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What should I do if acyclovir encounters acute renal failure?
Acyclovir, which is widely used clinically to treat herpesvirus infections, especially herpes simplex virus (HSV) and varicella-zoster virus.
However, as early as 2009, the State Drug Administration (NMPA) revised the drug instructions for acyclovir to add a black box warning that acyclovir can cause acute renal failure.
Image source: Screenshot of NMPA's official website
Then, when encountering patients with acute renal insufficiency or chronic kidney disease, how to adjust the dose/treatment regimen of acyclovir, or how to assess the risk of continuing acyclovir treatment, often confuses clinical workers.
The mechanisms by which acyclovir may cause acute kidney injury (AKI) and possible adjustments or alternatives are sorted out for the reader's reference.
01
Mechanism of acyclovir-induced acute renal failure[1]
Acyclovir has a low protein binding rate (9%-33%), drug metabolism is mainly through the liver, the main metabolites produced account for only 9%-14% of the administered amount, and about 45%-79% of the drug is filtered by the glomeruli in its original form and secreted through the renal tubules. And acyclovir has low solubility in urine, with a maximum solubility of 2.5 mg/mL at physiological pH.
If this low urinary solubility and high urinary output are accompanied by a decrease in urine output, it is easy to cause the drug to form crystals in the renal tubules, and with the accumulation of crystals in the renal tubules, eventually lead to tubular blockage and then cause kidney damage.
In addition, acyclovir may also trigger direct damage to tubular epithelial cells, leading to tubular cell degeneration and detachment, eventually causing acute renal failure and tubular dysfunction.
A large number of literature has proved that intravenous acyclovir is associated with AKI, and its incidence is 12%-48%, and the vast majority occurs within 2-3 days of medication, mainly rapid onset. However, the prognosis is usually good. The fastest recovery is 2 days, the longest is 2 weeks, and the recovery cycle is generally 7-15 days [2-4].
02
Independent risk factors for inducing AKI[2]
Renal insufficiency: an important independent risk factor for AKI (in patients with chronic kidney disease, daily monitoring of renal function is recommended for the first 2-3 days of use).
Diabetes: an important independent risk factor for AKI.
Concomitant use: vancomycin, NSAIDs (children should be wary of AKI that may be triggered by ceftriaxone plus acyclovir).
03
Difference between oral and intravenous [5-7]
Oral absorption of oral acyclovir is poor, about 15% to 30% is absorbed by the gastrointestinal tract. In pharmacokinetic studies, the steady-state peak plasma concentration of intravenous acyclovir (5-10 mg/kg per 8 hours) is 10-20 μg /ml, compared with only 0.6-1.6 μg/ml after multiple oral doses (200-800 mg).
▌Oral is mainly suitable for:
(1) Herpes simplex virus infection: it is used for the initial onset and recurrence of genital herpes virus infection, and this product is taken orally for prevention in recurrent cases.
(2) Shingles: it is used for the treatment of mild cases of herpes zoster and immunodeficiency in immunocompromised patients.
(3) Treatment of chickenpox in immunodeficient patients.
▌ Veins are mainly suitable for:
(1) Herpes simplex virus infection: it is used for the treatment of initial and recurrent mucosal skin infections in immunodeficiency patients and the prevention of recurrent cases, and is also used for the treatment of herpes simplex encephalitis.
(2) Shingles: it is used for the treatment of diffuse shingles in patients with severe immunodeficiency or diffuse shingles in immunocompromised patients.
(4) Treatment of acute retinal necrosis.
Conventional oral doses may result in the inability to reach therapeutic blood levels in severe infections.
04
How to prevent and deal with it
Acyclovir-induced renal failure [2,6-8]
1. Fully assess the patient's clinical basic situation and medication history, such as weight, kidney function, concomitant medication, underlying disease, allergy history, vancomycin and the use of nonsteroidal anti-inflammatory drugs.
2, in strict accordance with the instructions for the use of acyclovir dosage:
Dosage: Adults commonly used amount, according to body weight once 5-10mg / kg, every 8h instillation, a total of 5-10 days, the maximum daily dose of adults according to body weight of 30mg / kg, every 8h should not exceed 20mg / kg. The common amount of children, 250mg-500mg/m2 once according to body surface area or 10mg/kg once per body weight, 3 times a day, once every 8h instillation, for a total of 5-10 days, the highest dose in children is 500mg/m2 per body surface area every 8h.
Concentration: Acyclovir instructions on the preparation of the liquid prompt to take 0.5g of this product into 10ml of water for injection, so that the concentration is 50g / L, fully shake into a solution, and then dilute with sodium chloride injection or 5% glucose injection to 100ml, the final drug concentration of the preparation does not exceed 7g / L.
Drip rate: only for intravenous infusion, each infusion time is required to be more than 1h. Intravenous infusion should be done slowly, otherwise the drug crystal precipitation in the renal tubules may occur, causing damage to renal function.
Renal insufficiency: The instructions state that intravenous infusion of acyclovir should not be used in patients with acute or chronic renal insufficiency, but it is not included in the contraindications. A study analysis found that a reasonable adjustment of the dose of acyclovir in patients with chronic renal insufficiency did not significantly increase the incidence of AKI. In the case that other alternative drugs are not available, the dose should be adjusted for patients with chronic renal insufficiency, and carefully observe whether there are signs of renal failure (oliguria, anuria, hematuria, low back pain, bloating, nausea, vomiting, etc.), monitor the urine routine and renal function glomerular filtration rate can change, and stop the drug as soon as there is an abnormality.
Dose adjustment in case of renal insufficiency (intravenous):
Glomerular filtration rate (GFR): 50-80 ml/min, 5-10 mg/kg q8h, intravenous infusion;
GFR: 10-50 ml/min, 5-10 mg/kg q24h, intravenous infusion;
GFR: < 10 ml/min, 2.5-5 mg/kg q24h, intravenous infusion;
Hemodialysis: 2.5-5 mg / (kg ·d), intravenous infusion after extubation;
Peritoneal dialysis: 2.5-5 mg / (kg·d), intravenous infusion;
Continuous arteriovenous hemofiltration: 3.5 mg / (kg·d), intravenous infusion;
Continuous venous-venous hemofiltration: 5 to 10 mg/(kg·d) intravenous infusion.
Dose adjustment in case of renal insufficiency (oral):
Table 1 Oral dose adjustment of acyclovir in patients with renal insufficiency
Concurrent use of drugs: avoid the combination of nephrotoxic drugs, which may increase the risk of renal dysfunction.
Hydration: in intravenous infusion for 2 h, the concentration of the drug in the urine is highest, at this time the patient should be given sufficient water to prevent the drug from depositing in the renal tubules.
3. Once the AKI treatment measures occur[2]
(1) Immediately stop the drug, timely symptomatic treatment including the use of loop diuretics, body fluids and volume management.
(2) For patients with severe infections that cannot be stopped, it may be necessary to adjust the dose, and CRRT treatment may be required if necessary.
bibliography:
[1] Izzedine H,Launay-Vacher V,Deray G.Antiviral drug-induced nephrotoxicity. Am J Kidney Dis.2005;45(5):804-817.
[2] Lee EJ，Jang HN，Cho HS，et al. The incidence，risk factors，and clinical outcomes of acute kidney injury（staged using the RIFLE classification）associated with intravenous acyclovir administration. Ren Fail.2018;40（1）:687-692.
WANG Chunting. Analysis of Acute Renal Failure and Irrational Use of Acyclovir, Pharmacovigilance 2007, 4(5): 268-272.
Xu Bing. Clinical analysis of 13 cases of acute renal failure caused by acyclovir[J].China Clinical Research,2014,27(4):2.
[5] Lam NN，Weir MA，Yao Z，et al. Risk of acute kidney injury from oral acyclovir:a population-based study. Am J Kidney Dis.2013;61（5）:723-729.
[6] Instructions for acyclovir for injection, implementation of the standard Chinese Pharmacopoeia 2020 edition of the second part, Furen Pharmaceutical.
[7] Instructions for acyclovir tablets, the implementation of the standard Chinese Pharmacopoeia 2020 edition of the second part, Shandong Qidu Pharmaceutical.
[8] Diagnosis and treatment of infectious diseases, second edition.
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