Urology and Nephrology Center, Mansoura, Egypt
Correspondence and offprint requests to: Prof. Dr Mohamed A. Sobh, MD, FACP. Prof. of Nephrology and Head of Nephrology Department, Urology and Nephrology Center Mansoura University Mansoura, Egypt. Email: afdonia{at}hotmail.com
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Abstract |
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Methods. This retrospective study included 207 nephrotic patients who were steroid resistant, dependent or frequent relapsers and received CsA therapy. Among these patients 153 received daily ketoconazole therapy in a dose of 50 mg with concomitant decrease of one-third of the CsA dose while 54 patients received CsA alone. The majority of our cases were children (179 were below 18 years) and male to female ratio was 1.7:1.
Results. The great majority of the study population received the drugs for 12 years. Patients who received CsA and ketoconazole were comparable with those who received CsA alone regarding age, sex, duration of renal disease, renal pathology, severity of nephrotic syndrome, renal function, hepatic function and steroid response. Co-administration of ketoconazole significantly reduced mean doses of CsA by 37% after 1 month and 47% at 1 year with overall net cost savings of 37%. Hepatic functions remained within the normal range in both groups. Additionally, co-administration of ketoconazole significantly improved the response to CsA therapy, successful steroid withdrawal and decreased the frequency of renal impairment.
Conclusions. Co-administration of keto with CsA in idiopathic nephrotic patients significantly reduces CsA costs and may improve its response.
Keywords: cyclosporine; ketoconazole; nephrotic syndrome
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Introduction |
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In renal and cardiac transplants some drugs, particularly ketoconazole (keto) and diltiazem, have been given purposefully with CsA in an attempt to markedly reduce the dose and therefore the cost of CsA [3,4]. Concurrent administration of keto and CsA requires a 5080% reduction in the CsA dosage [46]. In addition to reduction of the costs of immunosuppressive therapy, some clinicians believe that keto may reduce CsA nephrotoxicity [5].
In a prospective randomized study including 100 kidney transplant recipients, we previously reported on the safety and financial benefits of co-administration of keto to CsA-treated kidney transplant recipients [4]. In a more recent study, we documented that long-term use of low-dose keto in CsA-treated kidney transplant recipients is safe and cost saving and may induce better graft function. Bone mineral contents, vitamin D blood levels and lipid profiles are not affected by long-term keto co-administration in CsA-treated kidney transplant recipients [6].
To the best of our knowledge, this is the first study that reports on the use of keto in patients with idiopathic nephrotic syndrome. The objective of this work was to study the cost savings and safety of co-administration of keto to CsA in patients with nephrotic syndrome.
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Subjects and methods |
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All patients initially received full steroid courses (prednisolone 2 mg/kg/day, maximum 80 mg for at least 4 weeks) followed by gradual reduction of the dose. They were steroid-resistant (99 patients), -dependent (111 patients) or -frequent relapsers (7 patients). 114 patients were treated with cytotoxic therapy and they were either resistant (29 patients) or sensitive but relapsed after discontinuation of cyclophosphamide (85 patients). Cyclophosphamide was discontinued before starting CsA therapy. Ultrasound-guided renal biopsies were performed in all patients prior to CsA treatment and the commonest pathologies were focal segmental glomerulosclerosis (FSGS) (60%) and minimal change disease (28%). Age below 2 years and presence of renal impairment, hepatic impairment or hypertension were considered as exclusion criteria for CsA therapy. No study patient was treated with diltiazem, verapamil or felodipine, as these agents may interact with CsA.
Dosage of CsA
Follow-up of our patients
Because of the potential side effects of CsA and keto therapy a strict follow-up schedule was adopted. Patients were followed-up weekly in the first month, every 2 weeks in the second month and every month thereafter.
At each visit patients were subjected to:
CsA level monitoring
Trough CsA level (just before the patient takes the morning dose of CsA) was estimated. The method used in this work was fluorescence polarization immunoassay using the TDX auto-analyser and kits produced by Abbott Diagnostics, IL, USA. It is a non-isotopic procedure with high specificity for the CsA parent compound by using monoclonal antibodies that do not cross-react with CsA metabolites.
CsA dose adjustment
The target CsA whole blood trough level was 100150 ng/ml in the first 2 months and 50100 ng/ml thereafter. In patients who have a CsA-induced remission with no evident side effects for 6 months, CsA was administered in a dose that achieves the lowest possible level that maintains remission. In other words, a level of as low as 3040 ng/ml is accepted so long as it maintains remission.
Assessment of CsA response
Patients were classified according to CsA response to complete responder (proteinuria <4 mg/h/m2 body surface area in children and 0.5 g/day in adults), partial responder (proteinuria between 4.1 and 40 mg/h/m2 body surface area in children and between 0.51 and 3 g/day in adults) or resistant (proteinuria >40 mg/h/m2 body surface area in children and >3 g/day in adults after 4 months CsA therapy) [7]. Renal dysfunction was defined as loss of 50% of renal function as measured by the doubling of base line serum creatinine or halving of creatinine clearance.
Steroid and CsA withdrawal
Gradual steroid withdrawal was adopted in 162 patients. This was performed in complete or partial CsA responders to enjoy steroid-free remission and in steroid-resistant cases to avoid side effects of ineffective steroids. CsA stoppage was performed for 42 patients after long-term CsA-induced remission.
Definitions
Hypertension was defined as diastolic blood pressure at or below the 95th percentile for age, sex and height in children [8] and blood pressure at or below 140/90 mmHg in adult patients [9]. Steroid resistance was defined as no response during the initial 8 weeks of steroid treatment. Steroid dependence was defined as a steroid response (protein-free urine on at least 3 consecutive days within 7 days) that is followed by relapse while receiving or within 2 weeks after discontinuing steroid treatment. Frequent relapser was defined as a responder who has two or more relapses within 6 months of the initial steroid response [10].
Statistical analysis
Qualitative data were displayed in cross tabulation, and quantitative data were described in terms of arithmetic mean±SD. As they showed obvious deviation from normal distribution, data of 24-h urinary protein at last follow-up were expressed as median (range) and were compared using MannWhitney non-parametric test. Bivariate techniques were used for initial evaluation of contrasts. Thus, the 2 and Fisher's exact tests were used for comparisons of frequencies of qualitative variables, and the unpaired t-test was used for comparisons of means of two quantitative variables. A P value of <0.05 was considered significant. The SPSS statistics package (SPSS V11.0, SPSS Inc., USA) was used for these analyses.
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Results |
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Although patients who co-administered keto with CsA had a lower frequency of hypertension compared with those who received CsA alone, this did not rank to statistical significance. Patients who received keto had a significantly lower frequency of renal impairment when compared with patients who received CsA alone (Table 4).
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Discussion |
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In this retrospective study, we observed persistence of CsA dose reduction and cost-savings until last follow-up (48% dose reduction and 37% net cost savings). Keogh et al. [3], First et al. [11] and Buttman et al. [12] reported greater CsA dose reductions in cardiac transplant recipients (80, 84 and 88%, respectively). This may be explained by the greater doses of keto that they used (200, 200 and 400 mg/day, respectively). In our study, we opted to use smaller doses of keto because we believed that this might be safer on long-term use, especially because the majority of our cases were children (86.5% below 18 years).
In this study the number of patients who experienced renal impairment was significantly lower in the keto group. We reported previously that co-administration of keto results in a more stable graft function in kidney transplant recipients [4,6]. Keogh et al. [3] noticed that there was a reduction in the rejection rate (despite similar doses of azathioprine, prednisolone and antithymocyte globulin) in keto-treated cardiac transplant recipients. They reported that the reason for this is unknown but reduced metabolism of corticosteroids might be responsible. Glynn et al. [13] found that keto increases the levels of methylprednisolone and prednisolone, and the area under the curve doubles after 6 days at a dosage of 200 mg/day. This may explain our success to lower steroid doses in the keto-group.
Cattran et al. [14] reported a loss of 50% of renal function in one-quarter of CsA-treated patients with steroid-resistant FSGS that were followed-up for 4 years. In our study 18.5% of CsA-treated patients lost 50% of renal function at a mean follow-up period of 2 years, co-administration of keto decreased this ratio down to 4.6%. The improvement in response to CsA and the preservation of renal function in the keto group may be explained by T-cell function inhibition by keto [15], an effect that may alter the disease process. Also, the parent compound rather than CsA metabolites is the predominant fraction in blood [16]. The parent CsA is known to be more immunosuppressive and less nephrotoxic than CsA metabolites [17].
CsA has shown promise in inducing remission in both steroid-dependent and steroid-resistant nephrotic syndrome, including that caused by FSGS [18]. Remission rates of 3070% have been reported [14,19]. In our study the response rate was similar (51%) but co-administration of keto improved the CsA response to 71%.
As the major reason for keto prescription was economic, a poorer outcome may be expected among these poorer patients. Interestingly, a better outcome was observed in the keto group. This observation may nullify the effect of possible selection bias in our study.
In the short- and long-term, we reported previously the absence of hepatotoxic effect of co-administration of keto and CsA in kidney transplant recipients [4,6]. Similarly, in this study serum bilirubin and liver enzyme levels remained within the normal range in both groups until the last follow-up. The safety of keto use may be explained by using small doses of keto and concomitant significant reduction in CsA dose, which is potentially hepatotoxic [20].
First et al. [16] reported discontinuation of keto therapy in four of 43 renal transplant recipients, mainly because of gastrointestinal intolerance and sexual dysfunction. However, Buttman et al. [12], using greater doses of keto, reported no related side effects in heart transplant recipients. In our study, we did not observe any significant side effects for keto. None of the patients in keto group stopped keto during CsA therapy.
Keogh et al. [3] noticed that there was a reduction in the rate of bacterial, viral and fungal infections in their study and explained this by the broad antimicrobial effects of keto. However, in our study the overall rate of infection was the same in both groups, this may be explained by the smaller dose of keto we opted to use.
We conclude that co-administration of low dose keto with CsA in idiopathic nephrotic patients safely results in significant reduction of CsA cost, which is of great concern in our developing country. On the other hand, despite improvement in CsA response and favourable effect on renal function noticed in keto-treated patients, a prospective study is needed to confirm these results. The big number of patients included and the absence of any impact of renal pathology or previous steroid response on the allocation of patients for keto treatment may not completely obviate possible selection bias in this retrospective study.
Conflict of interest statement. None declared.
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References |
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