Antiepileptic drug-induced severe granulomatous interstitial nephritis

Background

Granulomatous interstitial nephritis (GIN) is a type of tubulointerstitial nephritis characterised by tubulointerstitial infiltration of mononuclear cells and eosinophils. It accounts for about 6% of all tubulointerstitial nephritis1 and is detected in ∼0.5–0.9% of all renal biopsies. GIN has been linked to several antibiotics, non-steroidal anti-inflammatory drugs (NSAIDs), and granulomatous disorders like tuberculosis (TB) and sarcoidosis but is rarely reported with antiepileptic medications like phenytoin and levetiracetam.2 3

Levetiracetam is an antiepileptic medication that modulates synaptic neurotransmitter release by binding to the synaptic vesicle protein SV2A in the brain.4 It is predominantly excreted by the kidneys and requires dose adjustment according to the glomerular filtration rate. Phenytoin is a non-specific sodium channel blocker that is metabolised by the hepatic P450 enzyme system accounting for many of its drug–drug interactions, Less than 5% of phenytoin is excreted unchanged in the urine. Drug-induced GIN responds well to steroid therapy and discontinuation of the causal drug, which may lead to improvement in the patient’s renal function. Very few case reports have been published about antiepileptic drugs causing GIN.5

Case presentation

A man in his early 20s presented to the emergency department with a 4-day history of fever, cough with frothy sputum and shortness of breath. He had a history of neurocysticercosis and had suffered seizures for 7 years . During that time, he was initially prescribed levetiracetam 500 mg twice daily and phenytoin 300 mg once daily. Four years later, the dose of antiepileptics was increased to 1500 mg twice daily and 300 mg once daily, respectively, and a third antiepileptic clobazam 5 mg once a day was added due to a recurrence of seizures. At the time of initiation of therapy for seizures, the patient’s serum biochemistry results were within normal limits. These tests were not repeated. The patient was seizure free for 3 years prior to this index admission with good compliance to medication.

In this index admission, the patient presented to the emergency department with a 4 days history of high grade fever not associated with chills or rigors but responses toantipyretics. He had generalised weakness and decreased urine output. He also had a 4-day history of shortness of breath, initially on exertion which gradually progressed to breathlesness at rest, associated with orthopnoea and paroxysmal nocturnal dyspnoea. This was associated with expectoration of pink frothy sputum. There was no history of rash, abdominal pain or loose stool. There was no previous history of TB or illicit substance abuse. There was no history of NSAIDS use in past.

On examination, the patient was conscious and oriented. His blood pressure was 178/96 mm Hg, blood sugar was 136 mg/dL and oxygen saturation was 58% on room air. In the respiratory examination, bilateral diffuse coarse creptitations were heard. The rest of the systemic examination was within normal limits. There was no rash, organomegaly or lymphadenopathy.

Investigations

Blood and urine laboratory tests revealed (table 1)raised creatinine of 9.7 mg/dL and urine protein of 3+ on dipstick. Twenty-four hour urine protein was 5 g/day. Peripheral blood smear showed eosinophilia. Vitamin D was low at <8 ng/mL and parathyroid hormone (PTH) was raised with a value of 516 pg/mL. Urinanalysise did not reveal any active sediments. Chest X-ray showed diffuse fluffy opacities in bilateral lung fields suggestive of pulmonary oedema.

Ultrasound examination of the abdomen showed normal sized bilateral kidneys, with bilateral increased renal cortical echogenicity, suggestive of medical renal disease. No calculous or hydronephrosis was seen. Renal artery Doppler examination revealed an increased resistance index in segmental branches of the right renal artery with increased acceleration time. A 2D echocardiogram showed concentric left ventricular hypertrophy with grade II left ventricular diastolic dysfunction and normal ejection fraction consistent with a previous history of hypertension. Non-contrast head computerized tomography showed multiple calcified granulomas with no perilesional oedema.

Autoimmune serology including antinuclear antibodies was negative. Hepatitis B, HCV and HIV serologies were all negative. A drug-induced chronic systemic reaction was suspected in view of eosinophilia.

A kidney biopsy was performed and subsequently revealed changes of nephropathy with interstitial nephritis, a moderate degree of chronic parenchymal damage(figure 1) and epithelioid cell granulomas in interstitium(figure 2). Staining for acid-fast bacilli was negative.

Differential diagnosis

The patient was diagnosed as a case of GIN. Differential diagnosis of tubercular or fungal aetiologies, granulomatosis with polyangitis, sarcoidosis and drug-induced GIN were considered.

Treatment

Patient was stabilised with oxygen support, diuretics (furosemide) and nitroglycerin infusion for pulmonary oedema with hypertension. His blood pressure was controlled with calcium channel blockers (amlodipine), alpha 2 agonists (clonidine) and beta blockers (carvedilol).

In spite of adequate hydration, the patient’s renal function continued to deteriorate, and serum creatinine deteriorated to 10.4 mg/dL on day 4. The patient was dialysed once because of volume overload state and persistent severe metabolic acidosis. The patient became stable. There was no further requirement of dialysis.

On further workup, diagnosis of drug induced GIN was made and the patient was treated with pulsed steroid followed by oral prednisolone tapered over 3 months.

Outcome and follow-up

On 6-month follow-up, the patien’s renal function improved(table 2) with glomerular filteration rate, improving from 7.1 mL/min/1.73 m2 to 30.7 mL/min/1.73 m2. The 24-hour urine protein reduced from 2.4 g/day at discharge to 0.6 g/day.