoxication have revealed higher caffeine concentrations in the kidneys than that in other organs^13,14. Thus, the effects of caffeine are more pronounced in the kidneys than that in other organs.

In conclusion, we report a case of AKI diagnosed as a result of potentially lethal caffeine intoxication. Together with the results of a renal biopsy, several pathophysiologic mechanisms of AKI due to caffeine intoxication were considered.

AKI Acute kidney injury

bpm Beats/min

CHDF Continuous hemodiafiltration

CK Creatine kinase

Cr Creatinine

CRP C-reactive protein

GABA Gamma-aminobutyric acid

HD Hemodialysis

HR Heart rate

K Potassium

Lac Lactate

PDE Phosphodiesterase

RAAS Renin-angiotensin-aldosterone system

Ethics approval and consent to participate

Ethical approval was not sought for the present study because a case report is a medical activity.

Consent for publication

Written informed consent for publication of the clinical details was obtained from each of the patient and a copy of each consent form is available if requested by the Editor of the journal.

Competing interests

The authors declare that they have no competing interests.

Funding

None.

Author Contribution

All authors diagnosed and treated the patients. AM drafted and KI, MY and SH critically revised the manuscript. All authors read and approved the final manuscript.

Acknowledgement

We extend our heartfelt gratitude to Tadashi Kamio and the entire Intensive Care Unit team at our hospital for their exceptional dedication and invaluable contributions to the intensive care management of the patient in this case report. Their expertise and tireless efforts were crucial in saving the patient's life and ensuring a positive outcome. Their commitment to providing excellent patient care is deeply appreciated.

Availability of data and materials

The availability of anonymized data presented in this case report can be

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No competing interests reported.

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You are reading this latest preprint version

Non-Oliguric Acute Renal Failure Secondary to a Potentially Lethal Dose of Caffeine With Acute Intoxication: A Case Report

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Abstract

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Background

Case presentation

Discussion

List of abbreviations

Declarations

Competing interests

Funding

Author Contribution

Acknowledgement

Availability of data and materials

References

Additional Declarations

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Version 1