Predict The Clinical Efficacy Of Domestic Cyclosporine: Drug Concentration Or Expression Of Calcineurin In Podocytes Of Primary Nephrotic Syndrome

Nephrotic syndrome(NS) is characteristic of proteinuria, hypoalbuminemia, hyperlipoidemia and edema.Calcineurin inhibitor cyclosporine has been used to treat it for over30years. The whole blood concentration of cyclosporin should be carefully monitored because of their significant toxicity and narrow therapeutic window.It was the consensus that C2(the blood concentration of2hours after medication)could display the exposure of the drug in patients with renal transplantation. But there is little evidence about the best blood concentration monitor of the domestic cyclosporione (Tianke) in nephrotic syndrome.The relationship between the effect and the blood concentration is still controversy.Recently, the expression of calcineurin was observed in some NS patients with some pathological types(MN or FSGS),and associated with the injury of glomerular filtration barrier permeability.But there is no clue that whether the podocytes’ calcineurin expression difference is associated with the proteinuria and clinical efficacy of cyclosporine. The objective of this study was to prospectively observe the optimal monitoring point of cyclosporine blood concentration in patients with nephrotic syndrome,analyse the relationship between blood concentration and clinical efficacy or renal toxicity. Further more, to retrospectively study the expression of calcineurin in MN and FSGS patients,and figure out the relationship between calcineurin and proteinuia or clinical efficacy of cyclosporine.METHODS AND RESULTSPartl.Pharmacokinetic characteristics and clinical efficacyAll28patients were recruited to prospectively monitor the blood concentration of domestic cyclosporine (Tianke). The clinical data was collected including the demographic characteristics, urine analysis, blood biochemistry and pathological data. The blood was collected before and after taking the cyclosporine at0,1,2,3and4hours,whole blood concentration of CsA was tested by high liquid chromatography. To predict the AUC0-4, the optimal monitoring points of blood concentration were C1C2C3(r=0.992, P<0.05); C1C3(r=0.952, P<0.05) and C2(r=0.832, P<0.05),when selecting different number of monitor points.During the6months’ follow up, C0,C1,C2was monitored at the first,2nd,3rd and6th month. Clinical remission and side effects were evaluated. No significant differece was observed in complete remission(n=8), partial remission (n=13) and no remission (n=7)groups, when treated3m by cyclosporine.The Co and C1of the patients with renal damage (serum creatinine increasing more than30%) were significantly higher than those without renal damage (183.86±82.76ng/ml vs103.09±38.73ng/ml, P<0.05;892.97±367.48ng/ml vs479.35±287.9ng/ml, P<0.05).But C2(556.85±278.24ng/ml vs536.58±247.1ng/ml) has no significant difference between the two group.Part2The expression of calcineurin in podocyte and the proteinuia or clinincal efficacy of MN/FSGS patients treated with cyclosporineThe clinical records and follow-up data of NS patients(n=30, MN20, FSG10) were reviewed. The podocyte injury was assessed by immunohistochem-ical staining of WT1and immunofluorescence staining of Synaptopodin. The immunohistochemical staining of calcineurin was performed.Three patients without expression of calcineurin have no response to treatment until the end of6-month follow up. At the3rd and6th month, the expression of calcineurin in remission groups was significantly higher than that of no remission patients (11.26±4.18%and10.96±3.69%vs6.92±4.09%and3.93±2.38%, P<0.05). But the correlation between proteinuria and expression of calcineurin was not observed. The expression of Calcineurin with loss of synaptopodin was confirmed by serial section cutting.The loss of WT1of podocyte was more obvious in FSGS patients than MN patients.CONCLUSIONS Under our experiment conditions:1.In predicting the drug exposure in patients with nephrotic syndrome treated by cyclosporine(Tian Ke), the optimal monitor point of cyclosporine were C1C2C3, C1C3and C2when choosing different number of monitor points.2.The blood concentration of cyclosporine has no relationship with clinical efficacy,but higher Co and C1were observed in acute renal toxicity patients.3.The expression of calcineurin were higher in remission patients than no remission patients, when treated by Cyclosporine. But the correlation between proteinuria and expression of calcineurin was not observed.