Levamisole in steroid-sensitive nephrotic syndrome: usefulness in adult patients and laboratory insights into mechanisms of action via direct action on the kidney podocyte

Abstract

Minimal change nephropathy (MCN) is the third most common cause of primary nephrotic syndrome in adults. Most patients with MCN respond to corticosteroid therapy, but relapse is common. In children, steroid-dependent patients are often given alternative agents to spare the use of steroids and to avoid the cumulative steroid toxicity. In this respect, levamisole has shown promise due to its ability to effectively maintain remission in children with steroid-sensitive or steroid-dependent nephrotic syndrome. Despite clinical effectiveness, there is a complete lack of molecular evidence to explain its mode of action and there are no published reports on the use of this compound in adult patients. We studied the effectiveness of levamisole in a small cohort of adult patients and also tested the hypothesis that levamisole's mode of action is attributable to its direct effects on podocytes. In the clinic, we demonstrate that in our adult patients, cohort levamisole is generally well tolerated and clinically useful. Using conditionally immortalized human podocytes, we show that levamisole is able to induce expression of glucocorticoid receptor (GR) and to activate GR signalling. Furthermore, levamisole is able to protect against podocyte injury in a puromycin aminonucleoside (PAN)-treated cell model. In this model the effects of levamisole are blocked by the GR antagonist mifepristone (RU486), suggesting that GR signalling is a critical target of levamisole's action. These results indicate that levamisole is effective in nephrotic syndrome in adults, as well as in children, and point to molecular mechanisms for this drug's actions in podocyte diseases.

Clinical practice guidelines for the provision of renal service in Hong Kong: General Nephrology

“…(R)Mycophenolate (MMF) or cyclophosphamide (CTX) for the same duration are alternatives, particularly for patients who cannot tolerate high dose corticosteroids. Levamisole may also be considered For steroid‐resistant MCD, addition of calcineurin inhibitor can be considered.…”

Current understandings in treating children with steroid-resistant nephrotic syndrome

“…Levamisole was shown to be effective in reducing the frequency of relapses in adult patients with SSNS [91], which was supported by a systematic review of RCTs [92]. In children with SSNS, a recent open-label RCT showed that levamisole had comparable and satisfactory efficacy compared to MMF in maintaining sustained remission [93].…”

“…Levamisole is a synthetic imidazole derivative which, instead of suppressing immunity, enhances humoral immune response and macrophage activation [89] and induces type 1 (Th1) and type 2 (Th2) T-cell responses through enhancing IL-18 activity [90]. In a human podocyte model, levamisole was shown to induce expression of glucocorticoid receptor, and it has been suggested that glucocorticoid signalling is a critical target of levamisole action [91].…”

Levamisole therapy in children with frequently relapsing and steroid-dependent nephrotic syndrome: a single-center experience

“…Jiang reported that levamisole induced expression of glucocorticoid receptor (GR) and activated GR signaling in podocytes. Furthermore, levamisole was able to protect against podocyte injury in a puromycin aminonucleoside (PAN)-treated cell model [8]. …”

“…Numerous studies suggest that levamisole reduces the frequency of relapses and corticosteroid doses in children with FRNS and SDNS [8–16]. In most cases levamisole therapy did not cause any severe side effects.…”