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Saudi Journal of Kidney Diseases and Transplantation
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Table of Contents   
ORIGINAL ARTICLE  
Year : 2016  |  Volume : 27  |  Issue : 5  |  Page : 958-965
Cyclosporine therapy in steroid-dependent or steroid-resistant idiopathic focal and segmental glomerulosclerosis


1 Department of Medicine A (M8), Charles Nicolle Hospital; Faculty of Medicine, University of Tunis El Manar, Tunis, Tunisia
2 Department of Medicine A (M8), Charles Nicolle Hospital; Faculty of Medicine, University of Tunis El Manar; Laboratory of Kidney Pathology (LR00SP01), Charles Nicolle Hospital, Tunis, Tunisia

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Date of Web Publication22-Sep-2016
 

   Abstract 

Focal and segmental glomerulosclerosis (FSGS) is a heterogeneous entity. Previous few studies have evaluated the efficacy of calcineurin inhibitors in primary FSGS and have suggested positive benefit. In this single-center, retrospective study (1975-2014), we report our experience in Tunisian adults with primary FSGS treated with cyclosporine A (CsA). It includes patients histologically proven FSGS and managed in the Charles Nicolle Hospital at Tunis, Tunisia. The dose of CsA was adjusted to maintain a whole blood trough level of 80-150 ng/mL. The observation period was 6.8 ± 3.7 years after CsA treatment. Twenty-three patients with idiopathic FSGS, treated with CsA, were studied. The mean age was 26.69 ± 10.1 years, and the sex ratio was 2.83. Eight patients (35%) had a steroid-dependent nephrotic syndrome (NS), and 15 patients (65%) had for steroid-resistant NS. After a median follow-up of 16.5 months on CsA, we noticed complete remission of the NS in eight cases (35%) after 12.12 ± 8 months, partial remission in five (22%) after 3 ± 0.7 months, dose-dependent remission to CsA (2.87 mg/kg/day) in four (17%), and a no response in six patients (26%). Eleven patients (48%) showed improvement of renal function, while eight (35%) developed end-stage renal disease (ESRD) after 35.7 ± 20.9 months. Predictive factors of progression to ESRD were creatinine clearance <90 mL/min before introduction of CsA (P = 0.0054) and CsA-resistance (P = 0.053). Our study suggests that CsA is effective in the treatment of patients with idiopathic FSGS. Initial renal function and cyclosporineresistance are the predictive factors of ESRD in steroid-resistant or -dependent FSGS.

How to cite this article:
Gorsane I, Helal I, Yacoub I, Hamida F B, Abderrahim E, Abdallah T B. Cyclosporine therapy in steroid-dependent or steroid-resistant idiopathic focal and segmental glomerulosclerosis. Saudi J Kidney Dis Transpl 2016;27:958-65

How to cite this URL:
Gorsane I, Helal I, Yacoub I, Hamida F B, Abderrahim E, Abdallah T B. Cyclosporine therapy in steroid-dependent or steroid-resistant idiopathic focal and segmental glomerulosclerosis. Saudi J Kidney Dis Transpl [serial online] 2016 [cited 2019 Aug 24];27:958-65. Available from: http://www.sjkdt.org/text.asp?2016/27/5/958/190864

   Introduction Top


Focal and segmental glomerulosclerosis (FSGS) is one of th e most common causes of primary glomerular diseases worldwide that leads to end-stage renal disease (ESRD) in children and adults. The incidence of primary FSGS has increased considerably during the last 20-30 years. [1] The 5-year kidney survival rates approach 100% in patients with complete remission of proteinuria, 90% after partial remission and 60% with treatment resistance. [2]

The overall prognosis of FSGS is considered to be poor and up to 50% of patients develop ESRD within fi ve years; also, recurrence after kidney transplantation is seen in about 25% of patients. [3]

Management of patients with FSGS is a challenge. The goal of therapy is to induce a complete remission of proteinuria which will lead to better long-term preservation of renal function. Cyclosporine A (CsA), a known powerful immunosuppressive medication, has been used in the treatment of FSGS for over a decade. Corticosteroids and CsA remain the mainstay of treatment of FSGS, [4],[5] but longterm treatment can be associated with dosedependent nephrotoxicity. [6]

Detailed clinicopathologic analysis of primary FSGS in adults, particularly its treatment and prognosis, has not been reported from Tunisia in International Literature to date. In this study, we report our single-center experience on the clinical presentation, laboratory features, response to treatment, clinical course, and long-term prognosis in adults with primary FSGS treated with CsA.


   Patients and Methods Top


Patients

A single-center, retrospective study extending over a period of 40 years from 1975 to 2014 was carried out in the Department of Medicine A (M8) of Charles Nicolle Hospital at Tunis, Tunisia. Patients were eligible to enter this study if they had histologically proven primary FSGS and met one of the following criteria before being started on CsA therapy:

  1. Steroid-dependent nephrotic syndrome (SDNS) defined as patients who had complete remission after an initial four to eight-week course of daily steroids but who relapsed during tapering of steroid dose
  2. Steroid-resistant nephrotic syndrome (SRNS) defined as failure to respond to an initial course of at least four weeks of daily steroids.


We studied the epidemiological, clinical, and biological profile of these patients; the different therapeutic modalities before CsA; evolution under CsA; and complications seen and the prognosis and renal survival.

Initial management

Initial therapy for all patients comprised daily prednisone at a total dose of 1 mg/kg per day given in two divided doses (maximal dose, 80 mg/day). Once complete remission was achieved, steroid tapering was started. Patients who had the criteria for SRNS or SDNS were changed to CsA therapy. This dose of steroids was continued in conjunction with CsA until complete remission was achieved. Prednisone was then slowly tapered over three to six months.

Complete remission was defined as the disappearance of edema, the absence of proteinuria, and the normalization of serum albumin levels. Partial remission was defined as a significant and sustained improvement of the above indicators without total normalization.

Cyclosporine A therapy

CsA was started at a dose of 4 mg/kg per day, administered orally, most often in two divided doses to achieve a target level. Whole blood high-performance liquid chromatographic CsA trough levels were monitored initially and at four-week intervals, and dosages were adjusted to maintain levels of 80-150 ng/mL. Once remission was achieved, adjustments were made only when trough levels were >150 ng/ mL. Patients who continued to have episodic relapses were maintained at higher CsA levels (100-150 ng/mL).


   Statistical Analysis Top


Categorical variables were represented by their relative frequencies; quantitative variables were represented by their average. Comparisons of averages were performed using the Student's t-test. Comparisons of percentages were performed by the statistical test Chisquare.

P ≤0.05 was regarded as significant.

Survival data were studied by establishing a survival curve according to the Kaplan-Meier method.


   Results Top


Demographic, clinical, biological, and histological characteristics

Twenty-three patients with idiopathic FSGS, treated with CsA, were studied. The mean age was 26.69 ± 10.1 years (16-48 years), and the sex ratio was 2.83. One patient had a familial NS in the uncle and two of his brothers.

All study patients had a nephrotic syndrome (NS). Four patients (17.39%) had hypertension, 17 patients (73.91%) had microscopic hematuria, initial renal insufficiency was found in nine patients (39.13%), and 20 patients (86.95%) had hypercholesterolemia with an average value of 13.6 ± 5.44 mmol/L. The mean serum protein was 45.5 ± 7.03 g/L, mean serum albumin was 15.04 ± 7.31 g/L, and the average 24 h proteinuria was 7.01 ± 4.5 g.

Histologically, in addition to FSGS, vascular lesions were present in four patients (17%), and interstitial fibrosis was present in eight patients (35%).

Corticosteroids were the first therapeutic modality initiated in all patients. The initial dose was 1 mg/kg/day for 45.8 ± 40.3 months. Cyclophosphamide was tried in five patients at an average dose of 1.9 mg/kg/day. Mycophenolate mofetil (MMF) was prescribed in only one patient having SRNS. The dose was of 2 g/day for 16 months.

Outcomes after cyclosporine A therapy

Treatment with CsA was initiated in eight patients (35%) with SDNS and 15 patients (65%) with SRNS. The average dose was 3.15 ± 0.6 mg/kg/day.

Treatment with CsA was initiated after a mean duration of 13.4 ± 11.6 months of the diagnosis of FSGS. After a median follow-up of 16.5 months with CsA, the evolution was marked by a complete remission of NS in eight cases (35%) after a mean period of 12.12 ± 8 months, partial remission in five cases (22%) after a mean period of 3 ± 0.7 months, a dose-dependent remission to CsA (2.87 mg/ kg/day) in four cases (17%), and a no response in six patients (26%).

Eleven patients (48%) showed an improvement in renal function with CsA, and eight (35%) had impaired renal function reaching ESRD after an average of 35.7 ± 20.9 months. Among these eight patients, three were transplanted with good response and no recurrence of NS. Kidney biopsy was performed again in eight patients (35%) after an average of 44 ± 27.65 months of treatment with CsA. Indications were: dose dependence of CsA in three cases (13%), resistance to CsA in two cases (9%), impaired renal function, respectively, after 27 and 60 months, in two cases (9%) and no response to treatment in one patient (4%).

Interstitial fibrosis was present in seven of the eight cases (87.5%), and vascular lesions were present in 3/8 cases (37.5%). Lesions suggestive of renal toxicity were present in 6/8 patients (75%).

Side effects encountered during therapy with CsA were hypertension in 11 cases (48%), nephrotoxicity in nine (39%), interstitial fibrosis in seven cases, and vascular lesions in three cases. One patient had both interstitial fibrosis and vascular lesions, gingival hypertrophy was seen in eight cases (35%), tremors in eight cases (35%), and hirsutism and hypertrichosis in five cases (22%).

There were seven dropouts seen during therapy with CsA: CsA was stopped in two patients (9%) for complete and sustained remission in eight patients (35%) for nephrotoxicity, six patients (26%) for CsA-resistance, and one patient (4%) voluntarily stopped his treatment. The mean follow-up of our patients was 6.8 ± 3.7 years; one patient had sudden death of undetermined cause.

We conducted a comparative study between patients with SDNS (eight patients) and those with SRNS (15 patients). A statically significant difference was noted regarding age (P = 0.04) and creatinine clearance after CsA therapy (P = 0.04, [Table 1].
Table 1: Comparison of epidemiological, clinical, biological parameters and evolution under CsA between patients with SDNS and those with SRNS.

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A second comparative study was performed between patients with complete remission on CsA (8 patients) and the 15 remaining patients (5 patients with partial remission, 4 patients with dose-dependent remission of CsA and 6 patients with no response). There was no significant difference between the different epidemiological, clinical, and biological parameters compared, except for serum albumin (P = 0.004).


   Discussion Top


Factors predictive of cyclosporine A resistance

Univariate analysis showed that age, sex, presence of initial NS, response to steroid treatment, and the presence of vascular and/or interstitial fibrosis were not significantly associated with evolution to chronic renal failure. On multivariate analysis, factors predictive of progression to ESRD were creatinine clearance <90 mL/min before introduction of CsA P = 0.0054, [Figure 1] and CsA-resistance (P =0.053, [Figure 2].
Figure 1: Renal survival according to renal function before starting cyclosporine therapy (Kaplan– Meier).

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Figure 2: Renal survival according to treatment with cyclosporine (Kaplan–Meier).

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Primary FSGS is usually a progressive disorder with a spontaneous remission rate of under 5% and a 50% ESRD rate, over a period of five to eight years from the time of biopsy in patients that are either unresponsive to treatment or not treated. [7],[8]

Retrospective studies have suggested that complete remissions may occur in up to 60% of patients after prolonged treatment with immunosuppressive drugs. [9]

A major working classification recognizes five histologic variants of FSGS: FSGS not otherwise specified, perihilar, cellular, tip, and collapsing. [10] The histologic variants of FSGS have correlated with the outcomes in retrospective studies. [11] Some investigators have argued that the achievement of complete or partial re mission of NS is a better predictor of outcome in FSGS than the histological variant. [12]

Nephrotic-range proteinuria, with or without other features of the NS, is the classic presentation of primary FSGS. An elevated serum creatinine at presentation does not in itself adversely affect steroid response in adults with primary FSGS. [13]

One of the presumed pathogenic mechanisms of primary FSGS is a dysregulated autoimmune response; hence, the use of immunosuppressive agents is advocated in its treatment. It is now generally accepted that the predominant glomerular lesion in FSGS is injury to podocytes and calcineurin inhibitors (CNIs) have been shown to stabilize the podocyte actin cytoskeleton. [14]

FSGS is a difficult renal disease to manage, and the cumulative toxicity of the various agents used in the treatment might make the therapy as bad as or worse than the disease. [15] The initial treatment of primary FSGS usually involves corticosteroids [6],[9] and results in remission of proteinuria in about 25% of patients. [16],[17],[18] The current KDIGO guidelines on glomerulonephritis recommend initial treatment of primary FSGS with high-dose prednisone given for between four and 16 weeks, or until complete remission. CNIs are recommended for patients with FSGS who are resistant or intolerant to glucocorticoids and are continued for a minimum of one year if the patient is responsive. [19]

Corticosteroids were the first therapeutic modality used in our patients. Treatment with CsA was initiated in 35% of our patients for SDNS and in 65% for SRNS. Complete remission was achieved in only 35% of cases, partial remission in 22%, a dose-dependent remission to CsA in 17%, and a no response in 26% of patients.

The only medications that have been evaluated in randomized clinical trials (RCTs) and have been shown to increase the rate of partial and complete remission are CsA along with low-dose prednisone. [20],[21] MMF, which reduces proteinuria in steroid-resistant FSGS with less toxicity than CsA, has not been tested in large RCTs. [22]

A randomized, multicenter study of treatment of FSGS compared the efficacy of a 12-month course of CsA with a combination of oral pulse dexamethasone and MMF in children and adults with steroid-resistant primary FSGS; no difference was found. [23],[24]

Treatment with CNIs is associated with significant but different adverse effects, including nephrotoxicity and hypertension. This therapy has been associated with a relapse rate of up to 50%. [25]

Rituximab therapy for FSGS has been tried in small and uncontrolled studies. [26] Successful treatment with rituximab in a patient with FSGS and diminished renal function has been described. [27] Controlled studies must be performed to prove the efficacy of rituximab, to evaluate its cost-effectiveness, and to determine which patients will benefit.

In total, adult patients with primary FSGS and nephrotic range proteinuria should be treated with a prolonged course of corticosteroids. CsA may play a role in patients who fail to respond to prednisolone or as steroid-sparing agents in those who do respond. [28]

In our study, predictive factors of progression to ESRD were creatinine clearance <90 mL/ min before introduction of CsA and CsA-resistance. Other factors have been reported, including a higher percentage (>25%) of sclerosis in the glomeruli, nonselective proteinuria at the time of biopsy, and decreased concentrations of serum albumin at three months after renal biopsy. [29]


   Conclusion Top


CsA is effective in the treatment of patients with idiopathic FSGS. Initial renal function and CsA-resistance are the most common predictive factors of ESRD in steroid-resistant or -dependent FSGS. This study reports our experience in the treatment of primary FSGS with CsA. There is a need to evaluate new therapeutic agents and allow better appraisal of response to treatment.

Conflict of Interest: The authors declare that there is no conflict of interests regarding the publication of this paper.

 
   References Top

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Faul C, Donnelly M, Merscher-Gomez S, et al. The actin cytoskeleton of kidney podocytes is a direct target of the antiproteinuric effect of cyclosporine A. Nat Med 2008;14:931-8.  Back to cited text no. 14
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Correspondence Address:
Imen Gorsane
Department of Medicine A (M8), Charles Nicolle Hospital, Tunis
Tunisia
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DOI: 10.4103/1319-2442.190864

PMID: 27752004

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