Long-term effects of cyclosporine in children with idiopathic nephrotic syndrome: a single-centre experience

Amr El-Husseini, Fathy El-Basuony, Ihab Mahmoud, Hussein Sheashaa, Alaa Sabry, Rashad Hassan, Nohir Taha, Nabil Hassan, Nagy Sayed-Ahmad and Mohamed Sobh

Mansoura Urology and Nephrology Center and Mansoura University, Egypt

Correspondence and offprint requests to: Professor Mohamed A. Sobh, Mansoura Urology and Nephrology Center, Mansoura University, Egypt. Email: amr_2000_2002{at}yahoo.com



   Abstract
 Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 
Background. Because of its potential nephrotoxicity, the long-term use of cyclosporine (CsA) as treatment for nephrotic syndrome (NS) is controversial. The clinical outcome of the patients with NS treated with CsA is unclear.

Methods. This study reports the results of long-term CsA treatment in 117 children with idiopathic NS, who received CsA therapy for more than 2 years (median, 34 months). The mean age of children at initiation of CsA therapy was 11±4 years. The starting dose of CsA was 5 mg/kg/day, adjusted to maintain a trough level of 100–150 ng/ml in the first 2 months, 50–100 ng/ml thereafter. Later, a level as low as 30 ng/ml was accepted so long as it maintained remission. All patients received CsA between 1993 and 2003. Indications for treatment included steroid-dependent nephrotic syndrome (SDNS) in 74 patients and steroid-resistant nephrotic syndrome (SRNS) in 43 patients. Initial renal histology showed minimal change disease (MCD) in 38 patients and focal segmental glomerulosclerosis (FSGS) in 79 patients. Most patients were receiving moderate doses of prednisone. Sixty patients received cyclophosphamide prior to CsA. The observation periods were 5.8±3 years and 6.1±1.9 years before and after CsA treatment, respectively.

Results. Complete remission [proteinuria <4 mg/h/m2/body surface area (BSA)], partial remission (proteinuria between 4.1 and 40 mg/h/m2/BSA) and resistance to CsA (proteinuria ≥45 mg/h/m2/BSA) were observed in 82.1, 5.1 and 12.8%, respectively. Hypertension, renal impairment (>30% rise of serum creatinine), gingival hyperplasia and hypertrichosis occurred in 10.3, 6.0, 32.5 and 70.1%, respectively. Steroids were stopped in 102 patients, of which 31 relapsed. Out of 29 patients for whom CsA was intentionally discontinued while in remission, 22 relapsed. Of these, six patients were resistant to a second course of CsA. Post-therapy biopsies, performed in 45 patients (33 with SDNS and 12 with SRNS), showed mild stripped interstitial fibrosis and tubular atrophy in two SDNS patients (4.4%). At the last follow-up, one child had developed end-stage renal failure and two had chronic renal insufficiency.

Conclusions. Long-term CsA therapy in low doses is effective in the treatment of children with idiopathic NS, but the rate of relapse is high after drug withdrawal. Hypertension developed in 10% of patients and renal insufficiency in 6% (most patients with FSGS).

Keywords: cyclosporine; long-term; nephrotic syndrome; pathology; treatment



   Introduction
 Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 
Primary nephrotic syndrome (NS) is the most common glomerular disease in children [1]. The majority of children with NS respond to corticosteroids. However, >70% of children experience a relapse with recurrent episodes of oedema and proteinuria. Corticosteroids have adverse effects such as obesity, poor growth, hypertension, diabetes mellitus, osteoporosis and adrenal suppression [2]. On the other hand, resistance to corticosteroids has been shown to be the single most reliable predictor of progression to end-stage renal disease (ESRD) [3]. Thus, in both steroid-dependent nephrotic syndrome (SDNS) and steroid-resistant nephrotic syndrome (SRNS), the need for an alternative immunosuppressive treatment is evident.

Cyclosporine A (CsA) plays a confounding role in the treatment of NS in children [4]. The main indication for CsA in NS is resistance to steroids and cytotoxic agents, but it is also used in steroid-dependent and frequently relapsing patients with serious toxic side effects or those with contraindications for steroids and cytotoxic drugs [5]. Given the significant potential toxicities of this agent and its narrow therapeutic window, its use in non-transplant situations has generated much controversy [6].

The present retrospective study reported on a single centre evaluation of the safety of long-term use of cyclosporine and its ability to prolong the duration of a remission and to reduce the maintenance dose of prednisolone. Most previous studies have discussed the short-term results of CsA administration [7,8] or studied its long-term effects on a small number of patients [9–11]. A recent study that reported the long-term results on a large number of patients was a multicentre trial and examined only patients with SRNS [12].



   Subjects and methods
 Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 
Patient data
The data were collected retrospectively from both the outpatient and inpatient records of our centre. The study included all children with idiopathic SDNS or SRNS who were subsequently treated with CsA between January 1993 and January 2003. The data reviewed were: age at disease onset, age at the start of CsA treatment, gender, renal histology, response to steroid therapy, disease duration, number of steroid courses, history of cyclophosphamide therapy and its effect prior to CsA treatment, mean values of the maintenance doses of CsA and blood levels, response to corticosteroid withdrawal while on CsA, duration of CsA treatment, response to CsA therapy and discontinuation, and occurrence of CsA side effects. We also examined the biochemical data of the study population before and at regular intervals after the initiation of CsA, including serum creatinine, creatinine clearance, serum albumin, cholesterol and 24 h urinary protein levels. Plasma creatinine concentration was used for estimation of creatinine clearance according to Schwartz formula.

Management before CsA treatment
All children were given prednisolone, 2 mg/kg/day orally, for variable durations, but for at least 8 weeks. The criteria of SDNS and SRNS were established according to the International Study of Kidney Disease in Children [13]. Oral cyclophosphamide, 2 mg/kg/day for 12 weeks, was prescribed for children who showed evidence of steroid toxicity. A renal biopsy was considered unnecessary to initiate cyclophosphamide treatment, but was indicated before third-line drugs such as CsA. Ultrasound-guided renal biopsies were performed for all children prior to CsA treatment and biopsy specimens were examined by light microscopy and immunofluorescence microscopy. Electron microscopy was done only when the clinical picture and light microscopy were inconclusive or suggestive of secondary NS.

CsA therapy and patient follow-up
Patient selection
CsA was contraindicated in children with systolic or diastolic blood pressures above the 95th percentile for age, sex and height; children who were receiving anti-hypertensive medication; children with renal dysfunction and those whose renal tissues showed moderate to severe tubular atrophy, interstitial fibrosis, or both.

Protocol of CsA treatment
In the earlier years of the study period, CsA was given as an oral solution, Sandimmune (Sandoz). Later, the drug was given as Sandimmune neoral capsules (Novartis). Of the cohort, 90 patients (77%) received ketoconazole 50 mg/day concomitantly with CsA, to reduce the required dose and hence the cost of CsA. The initial dose of CsA was 4–5 mg/kg per day (two divided doses 12 h apart) in children over 6 years and 5–6 mg/kg per day (three divided doses 8 h apart) in children below 6 years to circumvent the higher rate of drug elimination. The dose was adjusted to maintain a whole blood trough level of 100–150 ng/ml in the first 2 months and 50–100 ng/ml thereafter. Oral prednisolone was given concomitantly with CsA at a dose of 0.5 mg/kg/day in SRNS and at double the dependency dose (the steroid dose below which the patient relapsed) in SDNS.

Patient follow up
All children received the combined therapy while in relapse. The patients were followed up once weekly in the first month, every 2 weeks in the second month and every month thereafter. At each visit, they were evaluated clinically and subjected to full laboratory assessment, including 24 h urinalysis for protein [corrected as mg/h/m2 of body surface area (BSA)] and CsA levels. The latter was measured by fluorescence polarization immunoassay, using a TDX autoanalyser and kits produced by Abbott Diagnostics (IL, USA). Response to therapy was categorized as complete remission (proteinuria <4 mg/h/m2 BSA), partial remission (proteinuria between 4.1 and 40 mg/h/m2 BSA) and no response (proteinuria ≥45 mg/h/m2 BSA after 4 months of CsA treatment). After 2 months of combined therapy with CsA and prednisolone, the latter was gradually tapered over 8 weeks and then stopped. When relapse occurred during steroid withdrawal, the pre-relapse prednisolone dose was re-instated in SRNS; in SDNS relapse with tapering of prednisolone was considered as failure of CsA treatment, and CsA was discontinued.

CsA dose manipulation
In children who maintained their partial or complete response to CsA monotherapy for 2 months, the drug was given in doses that achieved the lowest possible trough level that maintained such a response. In other words, a level of as low as 30 ng/ml was accepted so long as it maintained remission. Relapses while on CsA monotherapy were treated by increasing the CsA dose to achieve a level of 100–120 ng/ml. A lack of response to the increasing dose of CsA or the presence of an acceptable trough level at the time of relapse was an indication to resume prednisolone at a dose of 0.5–1 mg/kg/day for 4 weeks followed by gradual withdrawal.

Renal impairment was recognized when serum creatinine increased by 30% or more of its baseline level even if its absolute values were still in the normal range for age. CsA dose was reduced if its level was above 120 ng/ml. If renal dysfunction persisted, the dose of CsA was further reduced by 0.5–1 mg/kg/day irrespective of the blood level. When serum creatinine levels remained elevated or continued to rise, CsA was stopped. The persistence of renal impairment after CsA discontinuation was an indication for immediate renal biopsy. Other indications to discontinue CsA, in addition to resistance to CsA after 4 months of treatment and persistent renal dysfunction, were the child's parents’ desire to stop treatment, non-compliance and a new onset of hypertension requiring more than one drug. Relapses after CsA discontinuation were treated with CsA and prednisolone as described above.

Re-biopsy, after at least 12 months of continuous CsA administration, was performed in 45 of the patients at 12–60 months after the initiation of the CsA treatment. The specimens were examined by a single pathologist blinded to patient identity and clinical history. Tubular atrophy accompanying stripped interstitial fibrosis is considered the most reliable indicator of CsA nephrotoxicity, and the grade of the lesions was classified as group I (within normal limits), group II (slightly abnormal) or group III (moderate or severe), according to the criteria of Mihatsch et al. [14].

Statistical analysis
Comparisons between SDNS and SRNS patients and those between CsA-sensitive and resistant children were made employing the unpaired t-test for means of quantitative variables and the {chi}-square and Fisher exact tests for the frequencies of qualitative variables. The paired samples t-test was used to compare the means of the serum creatinine of the entire group before and after CsA treatment. The SPSS statistics package (SPSS V11.0, SPSS Inc., USA) was used for these analyses [15].



   Results
 Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 
Patient characteristics
In all, 117 children received CsA during the period studied. Their ages ranged from 1 to 17 years (5.3± 3.9 years) at the disease onset and from 2.5 to 18 years (11±4 years) at the initiation of CsA therapy. The duration of disease at the start of CsA treatment ranged from 1 to 13 years (6.1±3.0 years), during which period the patients had received 1–6 courses of steroid therapy (3.2±1.4 courses). They were 83 boys (71.9%) and 34 girls (29.1%). Of the cohort, 74 children were SDNS and 43 SRNS. Initial renal histology showed minimal change disease (MCD) in 38 patients and focal segmental glomerulosclerosis (FSGS) in 79 patients. The characteristics of children according to steroid response are shown in Table 1.


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Table 1. Characteristics of children according to their response to steroid therapya

 
Response to cyclophosphamide therapy
Of the children who showed steroid toxicity, 60 (32 SDNS, 28 SRNS) received oral cyclophosphamide, 2 mg/kg/day for 12 weeks. Only nine patients with SDNS (26.5%) and four patients with SRNS (15.4%) were responsive, while 25 with SDNS (73.5%) and 22 children with SRNS (84.6%) were resistant.

The response to CsA and outcome in SDNS
In SDNS (74 children), CsA was maintained for 34±12 months, with a mean maintenance dose of 1.3±0.8 mg/kg/day; 66 (89.2%) children attained complete remission under combined therapy with CsA and prednisolone, and eight children were resistant (10.8%). The time to complete remission ranged from 2 to 8 weeks (4.4±1.4 weeks). The discontinuation of prednisolone, while in remission, was carried out in all children who exhibited complete remission to combined therapy (n = 66). That resulted in relapse in 19 patients (25.7%), either while tapering prednisolone or within a month of its discontinuation. Resuming prednisolone treatment was followed by remission in 15 patients; four stayed in relapse. CsA monotherapy was discontinued in 15 children while in remission. Two children enjoyed complete remission without any immunosuppression through the last follow-up (cohort follow-up 10 and 27 months). While relapse occurred in the remaining 13 (86.7%)—resumption of CsA monotherapy was followed by remission in 10 of them.

The response to CsA and outcome in SRNS
In SRNS (43 patients), CsA was maintained for 33±12 months; the mean maintenance dose of CsA was 1.5±1 mg/kg/day. In response to combined therapy with CsA and prednisolone, 30 children (69.8%) attained complete remission, six children showed partial remission (13.9%) and seven children were resistant (16.3%). The time to complete or partial response ranged between 2 to 16 weeks (6.9±3.4 weeks). Withdrawal of prednisolone, while in remission, was carried out in 36 children (those who had complete or partial responses to combined therapy), but resulted in relapse in 12 children. Resuming prednisolone treatment was followed by remission in five patients; seven stayed in relapse. CsA monotherapy was discontinued in 14 children while in remission. Five children enjoyed complete remission without any immunosuppressive therapy through the last follow-up (cohort follow-up 5–24 months, 12.4±7 months). While relapse occurred in the remaining nine (64.3%), resumption of CsA monotherapy was followed by remission in six of them.

The serum creatinine and the creatinine clearance were stable after treatment. There was significant improvement in the serum albumin, cholesterol and the degree of proteinuria after CsA therapy (Table 2).


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Table 2. Laboratory parameters before and after CsA therapya,b

 
Side effects of CsA therapy
Gum hyperplasia and hypertrichosis were the most frequent side effects of CsA, occurring in 38 (32.5%) and 82 (70.1%), respectively; these side effects did not necessitate the discontinuation of the medication and did not differ among SDNS and SRNS patients. Hypertension occurred in 12 (10.3%) and renal dysfunction in seven (6.0%) of all children. Hypertension was noted within 1–8 weeks of the initiation of CsA treatment and it was significantly more frequent among SRNS children (eight, 18.6%) compared with SDNS (four, 5.4%), P = 0.027. Hypertension was mild to moderate and easy to control in 10 patients, but was severe and difficult to control in two patients. Angiotensin-converting enzyme inhibitors were used in 11, ß-blockers in seven and calcium channel blockers in two patients. Five children had persistent renal dysfunction despite reduction of CsA (Table 3). Discontinuation of the drug was followed by normalization of kidney function in two of the five, chronic renal dysfunction in two (mean creatinine clearance 77 ml/min/1.73 m2) while the remaining child progressed to ESRD.


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Table 3. CsA-related side effects according to the response to steroidsa

 
After exclusion of the five patients who developed frank renal dysfunction, the mean value of creatinine clearance decreased non-significantly from 125 ml/min/1.73 m2 before CsA treatment to 118 ml/min/1.73 m2 at the last follow-up (P = 0.156).

CsA was discontinued in 51 patients. Table 4 shows the reasons for CsA discontinuation in SDNS and SRNS children.


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Table 4. Indications for CsA discontinuation in SDNS and SRNS children

 
Post-treatment renal histology
Renal re-biopsies were performed in 45 patients and were compared with their pre-CsA treatment biopsies (Table 5). The indication in four was development of renal insufficiency, and their re-biopsies revealed a >50% worsening of glomerulosclerosis, tubular atrophy and interstitial fibrosis compared with the baseline biopsy findings. Tubular atrophy accompanied by stripped interstitial fibrosis, indicative of CsA nephrotoxicity, was found in two patients with SDNS, but it was mild and graded as group II [14]. The original pathology of these two cases was MCD, and their CsA doses and levels were comparable to other patients. Other pathological findings included an increase in the percentage of global sclerosed glomeruli in seven patients with SDNS and five with SRNS. Arteriolar lesions characterized by widening of the subendothelium were observed in one patient with ESRD and in two patients with chronic renal dysfunction.


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Table 5. Characteristics of patients who have undergone a second renal biopsy

 


   Discussion
 Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 
This study is one of the largest single-centre trials that investigated the use of a low dose of CsA in children with NS on long-term basis. In addition, this represents one of the longest-term follow-up studies of effects of CsA on childhood NS. Most patients were receiving moderate doses of prednisone. The benefit of CsA treatment was evaluated regarding the remission rate, dosage of prednisolone and renal outcome. CsA nephrotoxicity was histologically assessed by comparing post-treatment biopsy specimens with pre-treatment biopsy specimens in 45 patients. The findings indicate the efficacy of CsA in patients with SDNS and SRNS and further support the safety of long-term CsA therapy with a low dosage.

It is well-established that CsA is effective against SDNS. Filler [16] performed a meta-analysis of 22 randomized controlled trials in childhood NS and concluded that SDNS should be treated with cyclosporine. A multi-centre large-scale placebo-controlled study performed in Japan clearly showed that CsA treatment for 6 months significantly reduced the relapse rate and the total dose of corticosteroids necessary in patients with SDNS [17]. It was also reported that most patients with SDNS relapse on CsA withdrawal [18]. The trend of CsA dependency is more obvious when the duration of the therapy is short; thus the patients need prolonged CsA therapy [9]. However, a longer-term use of CsA may result in chronic renal injury [10,11]. In the present study, we treated SDNS patients with CsA, maintaining the trough level as low as possible so long as it maintained remission. CsA therapy was continued for >24 months (24–68 months). The long-term use of CsA reduces the relapse rate and improves steroid dependency in our patients with SDNS.

Several drug regimens have been used in the treatment of children with SRNS, with varied success. Chlorambucil is not effective in many cases with FSGS [19]. The International Study of Kidney Disease in Children reported no benefit of cyclophosphamide with alternate-day prednisolone over the same prednisolone regimen in patients with FSGS and SRNS [20]. CsA has been used in patients with SRNS with various results. Eight uncontrolled studies involving 60 children with SRNS reported complete remission in 20% of children. The rates of complete and partial remissions were significantly higher when the CsA was administered in combination with steroids [21]. An open study by the French Society of Pediatric Nephrology found complete remission in 42% of the patients (48% with MCD and 30% with FSGS) [22]. Hymes [23], using CsA at 80–200 ng/ml of trough levels for 12 months in combination with steroids, reported response to initial CsA therapy in 14 of 18 (78%) children with SRNS but CsA-dependent, frequent relapse in 9 of 14 (64%) patients and CsA-resistant relapse in three patients. In a recent systematic review and meta-analysis of nine randomized controlled trials involving 225 children, Habashy et al. [24] reported that CsA is effective in SRNS. In the current study, we treated patients with SRNS using a low dose of CsA in combination with prednisolone. A mean treatment time was 34.6 months, and CsA trough levels as low as 30 ng/ml were maintained. Thirty-six of the 43 (84%) patients responded to CsA; 30 patients, including 22 with FSGS, achieved complete remission, and six including four with FSGS, achieved incomplete remission. It appears that CsA therapy is often successful against SRNS, producing the preservation of renal function without serious adverse effects.

After stopping CsA therapy, 87% of patients with SDNS and 64% of patients with SRNS experienced a relapse. CsA was re-instituted in all relapsed cases, 73% responded and 27% exhibited secondary CsA resistance. The secondary resistance to CsA was also reported by Hymes [23] and Sairam et al. [25]. In contrast to these reports Hino et al. [9] reported that none of the initial responders in their patients developed resistance to CsA after relapse.

In patients with NS, CsA nephrotoxicity has been reported in patients with SRNS and those with SDNS, which is often undetectable by monitoring the serum creatinine level or other laboratory parameters. Moreover, it is likely that renal dysfunction may actually be caused by the natural progression of disease. We obtained post-treatment biopsy specimens in 45 patients and found mild tubulointerstitial changes in two children with MC and SDNS. Habib and Niaudet [26] compared post-treatment renal biopsy specimens with pre-treatment biopsy specimens in 42 NS children who received CsA with trough blood levels maintained at 100–200 ng/ml for 4–63 months; various grades of CsA nephrotoxicity were observed: mild in 18 patients, moderate in 15 and severe in nine patients. Hino et al. [9] found mild CsA nephrotoxicity in 15% of their patients with minimal change SDNS. In contrast with the previous data we obtained more favourable results with low levels of CsA; this may be explained by concomitant use of ketoconazole in most of our patients. We previously reported that co-administration of low dose ketoconazole with CsA in idiopathic nephrotic patients not only safely results in a significant reduction of CsA cost but also improves the CsA response and has a favourable effect on renal function [27]. The low rate of CsA nephrotoxicity in our patients (4.4%) may be explained also by the use of low doses of CsA.

We conclude that the long-term use of CsA in low doses with close monitoring of the trough level is beneficial to patients with SDNS and SRNS. The risk of nephrotoxicity may be low when CsA treatment is performed according to the protocol described here. Further adequately powered and well-designed randomized controlled trials are needed to confirm the efficacy of low-dose cyclosporine on a large-number of children with NS.



   Acknowledgments
 
The authors would like to thank Dr Sherine Hamdy, cultural anthropologist, for her help in proofreading this article.

Conflict of interest statement. None declared.



   References
 Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 

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Received for publication: 22. 3.05
Accepted in revised form: 13. 7.05





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