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      The effect of levamisole on kidney function in children with steroid-sensitive nephrotic syndrome

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          Abstract

          Background

          Levamisole is frequently used as a steroid-sparing agent in children with steroid-sensitive nephrotic syndrome. Side effects, such as neutropenia, gastro-intestinal upset and skin rash, have been reported. We noted an increase in creatinine in some of our patients, but literature on the effect of levamisole on kidney function is lacking.

          Methods

          A retrospective cohort study was conducted, including patients 1–18 years of age, treated for steroid-sensitive nephrotic syndrome with levamisole at Great Ormond Street Hospital for Children between January 2010 and January 2020. Data was collected on clinical observations and serum creatinine values before, during and after treatment. eGFR was calculated using the Schwartz equation.

          Results

          In total, 75 children were included in the analysis. The median duration of treatment was 19 (IQR 12–27) months. The median estimated GFR was 134 (IQR 119–160), 101 (IQR 91–113) and 116 (IQR 106–153) ml/min/1.73 m 2, respectively, before, during and after treatment with levamisole. The difference between eGFR before and after treatment compared with during treatment was statically significant ( P < 0.0001). During the treatment period, the eGFR decrease was not progressive. The median levamisole dose was 2.5 (IQR 2.3–2.6) mg/kg on alternate days, and the dose was not correlated with the decrease in eGFR ( r = 0.07, 95% CI − 0.22 to 0.35).

          Conclusion

          Levamisole significantly decreases eGFR. However, this decrease is not progressive or irreversible and would not be an indication to discontinue the treatment.

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          Most cited references10

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          Serum creatinine is a poor marker of GFR in nephrotic syndrome.

          In daily clinical practice creatinine clearance is used as marker of glomerular filtration rate (GFR). As a result of the tubular secretion process endogenous creatinine clearance (ECC) overestimates glomerular filtration rate, particularly in patients with impaired renal function. It has been suggested that the tubular handling of creatinine is altered in patients with a nephrotic syndrome. Inulin clearance (GFR) and creatinine clearance (ECC) have been simultaneously measured in a cohort of 42 patients with proteinuria and 45 healthy controls. The clearance of creatinine by tubular secretion (TScreat) can be estimated by ECC-GFR. TScreat was calculated in both groups. Regression analysis was performed to identify factors that independently influence tubular creatinine secretion. The mean age (+/-SD) of the patients was 41+/-13 years, serum albumin 26+/-9 g/l, median (IQR) proteinuria 4.5 (3.6-8.2) g/10 mmol creatinine, serum creatinine 103 (84-143) micromol/l, ECC 85 (69-118) ml/min/1.73 m2, and GFR 54 (36-83) ml/min/1.73 m2. Median TScreat amounted to 29 (21-36) ml/min/1.73 m2. In the healthy controls serum creatinine was 75 (70-81) micromol/l, ECC 118 (109-125) ml/min/1.73 m2, GFR 106 (102-115) ml/min/1.73 m2, and TScreat 11 (3.5-19) ml/min/1.73 m2. By regression analysis serum albumin was identified as an independent predictor of tubular creatinine secretion. We divided the patients in two subgroups based on serum albumin levels. TScreat was 24 (14-29) ml/min/1.73 m2 in patients with serum albumin levels >25.8 g/l, and 36 (28-54) ml/min/1.73 m2 in patients with serum albumin levels <25.8 g/l (P<0.01). Serum albumin levels influence tubular creatinine secretion. As a result, the endogenous creatinine clearance as well as estimated GFR using a modified MDRD equation more pronouncedly overestimate glomerular filtration rate in nephrotic syndrome.
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            A randomized clinical trial indicates that levamisole increases the time to relapse in children with steroid-sensitive idiopathic nephrotic syndrome

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              Effect of tyrosine kinase inhibitors on renal handling of creatinine by MATE1

              Creatinine is actively secreted across tubular epithelial cells via organic cation transporter 2 (OCT2) and multidrug and toxin extrusion 1 (MATE1). We previously showed that the tyrosine kinase inhibitor (TKI) crizotinib inhibits OCT2-mediated transport of creatinine. In the present work, we examined the inhibitory potency of TKIs, including crizotinib, on MATE1-mediated transport of creatinine. Then, we used the kinetic parameters estimated in this and the previous work to predict the potential impact of TKIs on serum creatinine level (SCr) via reversible inhibition of creatinine transport. Crizotinib inhibited [14C]creatinine uptake by MATE1-overexpressing cells, and the inhibitory effect increased with incubation time, being greater in the case of pre-incubation or combined pre-incubation/co-incubation (pre/co-incubation) than in the case of co-incubation alone. The inhibition was non-competitive, with K i values of 2.34 μM, 0.455 μM and 0.342 μM under co-, pre- or pre/co-incubation conditions, respectively. Similar values were obtained for inhibition of [3H]MPP+ uptake by MATE1-overexpressing cells. Gefitinib, imatinib, pazopanib, sorafenib, and sunitinib also inhibited MATE1-mediated creatinine uptake. Further, all these TKIs except pazopanib inhibited [14C]creatinine uptake by OCT2-overexpressing cells. In rat kidney slices, the ratio of unbound tissue accumulation of TKIs to extracellular concentration ranged from 2.05 to 3.93. Prediction of the influence of TKIs on SCr based on the renal creatinine clearance and plasma maximum unbound concentrations of TKIs suggested that crizotinib and imatinib might increase SCr by more than 10% in the clinical context. Accordingly, it is necessary to be cautious in diagnosing TKI-induced renal failure only on the basis of an increase of SCr.
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                Author and article information

                Contributors
                aoife.waters@gosh.nhs.uk
                Journal
                Pediatr Nephrol
                Pediatr Nephrol
                Pediatric Nephrology (Berlin, Germany)
                Springer Berlin Heidelberg (Berlin/Heidelberg )
                0931-041X
                1432-198X
                6 September 2021
                6 September 2021
                2021
                : 36
                : 11
                : 3799-3802
                Affiliations
                [1 ]GRID grid.424537.3, ISNI 0000 0004 5902 9895, Department of Pediatric Nephrology, , Great Ormond Street Hospital for Children NHS Foundation Trust, ; London, UK
                [2 ]GRID grid.424537.3, ISNI 0000 0004 5902 9895, Nephro-Urology Unit, UCL GOS Institute of Child Health; Department of Pediatric Nephrology, , Great Ormond Street Hospital for Children NHS Foundation Trust, ; London, UK
                Author information
                http://orcid.org/0000-0001-7617-7580
                http://orcid.org/0000-0002-6234-6221
                http://orcid.org/0000-0003-4520-5635
                Article
                5231
                10.1007/s00467-021-05231-4
                8497452
                34490520
                5edc281e-cbd9-4d2d-b27e-4b753cc11a29
                © Crown 2021

                Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.

                History
                : 10 April 2021
                : 17 June 2021
                : 22 July 2021
                Categories
                Brief Report
                Custom metadata
                © The Author(s), under exclusive licence to International Pediatric Nephrology Association 2021

                Nephrology
                levamisole,creatinine,egfr,nephrotoxicity
                Nephrology
                levamisole, creatinine, egfr, nephrotoxicity

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