PRESENTED BY
CLAUDIO PONTICELLI

Presentation Summary

Written by Jasna Trbojevic-Stankovic
Reviewed by Claudio Ponticelli

Introduction
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).

Figure 1. Etiologies of FSGS (12)

Furthermore, the response to CS therapy in FSGS patients may be genetically dependent since a significant rate of pathogenic mutations was found in adults with steroid-resistant nephrotic syndrome caused by FSGS (15). Based on this finding, genetic analysis may be advisable in children and adolescents, patients with steroid-resistant FSGS, those with extrarenal manifestations or family history of extrarenal manifestations, and kidney transplant candidates (14).

Corticosteroids for the treatment of IgA nephropathy
IgA nephropathy is an autoimmune disease caused by antibodies directed against polymeric hypogalactosylated IgA1 in the glomerular mesangium. The outcome of the disease is highly variable and proteinuria plays a significant causal role in its progression (16). The current KDIGO guidelines suggest initial ACE inhibitors or ARBs treatment if proteinuria is <1g/day and six months course of high-dose CS therapy should the initial treatment fail to achieve proteinuria reduction below 1g/day after 3 to 6 months (4). A large retrospective VALIGA study confirmed the superiority of steroid treatment over symptomatic antihypertensive therapy in proteinuric IgA patients, as it provided a significant reduction in proteinuria and better renal survival (17). However, these favorable effects of steroid treatment may be associated with a higher risk of adverse events, thus keeping the role of immunosuppression in IgA nephropathy highly controversial (18, 19). A recently published study evaluated effects of two immunosuppressive protocols for IgA nephropathy – steroids alone in patients with glomerular filtration rate (GFR) ≥ 60 ml/min, and combined with cyclophosphamide and azathioprine in patents with GFR between 30 and 59 ml/min. Thus, patients with worse kidney function received more aggressive treatment. Corticosteroid monotherapy achieved significantly more remissions and similar number of side effects than controls. There was also a non- significant trend to remission but more side effects in combined treatment; and neither regimen prevented a decline in GFR (20). On the other hand, a large meta-analysis of 12 randomized controlled trials found clear beneficial effects of steroid therapy on the kidney function and proteinuria in IgA nephropathy, but again associated with increased risk of side effects (21).  

References

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20. Rauen T, Fitzner C, Eitner F, et al. Effects of two immunosuppressive treatment protocols for IgA nephropathy. J Am Soc Nephrol 2018;29:317-325.

21. Lin Y, Jia J, Guo Y, et al. Corticosteroid for IgA nephropathy: Are they really therapeutic? Am J Nephrol 2018;47(6):385-394.

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