Membranous nephropathy caused by dimercaptosuccinic acid in a patient with Wilson’s disease: a case report and literature review

DMSA is a broad-spectrum metal chelating agent for the treatment of WD. In this case, after long-term use of DMSA, urinalysis showed proteinuria (2+) and 24-h urine protein was 4599.98 mg/24 h. Renal biopsy confirmed the diagnosis of membranous nephropathy was identified, and the laboratory tests demonstrated ANA (-), ANCA (-), and PLA2R (-). Tumor and infection indicators are normal. So, we ruled out the possibility of tumor and infection in the patient based on their clinical manifestations, tumor markers, infection indicators, blood tests, urine tests, and ultrasound results. At present, the patient is treated with oral medication to expel copper regularly, the blood copper is maintained at a low level, and the corneal K-F ring disappears. Copper staining of renal tissue showed no obvious copper particles were deposited in renal tubular epithelial cells and glomerular sacs. MN caused by WD was excluded, and there was no history of kidney disease or other renal involvement in patients. Therefore, we concluded that DMSA was the cause of membranous nephropathy in this patient.

Wilson’s disease (WD) is an inherited disorder that causes excessive accumulation of copper in the liver, brain, and other organs. The accumulation of toxic amounts of copper in the liver, brain, and other organs may cause various clinical conditions, often with prominent neurological, psychiatric, and liver-related symptoms [2]. Currently, the main treatment options for Wilson’s disease include D-penicillamine, trientine, zinc, and DMSA [3, 4] (Table 1). D-penicillamine is effective at removing copper from the body and can be used to treat all patients with symptoms of Wilson’s disease. However, it can cause a range of adverse reactions, including neurological deterioration in 10–20% of patients during the initial treatment phase. Early sensitivity reactions, such as fever, skin eruptions, lymph node swelling, neutropenia or thrombocytopenia, and protein in the urine, may occur during the first 1–3 weeks of treatment. Later effects of treatment with D-penicillamine may include nephrotoxicity, bone marrow toxicity, and dermatological toxicities. In 1969, trientine (triethylene tetramine dihydrochloride or 2,2,2-tetramine) was introduced as an alternative to D-penicillamine. Trientine is a chelator with a polyamine-like structure chemically distinct from D-penicillamine. It is similar to D-penicillamine in that it promotes the excretion of copper in the kidneys. Trientine is generally associated with fewer side effects than D-penicillamine, but it can still cause bone marrow depression [5], hepatotoxicity [6], and overly aggressive removal of copper, which can lead to neurological dysfunction. Besides, the high cost and lack of availability of trientine limit its use in China. Zinc works by inhibiting copper absorption in the intestine, It can be used as first-line treatment for asymptomatic patients, as well as maintenance treatment for ordinary patients and alternative treatment for penicillamine intolerant patients. Zinc is also effective in treating neurological symptoms associated with Wilson’s disease. It has few side effects, the most common of which are gastrointestinal irritation and numbness of the lips and limbs. Other potential adverse effects include decreased immune function and increased serum cholesterol and low density lipoprotein levels. In addition, zinc’s effects may be slow to manifest.

Table 1 Currently available oral treatments for Wilson’s disease

Dimercaptosuccinic acid (succimer; DMSA), a water-soluble analog of dimercaprol, has been used since the 1950s as an antidote for heavy metal toxicity [7]. DMSA can form complexes with copper ions and oral DMSA significantly increased urinary copper excretion [8]. DMSA was first used as a copper chelator for WD in China [9] and there are substantial experiences with the use of DMSA for WD treatment in China [10]. At present, the known side effects include: (i) Neurological deterioration: mainly manifested as increased muscular tension, mental symptoms appear or worsen. (ii)digestive tract reactions: mainly manifested as fatigue, abdominal distension, and decreased appetite. (iii) Allergic reaction: mainly manifested as fever, drug rash. (iv) Bleeding: mainly manifested as gum, epistaxis, skin petechiae, and ecchymosis [1]. However, there are few reports about membranous nephropathy caused by DMSA. The mechanism of it leading to membranous nephropathy is unclear. So far, several medications have been known to cause membranous nephropathy, mainly including: gold therapy; Penicillamine and Bucillamine; Mercury; Captopril; and NSAIDs. Wherein the penicillamine and busilamine are known to cause MN. The mechanism by which penicillamine and bucillamine produce MN is unknown but may involve modification of the immune response and/or hapten formation. Captopril is an angiotensin-converting enzyme inhibitor (ACE-I) that is commonly used to treat hypertension and reduce proteinuria. It was reported that ACEI can induce MN attributed to a sulfhydryl group, which is unique to captopril among the ACE-Is but a feature that it shares with penicillamine and bucillamine [11]. Therefore, it is speculated that mechanism by which the drugs stimulate the response may involved in the thiol group of the drugs, which permits covalent bonding to cellular macromolecules [12]. The DMSA contains two active sulfhydryl groups and has strong affinity with metal ions. Mercapto groups can covalently bind to macromolecules, making drugs containing mercapto groups may be used as haptens to induce antibody production. However, the role of DMSA in secondary MN needs to be further studied, as the literature regarding this topic is limited.

Membranous nephropathy (MN) is a glomerular disorder typified by the accumulation of an abundance of immune complexes on the epithelial aspect of the glomerular capillary loop. The prevailing clinical presentation is that of nephrotic syndrome (NS). The incidence of secondary MN constitutes approximately 30% of all cases of MN [13]. In a review of nine published series on MN, 6.6% of patients presented drug-induced disease [14]. In a cohort, a drug-induced etiology was identified in 14% of patients [15]. Pathologic findings frequently pose challenges in discriminating primary MN from drug-induced MN (DIMN), thus underlining the pivotal role of obtaining comprehensive clinical details concerning medication utilization. The treatment of MN (DIMN) begins with discontinuation of the culprit drug. In some instances, such as with gold salts, penicillamine, and bucillamine, regular monitoring of urine is necessary due to the high incidence of proteinuria and MN. Immunosuppressive therapy may be necessary in cases of severe nephrotic syndrome (NS) symptoms or lack of improvement [11]. Although DMSA induced membranous nephropathy is rarely reported, the therapeutic approaches are akin to those utilized for most drug-induced membranous nephropathy cases. In our case, hormone therapy has been verified as efficacious.

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