Cyclosporine therapy monitored with abbreviated area under curve in nephrotic syndrome

Abstract

Cyclosporin A (CsA) is an effective therapy for children with long-lasting nephrotic syndrome (NS). Long-term treatment can result in chronic CsA nephropathy (CsAN) and there is controversy concerning its incidence and severity. Trough levels are commonly used to monitor the drug concentration. We report a retrospective clinical and histological analysis of 18 children (12 males, 6 females) with steroid-dependent nephrotic syndrome (15 patients) and partially steroid-sensitive nephrotic syndrome (3 patients) treated with CsA for a long-term period (mean 4.9 years, range 2.2-6.9). Before CsA treatment all patients had normal creatinine clearance. CsA was started at a dose of 5 mg/kg per day administered orally in two divided doses and adjusted to maintain the mean CsA blood concentration between 250 and 350 ng/ml obtained from abbreviated area under the curve (AUC). A renal biopsy was performed after a mean period of 3.9 years (range 2.2-6.2) from the start of CsA treatment. Tubular, interstitial, and arteriolar lesions were evaluated in order to assess CsAN. The mean CsA dose and the mean CsA blood concentration were 4.4 mg/kg per day (range 3.6-5.8) and 276.6 ng/ml (range 162-346), respectively. No child had a worsening creatinine clearance during CsA treatment and follow-up after CsA discontinuation. If compared with the year before the start of CsA treatment, NS relapses and prednisone (PDN) dose significantly decreased during CsA treatment, 4/year versus 0.8/year (P <0.0001) and 0.9 mg/kg per day versus 0.2 mg/kg per day (P <0.0001), respectively. Histological analysis showed 15 patients with minimal change disease and 3 with focal segmental glomerulosclerosis. Clear-cut lesions diagnostic of CsAN were never found and only mild lesions were observed in 5 children (suggestive of CsAN in 2 patients and consistent with CsAN in 3 patients). Long-term CsA treatment is confirmed to be effective in preventing NS relapses and reducing PDN dose. Renal function is not a reliable indicator of CsAN. With the mean CsA blood concentrations used in our patients CsAN presented a low incidence (28%) and was generally mild. Renal biopsy should be performed 2-3 years from the start of long-term CsA treatment, especially if the mean CsA blood concentrations are not regularly monitored.

Risk Factors for Cyclosporin A Nephrotoxicity in Children with Steroid-Dependant Nephrotic Syndrome

“…Numerous studies have documented the prevalence of CsAN in patients who were treated for idiopathic nephrotic syndrome. Since 1986, Ͼ200 follow-up biopsies in patients who were treated with CsA for SDNS have been reported in the literature (1,(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27). These studies are difficult to compare because they vary in the number of biopsies, underlying renal pathology, duration of follow-up, dosages of CsA, and criteria to define CsAN.…”

Population Pharmacokinetic Approach to the Use of Low Dose Cyclosporine in Patients with Connective Tissue Diseases

“…[4][5][6][7] In a clinical setting, the typical practice of cyclosporine dosage adjustments is frequently used to determine its concentration and then adjust the dosage by a trial-and-error approach. However, controversy still surrounds the dosage regimen, therapeutic concentration range, and method of therapeutic drug monitoring of cyclosporine in the treatment of collagen diseases [8][9][10] ; the pharmacokinetics of cyclosporine show large variations in blood levels following its oral or intravenous administration, not only interindividually, but also intraindividually, 11) especially after oral dosing. 12) Recent studies reported low dose cyclosporine therapy, which was adjusted to gain of blood trough concentration approximate 80-150 ng/mL, was an effective and less toxic cyclosporine therapy for the regulation of connective tissue diseases with RA, 13) SLE, [14][15][16] and lupus nephritis.…”

The most appropriate therapeutic strategy for acute lower respiratory tract infections: a Delphi-based approach

“…The carriage of these strains, characterized by mutations of the ftsI gene encoding the reach optimal values, both the clinical/microbiological efficacy is ensured and the emergence of resistant bacteria is hampered. 31 As a matter of fact, an almost maximal consensus (98%) has been reached on the importance of the PK/PD profile of the antibiotic of choice for the patient's treatment and to avoid an increase of microbial resistance.…”