Single-centre experience with cyclosporin in 106 children with idiopathic focal segmental glomerulosclerosis

Ihab Mahmoud1, Fathi Basuni1, Alaa Sabry1,2, Amr El-Husseini1,2, Nabil Hassan1, Nagy Sayed Ahmad2, Mahmoud Elbaz3, Fatma Moustafa3 and Mohamed Sobh1,2

1 Department of Nephrology, 2 Department of Internal Medicine and 3 Department of Pathology, Urology and Nephrology Center, University of Mansoura, Egypt

Correspondence and offprint requests to: Professor Mohamed A. Sobh, Professor and Head of Nephrology Department, Mansoura Urology and Nephrology Center, Mansoura University, Egypt. Email: sobh10{at}yahoo.com



   Abstract
 Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 
Background. Although remission is achieved in most children with nephrotic syndrome by treatment with corticosteroids, a significant proportion of patients experience relapses. Continuous or repeated use of corticosteroids inevitably induces features of steroid side-effects. Cyclosporin (CsA) has been used in the treatment of idiopathic steroid-dependent and -resistant nephrotic syndrome. However, relapse often occurs shortly after the CsA treatment is terminated. Furthermore, long-term clinical outcome of patients treated with CsA is unclear.

Methods. We retrospectively reviewed the data of 106 nephrotic children having primary focal segmental glomerulosclerosis (FSGS) who received CsA between 1993 and 2002. Indications of CsA therapy were steroid resistance (n = 45) and steroid dependence with steroid toxicity (n = 61). Fifty-four patients received cyclophosphamide prior to CsA therapy. CsA starting dose was 6 mg/kg/day to be readjusted to maintain a whole blood trough level of 80–150 ng/ml. The drug was received for 6–48 months (mean: 22.1±11 months). The observation period was 5.8±3 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 4.1–40 mg/h/m2 BSA) and resistance to CsA (proteinuria ≥45 mg/h/m2 BSA) were observed in 71.7, 7.5 and 20.8% of patients, respectively. CsA-sensitive and -resistant patients differed only in the percentage of steroid responsiveness, being 66.7% in the former group and 22.7% in the later (P<0.0001). Logistic regression analysis identified steroid resistance as the only predictor of resistance to CsA (odds ratio: 12.9; P = 0.03). Hypertension, renal impairment (>30% rise of serum creatinine), gingival hyperplasia and hypertrichosis occurred in 12.3, 6.6, 22.6 and 51.9% of patients, respectively. With the exception of hypertrichosis, side effects were significantly more frequent among CsA-resistant children. We were able to stop steroids in 91 patients, of whom 31 patients relapsed. Out of 20 patients for whom CsA was intentionally discontinued while in remission, 16 patients relapsed. Of these, four (25%) were resistant to a second course of CsA. At the last follow-up, one child had developed end-stage renal failure and three had chronic renal insufficiency.

Conclusions. CsA is effective in the treatment of children with idiopathic FSGS, but with a high relapse rate on drug withdrawal. Renal dysfunction and hypertension, which may be drug-induced or natural progression, are the most serious complications; therefore, close monitoring is essential.

Keywords: cyclosporin; focal segmental glomerulosclerosis



   Introduction
 Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 
Focal segmental glomerulosclerosis (FSGS) is becoming an increasingly important cause of the nephrotic syndrome in both adults and children [1]. It is currently the most common primary glomerular disease to progress to end-stage renal disease (ESRD) [2].

High-dose corticosteroid treatment of FSGS in children is associated with a complete remission rate in between 0 and 50% of cases. Resistance to corticosteroids has been shown to be the single most reliable predictor of progression to ESRD [3]. On the other hand, prolonged administration of steroids in steroid-dependent or frequent-relapser idiopathic nephrotic syndrome (INS) may not only cause disabling side-effects, but also exposes children to the risk of steroid toxicity, including osteoporosis, growth retardation, cataract, diabetes and psycho-emotional disturbances. Review of the literature revealed that >5% of children treated for glomerulopathies with steroids for prolonged periods of time had died because of drug-induced side effects and not renal disease [4]. Thus, in both steroid-dependent nephrotic syndrome (SDNS) and steroid-resistant nephrotic syndrome (SRNS), the need for an alternative immunosuppressive treatment is mandatory.

Treatment of paediatric FSGS nephrotic syndrome with cyclophosphamide is associated with complete remission in only 25% of patients and no response in 57% [5]. Cyclosporin is another alternative to steroids. It is a well-known and effective immunosuppressive agent that was used for the first time in the treatment of INS in 1986 [6]. Although the drug was found to be very effective in reducing proteinuria in children and adults with SDNS and SRNS, its use has been limited by a high relapse rate and its potential for nephrotoxicity [7].

In the present study, we report a single-centre experience with CsA in the treatment of 106 children with idiopathic FSGS nephrotic syndrome. The principle aims of the study were to evaluate (i) the potential beneficial steroid-sparing action of low-dose CsA given for prolonged periods of time; (ii) the response to CsA discontinuation and a secondary course of the drug; and (iii) the tolerance of CsA.



   Subjects and methods
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 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 
Patient data
The data were collected retrospectively from both outpatient and inpatient records of the Urology and Nephrology Center, Mansoura University. The study included all children with steroid-dependent and steroid-resistant INS due to FSGS who were subsequently treated with CsA in the period from January 1993 to January 2002. The data reviewed were age at disease onset, age at the start of CsA treatment, gender, response to steroid therapy, disease duration, number of steroid courses, history of cyclophosphamide therapy and its effect prior to CsA treatment, time interval between renal biopsy and initiation of CsA therapy, mean value of maintenance CsA dose and blood level, response to corticosteroid withdrawal while on CsA, duration of CsA treatment, response to CsA therapy and CsA discontinuation, and occurrence of side effects to CsA. We also examined the biochemical records of the study population before and at regular intervals after the initiation of CsA. These included serum creatinine, serum albumin, serum cholesterol and 24 h urinary protein levels.

Management before CsA treatment
All children were administered prednisone (2 mg/kg/day orally) for ≥8 weeks at variable durations prior to CsA therapy. The definitions of steroid-dependent, steroid-resistant and frequent-relapser nephrotic syndrome were made according to the International Study of Kidney Disease in Children, 1981 [8]. Oral cyclophosphamide (2 mg/kg/day) for 12 weeks was prescribed for children with SRNS and those with SDNS who showed evidence of steroid toxicity. A renal biopsy was not considered necessary when cyclophosphamide treatment was decided but was indicated before a third-line drug, such as CsA. All children had renal tissue diagnosis within the year preceding initiation of CsA treatment. Ultrasound-guided renal biopsy was performed in all children and renal biopsy specimens were examined by light microscopy and immunofluorescence microscopy. Electron microscopy was done only when the clinical picture and light microscopic examination were inconclusive or suggestive of secondary nephrotic syndrome.

CsA therapy and patient follow-up
Patient selection
CsA was contraindicated in children with systolic or diastolic blood pressure above the 95th centile for age, sex and height, children who were receiving antihypertensive medication, children whose serum creatinine levels (corrected for age) were higher than normal and those whose renal tissue showed moderate to severe tubular atrophy and/or interstitial fibrosis.

Protocol of CsA treatment
In the earlier years, CsA was given as a Sandimmune (Sandoz) oral solution. In later years, the drug was given as Sandimmune Neoral capsules (Novartis). Eighty-one patients (76.4%) received ketoconazole 50–100 mg/day concomitantly with CsA to reduce the required dose and subsequently the costs of CsA. The initial CsA dose was 5 mg/kg/day given in three divided doses to overcome the higher rate of drug elimination in children. 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 prednisone was given concomitantly with CsA at a dose of 0.5 mg/kg/day in SRNS and double the dependent dose (the steroid dose below which the patient used to relapse) in SDNS.

Patient follow-up
All children received the combined therapy while in relapse. The patients were followed once weekly in the first month, every 2 weeks in the second month and every month thereafter. In each visit, the children were thoroughly 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 level. The later was done by fluorescence polarization immunoassay using a TDX autoanalyser and kits produced by Abbott Diagnostics, Illinois, USA. Response to therapy was categorized as complete remission (proteinuria <4 mg/h/m2 BSA), partial remission (proteinuria 4.1–40 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 prednisone, the latter was gradually tapered and stopped over 8 weeks. When complete relapse [return to pre-treatment levels of proteinuria and hypoalbuminaemia (serum albumin <3.5 g/dl)] occurred during steroid withdrawal, the pre-relapse prednisone dose was resumed in SRNS. In SDNS, however, relapse while tapering prednisone was considered CsA treatment failure and the drug 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 a dose 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 CsA dose to achieve a level of 100–120 ng/ml if the level was <80 ng/ml at the time of relapse. A lack of response to increasing CsA dose or the presence of an acceptable level at the time of relapse was an indication to resume prednisone at a dose of 0.5–1 mg/kg/day for 4 weeks followed by gradual withdrawal.

Renal function impairment was recognized when serum creatinine increased by ≥30% of its basal level, even if values were still in the normal range for age. CsA level was checked and dose reduced if the level was >120 ng/ml. If renal dysfunction persisted, CsA dose 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 of immediate renal biopsy.

In addition to resistance to CsA after 4 months of treatment and a persistent renal dysfunction, the child's parents' desire to stop treatment, non-compliance and new-onset hypertension requiring more than one drug were indications to discontinue CsA. Relapses after CsA discontinuation were treated with CsA and prednisone as described above.

Statistical analysis
Comparisons between SDNS and SRNS patients, and those between CsA-sensitive and -resistant children were made employing unpaired t-tests for means of quantitative variables and chi-square/Fisher's exact test for the frequencies of qualitative variables.

The paired samples t-test was used to compare the means of serum creatinine of the whole group before and after CsA treatment. All analyses were carried out using the computer package SPSS for Windows®, version 11.



   Results
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 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 
Patient characteristics
A total of 106 children received CsA during the study period. Their ages ranged from 1.5 to 15 years (mean: 5.1±4.3 years) at disease onset and from 3 to 16 years (mean: 11±4 years) at the initiation of CsA therapy. The disease duration at the start of CsA treatment ranged from 1 to 15 years (mean: 5.8±3 years), during which period the patients received one to seven courses of steroid therapy (mean: 3±1.3 courses). There were 72 boys (67.9%) and 34 girls (32.1%). Sixty-one children were SDNS and 45 were SRNS. They were comparable in terms of pre-treatment characteristics (Table 1).


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Table 1. Pre-treatment characteristics of SDNS and SRNS childrena

 
Response to cyclophosphamide therapy
Fifty-four children (25 SRNS and 29 SDNS), who showed evidence of steroid toxicity, received oral cyclophosphamide therapy (2 mg/kg/day) for 12 weeks. Three SRNS patients (6.7%) and 10 SDNS patients (16.4%) were responsive. Meanwhile, 22 SRNS children (48.9%) and 19 SDNS children (31.1%) were resistant.

Response to CsA and outcome in SDNS
In the SDNS patients (61 children), CsA was maintained for 22.6±10 months; the mean maintenance dose of CsA was from 1.9±0.9 mg/kg/day. Fifty-six (91.8%) children attained complete remission in response to combined therapy with CsA and prednisone and five children were resistant (8.91%). The time to complete remission ranged from 2 to 6 weeks (4.4±1.4 weeks). Discontinuation of prednisone, while in remission, was carried out in all children who exhibited a complete or partial response to combined therapy, resulting in relapse either while tapering prednisone or within a month of its discontinuation in 13 patients (21.3%).

Twelve children had CsA monotherapy discontinued while in remission. Relapse occurred in 11 (91.7%) (resumption of CsA monotherapy was followed by remission in eight of the 11) and the remaining child enjoyed complete remission until the last follow-up (range: 5–24 months; mean: 12.4±7 months) without any immunosuppression.

Response to CsA and outcome in SRNS
In SRNS patients (45 children), CsA was maintained for 21±12 months; the mean of the maintenance dose of CsA was 2.2±1 mg/kg/day. Twenty patients (44.4%) attained complete remission in response to combined therapy with CsA and prednisone.

Eight children showed partial remission. The time to complete or partial response ranged from 2 to 16 weeks (mean: 9.9±3.4 weeks). Withdrawal of prednisone, while in remission, was carried out in 28 children (those who exhibited a complete or partial response to combined therapy) and resulted in relapse in 13 children; resuming prednisone was followed by remission in seven patients while six maintained relapse.

Nine patients had CsA monotherapy, which was discontinued while in remission. Relapse occurred in four patients (44.4%) [resumption of CsA monotherapy was followed by remission in two (50%)] and the remaining five children enjoyed complete remission until the last follow-up without any immunosuppression.

CsA was stopped in 44 children, of whom 27 were SRNS. Table 2 shows the aetiology of CsA discontinuation in SDNS and SRNS children. Twenty-two children (10 SRNS and 12 SDNS) had CsA monotherapy discontinued while in remission.


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Table 2. The indication for CsA discontinuation in SDNS and SRNS children

 
In both groups (SDNS and SRNS), CsA-sensitive and -resistant patients differed only in the percentage of steroid responsiveness (66.7% in the former group and 22.7% in the latter; P<0.001) and in the number of steroid courses prior to CsA therapy (3.2±1.3 vs 2.3±1; P = 0.005) (Table 3).


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Table 3. Characteristics of 106 children with FSGS according to their response to CsA therapya

 
Post-treatment laboratory findings
Study of post-treatment laboratory characteristics in both groups revealed that serum albumin was statistically significantly higher, serum cholesterol significantly lower and 24 h urinary protein excretion significantly lower in SDNS compared with SRNS (Table 4).


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Table 4. Post-treatment biochemical characteristics of SDNS and SRNS children

 
Side effects of CsA therapy
Gum hyperplasia and hypertrichosis were the most frequent side-effects of CsA, occurring in 24 (22.6%) and 55 (51.9%) patients, respectively. Hypertension occurred in 13 (12.3%) and renal dysfunction in seven (6.6%) of all children. Hypertension was significantly more frequent among SRNS children (n = 9, 20%) compared with SDNS sufferers (n = 4, 6.6%) (P = 0.04) and among CsA-resistant patients (n = 6, 27.3%) compared with CsA-sensitive ones (n = 7, 8.3%) (P = 0.03). Patients who were resistant to CsA were also more vulnerable to develop persistent renal dysfunction (Table 5). Seven children had persistent renal dysfunction despite CsA dose reduction. Discontinuation of the drug was followed by normalization of serum creatinine in three children and chronic renal dysfunction in three others. The remaining child progressed to ESRD.


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Table 5. CsA-related side effects according to the response to steroids and CsAa

 
After exclusion of the seven patients who developed frank renal dysfunction, the mean value of serum creatinine non-significantly increased from 0.54±0.16 mg/dl before CsA treatment to 0.63±0.42 mg/dl at the last follow-up (P = 0.02). However, serum creatinine values remained in the normal range for age in those patients.

Renal histology
Renal biopsy was performed for the three patients with chronic renal insufficiency and for the child with ESRD, and compared with their pre-CsA treatment biopsy.

This revealed >50% worsening in glomerulosclerosis, tubular atrophy and interstitial fibrosis compared with the basal biopsy findings. Striped interstitial fibrosis and tubular atrophy was not observed in any of the rebiopsied kidneys.

Arteriolar lesions characterized by widening of the subendothelium were observed in the patients with ESRD and in two patients with chronic renal dysfunction.



   Discussion
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 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 
No therapy has been proven effective in steroid-resistant FSGS by a controlled study. However, uncontrolled trials during the past decade have suggested that the disease is not as unresponsive to all treatment as previously thought. Specifically, treatments with CsA or with intravenous methylprednisolone combined with an alkylating agent have been claimed to be effective [9].

It was known that CsA impairs interleukin-2 secretion and action, and it was not illogical to imagine that it might interfere with the hypothetic lymphokine responsible for proteinuria [10]. In addition, CsA compared favourably with alkylating agents by its lack of cytotoxicity. These elements were considered sufficient basis to undertake treatment trials. The first results were encouraging, as they showed that CsA could induce remission in patients with INS that had resisted conventional therapy [11].

Because different treatments are advocated by different centres, lack of consensus among centres may present obstacles for multicentre trials. The present study has the advantage of including a large number of FSGS cases with a long-term follow-up period in a single centre; thus, circumventing the variability in working protocols and definition of various conditions among different centres. Although it was designed as a retrospective analysis, the abundance of cases with uniformity of the clinical and pathological presentation, and of procedures of diagnosis and treatment may empower the study to highlight the efficacy and limitation of therapy. In the present study, CsA therapy was effective in inducing complete remission in 81 patients with FSGS, giving a total complete response in 76.4% of the cases. If partial response to CsA was included, the total CsA sensitivity would become 84%.

This primary response rate is comparable to, or higher than, that reported in previous studies. Meyrier et al. [12] observed a complete response rate to CsA of 23.9%. Ingulli et al. [13] were able to achieve a >80% response rate in 21 steroid- and cyclophosphamide-resistant FSGS patients by the long-term use of very high doses of CsA (mean dose of 7 mg/kg/day for a mean duration of 27.5 months and followed-up for a mean duration of 8.5 years). Despite its efficacy in inducing remission, almost all patients relapsed when CsA was stopped. In a multicentre prospective study conducted in four university hospitals in Korea, CsA plus prednisolone induced complete remission in four out of five patients with FSGS (80%) in which case previous steroid responses did not affect the response to CsA [14]. In a follow-up study for 7–91 months with repeat renal biopsy, CsA induced complete remission in 14.3% and partial remission in 42.9% of FSGS patients [15]. Lieberman and Tejani [9] conducted a randomized double-blind placebo-controlled trial of CsA in INS to test the efficacy and safety of a 6 month course treatment. All FSGS patients who received the CsA experienced a diminution of their proteinuria as opposed to only two out of 12 placebo-treated patients. In a study by Waldo et al. [16], CsA, combined with prednisone after initial aggressive course of pulsed methylprednisolone, induced complete remission in 80% of steroid-resistant FSGS cases; 70% had sustained remission for a follow-up duration ranging from 12 to 42 months. In the same study, one patient (10%) relapsed and failed to achieve remission after reintroduction of the aggressive immunosuppression and progressed rapidly to ESRD.

In an attempt to identify factors that may predict a lack of response to CsA, Singh et al. [17] compared the biochemical variables and the renal biopsy specimens in CsA-responder vs non-responder FSGS patients. No histological differences could be dis cerned between the two groups while proteinuria was significantly greater in the non-responders, suggesting that the more severe form of FSGS does not respond to CsA therapy. On other hand, Alexopoulos et al. [18] concluded that age and plasma creatinine at biopsy were independent risk factors leading to ESRD and that the severity of tubulointerstitial fibrosis is predictive of response to therapy.

This beneficial effect of CsA allowed successful withdrawal of the concomitant corticosteroids in 79.8% of our 89 CsA-responsive cases without relapse of the nephrotic syndrome. Unfortunately, however, most cases showed some sort of CsA-dependency, as only 27.3% of the 22 responsive cases in whom CsA discontinuation was tried showed successful weaning of CsA. Moreover, resumption of CsA failed to reinduce remission in 26.7% of them, a phenomenon called secondary CsA resistance [19]. On the other hand, Waldo et al. [16] successfully discontinued CsA in five FSGS patients while in remission: only one of them had a relapse, which responded to oral prednisone therapy in <4 weeks. The other four patients had sustained remission [16]. In a recent study, 12 out of 22 FSGS cases responded to CsA initially. After CsA withdrawal only two cases had sustained remission while 10 cases relapsed. On reinstitution of CsA, seven out of 10 cases showed secondary resistance to the effect of CsA while only three out of 10 re-entered into the remission and was identified as CsA-dependent [19].

The behaviour of the FSGS cases under CsA therapy differed significantly depending on whether they were sensitive or resistant to previous steroid therapy. In our study, the sensitivity to CsA was significantly more in the steroid-sensitive cases (100%) than in those resistant to steroid (62.2%). Moreover, the former group need significantly lesser time to attain remission (4.4±1.4 weeks) compared with the latter (9.9±3.4 weeks). In accordance with the present results, Meyrier et al. [12] observed that the remission rate of nephrotic syndrome in a FSGS subgroup of patients depended on previous steroid sensitivity, being 67.6% in steroid-sensitive and 36.1% in steroid-resistant cases. Additionally, in our study, the ability to taper down or discontinue the concomitant steroid was significantly more successful in the steroid-sensitive than in the steroid-resistant patients: 46.4% of cases relapsed in the latter group, while only 8.2% of the former experienced relapse. Looking at this point from another perspective, it was evident that the only factor significantly determining sensitivity to CsA was the previous response to steroid therapy, as the previous sensitivity to steroid was the only significantly different parameter between the CsA-sensitive and -resistant groups. On the other hand, discontinuation of CsA resulted in relapse significantly more in steroid-sensitive than in steroid-resistant cases. It has been suggested that steroid-sensitive INS represents the best indication of CsA treatment [12]. The drug allows suppression or drastic diminution of corticosteroid needs. This in turn suppresses steroid toxicity and allows catch-up growth. However, many CsA-sensitive children relapse when CsA is tapered to a stop. Prolonged exposure to CsA raises the concern of CsA nephrotoxicity.

The mechanism by which CsA affects proteinuria in FSGS is open to speculation. There is consistent evidence, from both experimental and human studies, that the highly lipophilic CsA molecule diminishes or abolishes proteinuria by two differing mechanisms [12]: the first is its immunosuppressive action, which is presumably directed towards the secretion of glomerular permeability factor, and the second appears to be a non-immunological effect on glomerular permselectivity, explaining reduced proteinuria in various aetiologies of nephrotic syndrome with no immunological background. In an experimental study, CsA, but not saline or vehicle, abrogated proteinuria in isolated rat glomeruli incubated with sera from patients with FSGS; an effect that was accompanied by a 5-fold increase in glomerular cAMP in CsA-treated rats, without ultrastructural changes of epithelial or endothelial cells. In an experimental study where glomeruli were isolated from Sprague–Dawley rats following intraperitoneal administration of CsA, cremphore and saline for 5 days before being incubated with serum from patients with FSGS, the glomerular albumin permeability for the CsA-treated group was not increased; however, it was markedly increased in the saline- and cremphore-treated rats. At the same time, glomerular cAMP increased 5-fold in CsA-treated rats compared with saline- and cremphore-treated rats without ultrastructural changes of epithelial or endothelial cells. The authors concluded that CsA may have a direct protective effect on the glomerular filtration barrier and postulated that increased levels of cAMP may play an important role in protecting the glomerlui and may contribute to remission of proteinuria in FSGS patients independent of its immunological and haemodynamic correlates [20].

Another recent study [21] showed that a factor(s) can increase the permeability of glomerular capillaries and cause proteinuria and that normal plasma contains substances capable of blocking or inactivating the FSGS permeability factor. In addition, pharmacological agents, including CsA and indomethacin, block permeability activity in vitro.

Therapy with CsA is not free from drawbacks: hypertrichosis and gum hyperplasia are not uncommon. Fortunately, in our study, these side effects were not severe enough to interfere with continuation of therapy. On the other hand, occurrence or exacerbation of hypertension was observed in 12.3% of cases and some degree of deterioration of renal function was noticed in 6.6% of cases. Hypertension and renal dysfunction were more frequent among our steroid- and CsA-resistant cases. Of the whole group of patients, only one progressed to ESRD and three remained with chronic renal insufficiency. These results imply substantial amelioration of the historical natural course of FSGS and, thus, entail a beneficial effect of the treatment protocol and are even more optimistic than the results of previous reports using CsA in INS [12,17,22]. The superiority of our results may be due to better selection of cases with early disease and normal starting kidney function, and good follow-up of cases with close monitoring of CsA doses and blood levels. Moreover, appropriate action was taken promptly according to the clinical or laboratory results.

The concern about long-term nephrotoxic effects of CsA, particularly in native kidneys, has been substantiated previously. Data from patients with autoimmune disorders and non-renal transplant recipients have indicated that interstitial fibrosis will develop in most native kidneys after 2 years of CsA therapy at >5 mg/kg/day [23]. However, most patients with FSGS have interstitial fibrosis at diagnosis and this progresses along with their glomerular disease [24]. This makes it difficult to clearly distinguish CsA toxicity from disease progression in patients with FSGS. In the present study, it may be argued that, since deterioration of renal function was more frequent in CsA-resistant cases (while taking comparable doses of the drug for even shorter duration) in addition to absence of specific histological lesions pathognomonic for CsA toxicity, these effects may represent, at least partly, disease progression. Overall, the toxic effects of CsA were not too devastating to dispute the benefit of this drug, especially where its application is wisely judged.

A fundamental problem in the interpretation of data of therapeutic trials in FSGS is the uncertain natural history of the condition. There are ~10% of patients who will either remit the disease or have a prolonged period of clinical stability with minimal proteinuria and no progression [25]. Although novel therapeutic approaches can remit the nephrotic syndrome, it remains to be shown that they can prevent progression of the underlying glomerular disease. Because of the retrospective nature of the study, there may be significant variability in the CsA dose and the rate of tapering of the drug, since these decisions were driven by the clinical response of the patients. Thus, prospective studies are needed badly. Nevertheless, our study has presented data from a large number of cases sharing the same histopathological entity and managed with the experience of one treating team, thus, making drawing credible conclusions possible.

In summary, treatment with CsA can be a good therapeutic option in both steroid-sensitive and steroid-resistant FSGS children, which may save the toxic effects of long-term large doses of steroids and improve the control of cases and possibly ameliorate the natural progressive course of the disease. The concern over nephrotoxic effects of CsA may be outweighed by its beneficial effect, provided that the selection of cases and their follow-up are carried out sensibly.

Conflict of interest statement. None declared.



   References
 Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 

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Received for publication: 5.11.03
Accepted in revised form: 7. 5.04





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