Amiodarone is well known for many side effects, some severe and life-threatening, including pulmonary toxicity, hepatotoxicity, and thyrotoxicity. One of the organs that could also be affected by Amiodarone is the Kidney, which, fortunately, is not a common occurrence. Searching literature does not return much information regarding the renal side effects of Amiodarone. As listed in the references, There have been a few case studies.
In one study by R. Luciani et al., renal impairment has been attributed to severe hypothyroidism, caused by Amiodarone and not a direct effect of Amiodarone . In another report by Pintavorn et al., amiodarone-induced phospholipidosis was shown in the biopsy samples, but this patient has also received many other medications during hospitalization, many of them known to be nephrotoxic . Our patient started with a normal renal function in the following case and did not receive any other nephrotoxic medications. Her TSH did rise, but T4 remained normal.
An 80-year old female was referred for cardiac review after noticing an “irregular” pulse on a routine check-up. Her only complaint was slight fatigue; otherwise, she was feeling well, with good exercise tolerance. She was independent for all daily activities, driving and played tennis once a week. Her past medical history was only remarkable for hypertension and gout. Her father died from a stroke at the age of 59. She was a non-smoker with no diabetes. Her BP was 110/60 mmHg, and pulse was 115 bpm, in Atrial Fibrillation. Her physical exam was otherwise unremarkable. She was on Telmisartan HCTZ 80/12.5, Crestor 5 mg/d, Amlodipine 5 mg/d, and Atenolol 50 mg BID. Her renal function was normal.
During the first visit, she was started on Rivaroxaban 20 mg daily, and her Atenolol was switched to Sotalol, 40 mg BID, which was increased to a maximum of 120 mg BID within three weeks. Despite this higher dose, she remained in Atrial Fibrillation.
At this time, Sotalol was ceased, and she was started on Amiodarone; 400 mg TDS for three days, 400 mg BID for five days, then 200 mg/d. Two weeks later, she was in sinus rhythm and was feeling “more energetic.”
Nearly one month after initiation of Amiodarone, her Creatinine and TSH started rising (115 mmol/L and 7.9 mIu/L, respectively), while T4 remained stable. Two months later, her Creatinine was 245 mmol/L (2.77 mg/dl), and TSH rose to a maximum of 13.
As a result, most of her medications, including Rivaroxaban and Amiodarone, were ceased, and she was back on Atenolol 50 mg daily and Amlodipine 5 mg daily. She remained in Sinus rhythm and was asymptomatic. Her lab results are attached below.
One month later, after cessation of Amiodarone, she remained in Sinus rhythm, and Creatinine was improving. She was asymptomatic all along. Her BP was stable at 130/70 mmHg and heart rate 55 bpm. When eGFR reached 37, she was restarted on Rivaroxaban, 15 mg daily. Her renal function improved steadily, LV function normalized, and mitral regurgitation reduced significantly.
Extensive research has shown that Drug-induced Phospholipidosis (DIP) plays a significant role in the pathophysiology of Amiodarone-induced renal toxicity, which is an excessive accumulation of phospholipids in lysosomes of various tissue types.
Pulmonary and Hepatic Phospholipidosis has been well-recognized and documented side effects of Amiodarone, but Renal Phospholipidosis is less recognized, especially in the drug-induced form. DIP was first reported in 1948 when Nelson and Fitzhugh observed the induction of foamy macrophages in rats treated with chloroquine.
Some other drugs that are known to cause Phospholipidosis include Gentamycin, Chloroquine, and Hydroxychloroquine, as well as Perhexiline. These are cationic amphiphilic substances that cause an acquired form of Lysosomal Storage Disease by deactivating various types of lysosomal phospholipases. However, the exact mechanism of DIP is not well-known, which limits the use of some highly effective drugs, such as Amiodarone.
As more genetic links are being discovered regarding the susceptibility of individuals to develop DIP, assays become available to assess the possibility of these side effects before initiating these medications, minimising the side effects. Whether our patient has a genetic susceptibility to DIP is not known. Although there is no objective evidence of Amiodarone-induced nephrotoxicity (like a renal biopsy), in this case, the presence of a strong “temporal association” and lack of any other nephrotoxic agents or conditions significantly raises the possibility of an association between Amiodarone and Acute Kidney Disease. Regardless of the presence or absence of objective evidence, this case should raise the awareness of the presence of Drug-Induced Phospholipidosis (DIP) as a potential pathologic mechanism of Amiodarone-induced nephrotoxicity and the need to assess renal function after initiating Amiodarone.
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2. Pintavorn P, Cook WJ. Progressive renal insufficiency associated with amiodarone-induced phospholipidosis. Kidney Int. 2008;74(10):1354–1357. doi:10.1038/ki.2008.229
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