Abstract
Nephrotic syndrome is one of the most common glomerular disorders in childhood. Glucocorticoids have been the cornerstone of the treatment of childhood nephrotic syndrome for several decades, as the majority of children achieves complete remission after prednisone or prednisolone treatment. Currently, treatment guidelines for the first manifestation and relapse of nephrotic syndrome are mostly standardized, while large inter-individual variation is present in the clinical course of disease and side effects of glucocorticoid treatment. This review describes the mechanisms of glucocorticoid action and clinical pharmacokinetics and pharmacodynamics of prednisone and prednisolone in nephrotic syndrome patients. However, these mechanisms do not account for the large inter-individual variability in the response to glucocorticoid treatment. Previous research has shown that genetic factors can have a major influence on the pharmacokinetic and dynamic profile of the individual patient. Therefore, pharmacogenetics may have a promising role in personalized medicine for patients with nephrotic syndrome. Currently, little is known about the impact of genetic polymorphisms on glucocorticoid response and steroid-related toxicities in children with nephrotic syndrome. Although the evidence is limited, the data summarized in this study do suggest a role for pharmacogenetics to improve individualization of glucocorticoid therapy. Therefore, studies in larger cohorts with nephrotic syndrome patients are necessary to draw final conclusions about the influence of genetic polymorphisms on the glucocorticoid response and steroid-related toxicities to ultimately implement pharmacogenetics in clinical practice.
Highlights
Nephrotic syndrome is one of the most common glomerular disorders in children and affects 1–7 per 100,000 children per year (Dutch data 1.52/100,000) with a male predominance (2:1) [1]
This review describes the mechanisms of glucocorticoid action and clinical PK and PD of prednisone and prednisolone in nephrotic syndrome patients
Glucocorticoids are essential in the treatment of childhood nephrotic syndrome
Summary
Nephrotic syndrome is one of the most common glomerular disorders in children and affects 1–7 per 100,000 children per year (Dutch data 1.52/100,000) with a male predominance (2:1) [1]. This review describes the mechanisms of glucocorticoid action and clinical PK and PD of prednisone and prednisolone in nephrotic syndrome patients. Several pharmacokinetic studies performed in both pediatric [30, 31, 34, 40] and adult [37, 38, 42] nephrotic syndrome patients have confirmed the increase in unbound fraction, but unchanged steady-state unbound concentration of prednisolone. Pharmacokinetic studies for other highly protein-bound drugs showed similar results with an increase of total volume of distribution, total clearance, and free fraction of the drugs, but unchanged free drug concentrations in steady state [43]. Patients with nephrotic syndrome have decreased serum albumin and transcortin levels in the active phase of disease, leading to a decreased protein binding of prednisone and prednisolone [37, 38]. Renal excretion of unchanged drugs is approximately 2–5% for prednisone and 11–24% for prednisolone after administration of either one of the drugs [32]
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