Concomitant administration of cyclosporine and ketoconazole in idiopathic nephrotic syndrome

Amr El-Husseini, Fathy El-Basuony, Ahmed Donia, Ihab Mahmoud, Nabil Hassan, Nagy Sayed-Ahmad and Mohamed Sobh

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



   Abstract
 Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 
Background. The deliberate use of ketoconazole to reduce the need for cyclosporine (CsA) is not new, but it is particularly relevant because of the high cost of CsA. Many studies have documented this benefit in renal and cardiac transplants, but this co-administration has not been reported in patients with nephrotic syndrome.

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 1–2 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



   Introduction
 Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 
The majority of children with nephrotic syndrome respond to corticosteroids. However ~70% of children experience a relapsing course with recurrent episodes of oedema and proteinuria. Corticosteroids have adverse effects such as obesity, poor growth, hypertension, diabetes mellitus, osteoporosis and adrenal suppression [1]. Cyclosporine A (CsA) is a well-known and effective immunosuppressive agent in the treatment of steroid-dependent and steroid-resistant nephrotic syndrome [2]. However, it is expensive, which makes it unaffordable to a large proportion of patients from developing countries.

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 50–80% reduction in the CsA dosage [4–6]. 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.



   Subjects and methods
 Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 
This retrospective study comprised 207 patients known to have idiopathic nephrotic syndrome and to have received CsA (Neoral, Novartis) treatment in the Mansoura Urology and Nephrology Center between 1993 and 2002. The majority of our cases were children (86.5% were below 18 years) and male to female ratio was 1.7:1. Among our patients 153 received daily keto (Nizoral, Janssen–Cilag) therapy in a dose of 50 mg with concomitant reduction of one-third of the CsA dose (keto group) while 54 patients received CsA alone (non-keto group). Patients were allocated to either group allover the study period. The major reason for keto prescription was economic (in patients in whom insurance does not cover CsA cost). Other factors that determined keto prescription were the prescribed dose of CsA (in small children who receive doses as low as one capsule of 25 mg bd and maintain acceptable trough levels, keto cannot be added as reduction of CsA dose will be inapplicable), the treating physician preference and the trough level after initial doses of CsA. Neither renal pathology previous steroid nor cyclophosphamide response had an impact on the patient allocation. In keto group, keto was added concomitant to or soon (within 1 month) after CsA. No crossover occurred between the groups.

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

  1. In adults and children above 6 years: initial dose was 4–5 mg/kg/day orally, in two divided doses 12 hours apart.
  2. In children below 6 years: initial dose was 5–6 mg/kg/day orally, in three divided doses 8 h apart.

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:

  1. Clinical evaluation: thorough history taking with special stress on patient's compliance to therapy and occurrence of possible side effects to CsA and or keto therapy such as gastro-intestinal disturbances, headache, seizure, hypertrichosis and infection.
    Thorough clinical examination with stress on presence or absence of oedema, gum hyperplasia, infection, hypertension and gynaecomastia was performed.
  2. Laboratory evaluation: urine analysis, 24-h collection for urine protein, blood sample drawn for serum albumin, cholesterol, creatinine, liver function tests, complete blood count and whole-blood CsA trough level.

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 100–150 ng/ml in the first 2 months and 50–100 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 30–40 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 Mann–Whitney non-parametric test. Bivariate techniques were used for initial evaluation of contrasts. Thus, the {chi}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.



   Results
 Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 
This retrospective study included 207 patients with idiopathic nephrotic syndrome. One group of patients (non-keto group) received CsA alone (54 patients) while the other group (keto group) received concomitant CsA and keto (153 patients). The characteristics of the two groups were comparable (Table 1).


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Table 1. Characteristics of both groups at initiation of therapy

 
Although the duration of treatment and the response to CsA withdrawal were similar in both groups, the response to CsA and successful steroid withdrawals were significantly better in the keto group (Table 2). Further statistical analysis revealed that renal pathology had not significant effect on CsA response in either groups. However, the impact of previous steroid response on CsA response was highly significant (P<0.001) in the keto group while it was marginally significant (P = 0.054) in the non-keto group. CsA discontinuation was successfully performed for 11 patients and was complicated by relapse of proteinuria in 31 patients in whom complete remission was achieved in 22 patients after CsA resumption.


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Table 2. Data of CsA therapy in the two study groups

 
At initiation of therapy, both groups were comparable regarding kidney function, degree of proteinuria, serum albumin and serum cholesterol. At last follow-up while on CsA therapy, these parameters were better in the keto group but did not rank to statistical significance except for serum cholesterol (Table 3). Nevertheless, initial 24 h urinary protein and serum cholesterol showed a highly significant (P>0.001) decrease while serum albumin showed highly significant elevation when compared with last follow-up values of the same group.


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Table 3. Kidney function, serum albumin and cholesterol before and after treatment in the two study groupsa

 
The economic effect of keto therapy was a reduction in the cost of CsA therapy by 37% (from 327 to 206 Egyptian pounds/patient/month) after 1 month and 47% (from 249 to 133 Egyptian pounds/patient/month) at 1 year. When the cost of the keto (25.5 Egyptian pounds/patient/month) was included, the net cost savings was ~37% (1682 Egyptian pounds/patient/year).

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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Table 4. Effect of co-administration of keto on the development of hypertensiona and renal dysfunctionb

 
Keto was generally well tolerated. None of our patients stopped keto during CsA treatment. Serum bilirubin and alanine aminotransferase levels almost remained within the normal range and the overall rate of infection was the same in the two groups. None of the keto-treated patients developed thrombocytopenia or haemolytic anaemia. Gum hyperplasia was observed in 6.6% of the keto and 10.4% of non-keto group but this did not rank to statistical significance. The only side effects attributable to keto therapy were transient visual flashes in one patient and gastrointestinal symptoms in two patients, which resolved spontaneously with no need to stop the therapy.



   Discussion
 Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 
CsA plays a confounding part in the treatment of nephrotic syndrome. The main indication for CsA in nephrotic syndrome is resistance to steroids and cytotoxic agents, steroid-dependent and multi-relapsing cases with serious toxic side effects or with contraindications for steroids and cytotoxic drugs [2]. However, CsA is expensive, which makes it unaffordable to a large proportion of patients from developing countries. Keto has been reported to reduce the dosage requirement of CsA in transplant patients by previously 75–80% [11]. In prospective randomized studies we reported on the short- and long-term safety and financial benefits of the co-administration of keto to CsA-treated kidney transplant recipients [5,7]. However the concomitant use of CsA and keto in patients with nephrotic syndrome has not been reported in the literature.

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 30–70% 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.



   References
 Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 

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Received for publication: 7. 9.03
Accepted in revised form: 10. 3.04