Valacyclovir-associated acute kidney injury

Abstract

A man in his 70s presented to hospital with an acute kidney injury. He recently had started taking valacyclovir for treatment of shingles. The valacyclovir was stopped and his acute kidney injury improved. Work-up for other causes of acute kidney injury was negative and he was diagnosed with valacyclovir-associated acute kidney injury. He was discharged home after four days in the hospital with improving renal function.

Background

Valacyclovir is a commonly used antiviral drug for treatment of shingles. While it is usually safe,¹ there have been reports of acute kidney injury associated with this drug.^2–8 Clinicians should be aware of the potential for acute kidney injury as an adverse reaction to valacyclovir treatment and take steps to prevent it from occurring. This paper will present a case of valacyclovir-associated acute kidney injury and discuss its pathophysiology, diagnosis, management and prevention.

Case presentation

A man in his 70s presented to a suburban hospital emergency department complaining of dysarthria and ataxia which had developed that day, as well as two days of anorexia, nausea, malaise and a general body itch. Three days prior to presentation he had been to his general practitioner and was diagnosed with shingles in the right L1 dermatome, and had begun a course of oral valacyclovir 1 g three times per day.

His medical history included hypertension, osteoarthritis, lumbar spine radiculopathy, wet macular degeneration and type 2 diabetes mellitus. His diabetes was well controlled on oral hypoglycaemic agents and weekly dulaglutide injections. His medication list included metformin, sitagliptin, tapentadol, paracetamol, magnesium aspartate, fexofenadine, diclofenac and dulaglutide and aflibercept injections. He had no recent changes to his medication list apart from starting valacyclovir.

He lived at his home, receiving some assistance for activities of daily living as he had limited mobility secondary to his chronic back pain and knee osteoarthritis.

Routine blood tests three weeks earlier had shown that his renal function was normal, with creatinine of 66 µmol/L and estimated glomerular filtration rate (eGFR) greater than 90 mL/min/1.73 m².

On examination he was hypertensive and other vital signs were normal. He was generally weak, but there was no focal neurological deficit. Head and neck, chest, and abdomen examinations were unremarkable. He was clinically euvolaemic. There was no palpable flank mass or abdominal bruit. He had pain and tenderness to palpation of his lumbar spinal region and a vesicular rash on his right lower abdomen consistent with shingles.

Blood tests revealed acute kidney injury with creatinine of 374 µmol/L and eGFR of 13 mL/min/1.73 m². His serum sodium was 129 mmol/L, potassium was 5.5 mmol/L, bicarbonate was 17 mmol/L and urea was 14.0 mmol/L (table 1).

Table 1.

Serial biochemistry and haematology during admission

Parameter	Baseline	Day 0	Day 1	Day 2	Day 3	Day 4	Postdischarge
Creatinine (µmol/L)	66 (60–110)	374	388	260	198	140	72
Sodium (mmol/L)	132 (135–145)	129	130	131	136	135
Potassium (mmol/L)	4.3 (3.5–5.2)	5.4	5.5	4.9	4.7	4.0
Bicarbonate (mmol/L)	25 (22–32)	21	22	23	26	26
Urea (mmol/L)	6.6 (3–8)	13.9	14.0	10.2	8.7	7.3	6.5
Magnesium (mmol/L)			0.82 (0.7–1.1)	0.72
Calcium (albumin-adjusted) (mmol/L)			2.27 (2.1–2.6)	2.23
Phosphate (mmol/L)				1.35 (0.75–1.5)
Haemoglobin (g/L)	138 (135–180)	129	147	137
White cell count (×109/L)	6.53 (4–11)	9.11	8.37	6.36
Platelet count (×109/L)	167 (150–400)	127	167	143

Laboratory reference ranges are included in the first completed column of each row.

Investigations

The patient’s renal tract ultrasound was normal. Urine analysis was positive for small amounts of red and white blood cells. There were some hyaline casts seen, but no crystals. There were no muddy brown casts or dysmorphic red blood cells. Urinary albumin to creatinine ratio and protein to creatinine ratio were 40 and 157, respectively (table 2). Infectious, inflammatory, autoimmune and metabolic panels were negative (tables 2–5).

Table 2.

Urine analysis

Urine epithelial cells	<10×106/L
Urine erythrocytes	10–100×106/L
Urine leucocytes	10–100×106/L
Urine casts	A few hyaline casts seen
Urine microscopy	Cells of glomerular origin not seen
Urine culture	No growth
Urine albumin to creatinine ratio (mg/mmol creatinine)	40 (<2.5)
Urine protein to creatinine ratio (mg/mmol creatinine)	157 (<13)
Urine sodium (mmol/L)	74
Urine fractional excretion of sodium	9.79%

Table 3.

Autoimmune marker screening

Rheumatoid factor (kU/L)	<10 (<14)
Skin intercellular antibodies	0
Skin junctional antibodies	0
Antinuclear antibodies (IU/mL)	3 (<7)
Anti-Ro	Not detected
C3 (g/L)	1.42 (0.86–1.98)
C4 (g/L)	0.27 (0.16–0.52)

Table 4.

Metabolic screening

Alpha-1 globulins (g/L)	2 (2–4)
Alpha-2 globulins (g/L)	11 (5–9)
Beta globulins (g/L)	8 (6–10)
Gamma globulins (g/L)	14 (8–16)
QEP	No paraprotein detected
Free kappa (mg/L)	60.3 (3.3–19.4)
Free lambda (mg/L)	29.8 (5.7–26.3)
Kappa to lambda ratio	2.02
IgA (g/L)	5.87 (0.6–3.4)
IgG (g/L)	12.2 (5.8–13.7)
IgM (g/L)	0.29 (0.3–1.7)
HbA1c	6.4%
Ferritin (mg/L)	205 (30–620)
Iron (mmol/L)	19 (9–30)
Transferrin (mmol/L)	31 (23–43)
Transferrin saturation	31% (14%–45%)
Cholesterol (mmol/L)	3.5
Triglycerides (mmol/L)	1.7
Parathyroid hormone (pmol/L)	3.6 (1.6–9.0)
TSH (mU/L)	0.99 (0.4–4)
Free T4 (pmol/L)	14 (9–19)
INR	1.0
APTT (s)	31.9 (27.5–38.5)
Fibrinogen (g/L)	4.9 (2–4)
Albumin (g/L)	36 (35–50)
Globulins (g/L)	32 (25–42)
Bilirubin (mmol/L)	17 (<20)
ALT (U/L)	25 (<40)
ALP (U/L)	100 (30–110)
GGT (U/L)	121 (<60)

ALP, Alkaline phosphatase; ALT, Alanine aminotransferase; APTT, Activated partial thromboplastin time; GGT, Gamma-glutamyl transferase; HbA1c, Glycated haemoglobin; INR, Internal normalised ratio; QEP, Quantitative protein electrophoresis; TSH, Thyroid stimulating hormone.

Table 5.

Viral serological screening

Hepatitis B surface antigen	Not detected
Hepatitis B core antibody	Not detected
Hepatitis C antibody	Not detected
Hepatitis A IgG	Detected
Hepatitis A IgM	Not detected
EBV IgG	Detected
EBV IgM	Not detected
CMV IgG (AU/mL)	215.7
CMV IgM	Not detected
HIV antigen/antibodies	Not detected

CMV, Cytomegalovirus; EBV, Epstein-Barr virus.

Differential diagnosis

The patient presented with acute kidney injury without any obvious cause. Prerenal causes of his renal failure were considered; however, there was no intercurrent illness which would account for the decreased renal arterial perfusion and his fractional excretion of sodium was 9.79%; a value above 1% reliably rules out prerenal failure.⁹ A renal tract ultrasound was promptly obtained and this ruled out any structural or postrenal causes.

Among the intrarenal causes of acute kidney injury, drug-induced, immune or inflammatory nephritis (eg, lupus nephritis) and glomerular deposition diseases (eg, myeloma) are common causes.¹⁰ Targeted laboratory testing did not support any infectious, immune or inflammatory cause of his kidney injury. His medication history was also reviewed; potential nephrotoxins diclofenac and paracetamol had been taken within therapeutic limits for months prior to this illness without evidence of renal impairment. The combination of a strong temporal relationship between the patient’s valacyclovir usage and his kidney injury and the absence of a suitable alternative explanation led us to make the diagnosis of acute kidney injury associated with valacyclovir.

Treatment

The patient was admitted to the medical ward for supportive care and further work-up. His valacyclovir was stopped immediately and his metformin and diclofenac were withheld. He received intravenous hydration 1–2 L/day and was placed on a low-potassium diet. His urine output and fluid balance were monitored closely, as well as his serum biochemistry. His creatinine peaked at 388 µmol/L on day 1 of admission and improved every day thereafter (figure 1). His serum sodium, potassium and bicarbonate returned to within the normal range by day 4 without any specific treatment for electrolyte disturbance. He maintained good urine output during the admission and his symptoms of anorexia, nausea, malaise and itch resolved. He was discharged home on day 4.

Figure 1.

Creatinine trend.

Outcome and follow-up

The patient was reviewed at the hospital’s outpatient clinic three months after discharge. He remained well with no signs or symptoms of kidney disease. His renal function had returned to the normal range (creatinine 72 µmol/L). He remained troubled by pain from osteoarthritis of his right knee, for which he had been referred for orthopaedic review for consideration of arthroplasty. He was advised to avoid taking valacyclovir and acyclovir in the future and was discharged into the care of his general practitioner.

Discussion

Valacyclovir is a prodrug of acyclovir, a DNA polymerase inhibitor used to treat herpetic viral infections. Acute kidney injury is a known complication of acyclovir therapy, particularly in patients receiving high-dose intravenous acyclovir.^{11 12} Because valacyclovir is rapidly metabolised to acyclovir, it may have similar adverse effects.² While initially sparse, reports of valacyclovir-associated acute kidney injury are emerging.^2–8

There are several proposed mechanisms for valacyclovir nephrotoxicity. Valacyclovir’s active metabolite acyclovir is insoluble in urine, so elevated circulating levels of the drug and/or decreased glomerular filtration may lead to obstructive uropathy secondary to renal tubular crystal deposition.¹³ Other reported mechanisms of valacyclovir-associated acute kidney injury include acute interstitial nephritis and acute tubular necrosis.² Risk factors for this condition include elderly patient age, pre-existing renal disease, concurrent use of nephrotoxic medications and decreased circulating blood volume, for example, from dehydration.¹⁴

The diagnosis of valacyclovir-associated acute kidney injury is largely based on an acute rise in serum creatinine shortly after administration of valacyclovir.^{4 7} Birefringent, needle-shaped crystals (insoluble acyclovir particles) seen on urinary microscopy support the diagnosis but are not always seen.⁵ There may be muddy brown casts, indicating acute tubular necrosis.⁸ Pyuria, albuminuria, hyponatraemia, hyperkalaemia and microscopic haematuria may also be present,^{2 3 5} although these are non-specific findings. Acute kidney injury with normal urine output has been reported,^{6 8} as well as oliguria, azotaemia and anuria.^{3 4 7} Valacyclovir-associated neurotoxicity may be seen in association with acute kidney injury; manifestations include confusion, abnormal movements, stupor and coma.^{7 8} Response to cessation of valacyclovir is also an important consideration in the diagnosis of valacyclovir-associated acute kidney injury; renal function usually begins to improve within one to two days.

Recognising valacyclovir-associated acute kidney injury and stopping the medicine are key to treating the condition.^{13 14} Intravenous fluid is often administered to supplement urine production and drug excretion. Other nephrotoxic medications should be withheld.¹³ Treatment is otherwise supportive and includes strict fluid balance and urine output monitoring, as well as monitoring of serum biochemistry. Electrolyte disturbance (eg, hyperkalaemia) usually resolves with treatment of the underlying renal dysfunction but may need direct treatment if it is severe or life-threatening.³ If anuria and/or fluid overload develop, temporary renal replacement therapy may be required.^{3 4}

Valacyclovir-associated acute kidney injury may be prevented by increased awareness of the condition and its risk factors. Measurement of serum creatinine and calculation of creatinine clearance before administering valacyclovir and other potential nephrotoxins are advised. Valacyclovir should be used with caution in patients with risk factors for toxicity, particularly the elderly, and dose reduction may be necessary. Patients should be instructed to maintain adequate hydration while taking valacyclovir and be educated about the signs and symptoms of acute kidney injury and when to stop taking the drug. Patients who have had valacyclovir-associated acute kidney injury should have the episode listed on their medical record and advised to avoid using the drug in the future.

This case demonstrates a case of valacyclovir-associated acute kidney injury and illustrates the importance of a systematic approach to history and examination in such cases. Clinicians need to be aware of the risk factors for valacyclovir-associated nephrotoxicity and modify them where possible or avoid the drug altogether. The condition should be suspected in patients with acute kidney injury shortly after initiation of valacyclovir therapy. The cornerstone of treatment is cessation of valacyclovir, with other supportive treatments as indicated.

Learning points.

• Valacyclovir treatment may be associated with acute kidney injury, and clinicians should be aware of this and elicit a history of recent exposure to valacyclovir and other nephrotoxins when patients present with acute kidney injury.

• Risk factors for valacyclovir-associated acute kidney injury include elderly patient age, dehydration and concurrent use of nephrotoxic agents.

• Valacyclovir-associated acute kidney injury usually resolves quickly after stopping valacyclovir.

• The risk of valacyclovir-associated acute kidney injury can be mitigated by dose reduction where appropriate, avoiding combinations of nephrotoxic medications and maintaining adequate hydration during therapy.

Ethics statements

Patient consent for publication

Obtained.