Written by Jasna Trbojevic-Stankovic
Reviewed by Claudio Ponticelli
Cortisol is an essential glucocorticoid hormone with a very distinct circadian rhythm regulated by the suprachiasmatic nucleus in the hypothalamus. Healthy individuals have the lowest cortisol levels at midnight, followed by an overnight rise to peak in the morning, and then slowly decline throughout the day (1). Only 10% of cortisol is in a free, bioavailable form, while the rest is bound to transcortin and albumin. The synthetic corticosteroid analogs, in contrast, have much lower affinity for carrier proteins and thus higher bioavailability. Based on their half-lives in plasma, synthetic corticosteroids (CS) are subdivided into short-acting (prednisone, methylprednisolone, deflazacort), intermediate-acting (parametasone, triamcinolone) and long-acting (dexamethasone, betamethasone). They all exert anti-inflammatory and immunosuppressive activity predominantly via the classic genomic effect, mediated by cytosolic receptors (2, 3). CS exert numerous side effects that are dose and time-dependent but also influenced by individual factors. Adverse effects of CS can be alleviated by reducing drug dosage in certain population groups, including the chronic kidney disease (CKD) patients, timing administration of short-acting CS in a single dose between 8 and 9 A.M. to mimic the physiological circadian rhythm, and by advising low sodium and low-calorie diet, increased physical activity and smoking cessation. CS have been extensively used in the treatment of different renal diseases, but the optimal dosing protocols for specific conditions are still a matter of debate.
Corticosteroids for the treatment of minimal change disease
CS analogs represent the standard treatment for the minimal-change disease (MCD). The recommended initial daily dose of prednisone for adult patients is 1mg/kg (maximum 80mg), or 2mg/kg (maximum 120mg) on alternate days (4). If tolerated, this dose can be continued to a maximum of 16 weeks in case complete remission does not occur earlier. In children, prednisone should be administered as a single daily dose of 60mg/m2 or 2mg/kg (maximum 80mg) for 4 to 8 weeks, followed by an alternate-day dose of 40mg/m2 (maximum 40mg) for 2 to 5 months with tapering (4). The rate of remission with these treatment protocols is very high. Nevertheless, as many as 60% of the patients either develop frequent relapses or become steroid dependent later on. Several studies investigating if a longer duration of initial CS treatment might reduce the risk of relapse in children with MCD yielded conflicting results (5-9). Furthermore, higher maintenance prednisolone dose was not associated with a lower risk of relapse (10).
Corticosteroids for the treatment of focal segmental glomerulosclerosis
Focal segmental glomerulosclerosis (FSGS) refers to a histologic pattern that is recognizable in several etiologies (11) which are linked by podocyte injury and depletion (12), (Figure 1). The recommended initial treatment strategy for primary FSGS is 1mg/kg/day (maximum 80mg) prednisone for at least 4 weeks, up to a maximum of 16 weeks if remission is not achieved (4). Calcineurin inhibitors can be considered as alternative first-line therapy for patients with steroid-resistance or steroid-intolerance (4). At the latest KDIGO Conference, the minimum duration of 16 weeks of high-dose corticosteroids as first-line therapy for FSGS was suggested, but remained dubious given its potential for toxicity. Nevertheless, data to support alternative first-line agents or combination therapies with lower doses of corticosteroids are still insufficient (13).
Recent studies have emphasized the importance of early clinical differentiation between primary and maladaptive FSGS, since their presentations and prognosis may differ. The primary FSGS is characterized by a full-blown nephrotic syndrome and poor prognosis, while maladaptive FSGS usually manifests with non-nephrotic proteinuria and a slower rate of progression (14).