Carbimazole induced nephrotoxicity.

Sir,

Carbimazole used in the treatment of hyperthyroidism may rarely cause an acute kidney injury (AKI) and this can gradually progress to chronic kidney disease (CKD), if left undiagnosed. The exact mechanism is not yet clear.[14]

We encountered a 46-year-old married woman, referred by the nephrologist to us, for optimizing the management of hyperthyroidism as Carbimazole-induced nephrotoxicity was being suspected. She was initially diagnosed to have mild subclinical hyperthyroidism in 2009, 6 months after the delivery. However, she was not given any antithyroid medication. Later, her Thyroid function test (TFT) had become normal and her Ultrasonography (USG) neck showed a small multi-nodular goiter (MNG). Fine Needle Aspiration Cytology (FNAC) revealed only a benign nodule. She was advised to repeat TFT every 6 months and was on regular follow-up for nearly 10 years. In 2019, her TSH was found to be 0.01 mIU/L. This prompted her family physician to initiate her on tablet Neomercazole. In 2018, her baseline creatinine was 1.2 mg/dL; from then on, it began to gradually rise and it reached 2.1 mg/dL when she came to us in April 2021. She had no history of taking ayurvedic treatment or Non-steroidal anti- inflammatory drugs (NSAIDs) on a regular basis. In 2021, her abdominal ultrasound showed grade 2 renal parenchymal disease. Her anti-nuclear antibodies (ANA) status was positive and the ANA profile showed that histones were strongly positive (+++), Sjogren syndrome type A antigen (SSA) was positive (+) and dsDNA was borderline positive. All these were suggestive of drug-induced lupus nephritis [Table 2].

Table 2

Laboratory parameters of the patient[5]

Parameters	Before discontinuation of Neomercazole and thyroidectomy		After thyroidectomy and discontinuation of Neomercazole
	8/4/2021	14/4/2021	22/4/2021	05/5/2021	21/5/2021	3/6/2021	7/06/2021
Creatinine	1.96		2.13	1.58	1.64	1.76	1.60
Urea		36.4	51.3		54.2
FBS					104
HbA1C		5.5
GRBS		132
Urine Albumin	2+				1+
dsDNA	Borderline +
Histones	+++
TSH	0.79
Free T4	1.16
Anti-TPO antibody	0.51
Anti-TSH receptor antibody	<0.8

The criteria used in the diagnosis of drug-induced lupus erythematosus (DILE) are:[12]

Exposure to a medication known to be associated with DILE

Absence of clinical history of SLE

Presence of ANA and anti-histone antibodies (>75%)

Clinical improvement and progressive lowering of ANA titers after drug discontinuation

Her TFT was normal and the USG neck showed an MNG with nodules ranging from Thyroid Imaging Reporting and Data Systems (TIRADS 2) to TIRADS 4. USG-guided FNAC of the TIRADS 4 nodule was difficult as it was only 0.4 cm in size. In view of the fact that Carbimazole is a likely culprit causing renal injury (in the context of anti-histone antibody positive), we felt it was prudent to definitely cure her hyperthyroidism and also eliminate the risk of thyroid cancer (TIRADS 4 nodules) with a total thyroidectomy as she was currently euthyroid. She could have relapsed to hyperthyroidism if the surgery was delayed and it would be difficult to re-introduce antithyroid medication in this clinical setting. Thus, a total thyroidectomy was done on April 15, 2021. Then, she was initiated on tablet thyroxine 100 mg AM OD. After 2 weeks, her serum creatinine was found to be approaching the baseline levels (serum creatinine: 1.5 mg/dL) [Table 2].

In this case, the serum creatinine increase was consistent with Kidney Disease Improving Global Outcomes (KDIGO's) definition of CKD stage III a, and the timing of both the increase with the initiation of Carbimazole and the decrease with the withdrawal of Carbimazole was significant. For further clarity, we have attached the laboratory reports and biopsy report of the patient.

BIOPSY REPORT

Right lobe and isthmus: follicular adenoma

Left lobe: Multi-nodular goiter with degenerative changes. Toxic goiter with treatment-related changes.

A similar condition to this is described in a case report published by Shella and Sullivan[3] that depicts the condition of a 72-year-old man who was treated with Methimazole for his hyperthyroidism and following which, he developed AKI. In this patient, the baseline serum creatinine had risen 1.6 times above the baseline within 1 month of Methimazole initiation and returned to baseline within 2 weeks of discontinuation of the same. This case scenario adds strength to the case above.[3]

The relationship of Carbimazole initiation and discontinuation with serum creatinine change lends significant credence to its causative likelihood.

A Naranjo nomogram can be used to decide whether any drug is likely to be a culprit in an adverse drug reaction [Tables 1 and 3].[5]

Table 1

Naranjo nomogram[5]

Score	Interpretation
Total score ≥9	Definite
Total score 5-8	Probable
Total score 1-4	Possible
Total score ≤0	Doubtful

Table 3

Naranjo nomogram as applied to this patient

1. Are there previous conclusive reports on this reaction? (1/0/0)	1 (Carbimazole has a documented association with nephritis)
2. Did the adverse event occur after the suspected drug was administered? (2/1/0)	2 (Serum creatinine increased 1.75 times above the baseline in the absence of other contributing nephrotoxins)
3. Did the adverse reaction improve when the drug was discontinued or a specific antagonist was administered? (1/0/0)	1 (Serum creatinine returned to baseline within 2 weeks of Carbimazole discontinuation)
4. Did the adverse reaction reappear when the drug was re-administered? (2/1/0)	0 (Carbimazole was not re-administered)
5. Are there alternative causes (other than the drug) that could have caused the reaction? (1/2/0)	2 (The patient’s presentation is not consistent with pre-or postrenal AKI, and no other medication changes were made after Carbimazole initiation)
6. Did the reaction reappear when a placebo was given? (1/1/0)	0 (Placebo was not administered)
7. Was the drug detected in the blood (or other fluids) in concentrations known to be toxic? (1/0/0)	0 (Carbimazole concentrations are not routinely monitored; thyroid function tests did not demonstrate hypothyroidism)
8. Was the reaction more severe when the dose was increased or less severe when the dose was decreased? (1/0/0)	0 (Carbimazole dose was not adjusted; Carbimazole was discontinued)
9. Did the patient have a similar reaction to the same or similar drugs in any previous exposure? (1/0/0)	0 (The patient had not previously taken Carbimazole and had not ever been on propylthiouracil)
10. Was the adverse event confirmed by any objective evidence? (1/0/0)	1 (Laboratory monitoring demonstrated increased serum creatinine, and anti-histone antibodies, which are a feature of drug-induced toxicity, were also positive)
Total points	7 (Probable adverse reaction)

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Conflicts of interest

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