Minimal change disease (MCD) is the most common cause of nephrotic syndrome (NS) in children, accounting for > 90% of cases as opposed to 15% in adults [1] . Its incidence and prevalence are 2 - 7 and 10 - 50 cases/100,000 children, while such data are limited in adults since the disease is uncommon [2] . Since MCD is common in children and with 90% response to Corticosteroids (C), kidney biopsy is limited only to those who manifest C-refractoriness (45%) and C-resistance (10%) to avoid the technical difficulties in their biopsy [3] . On the other hand, kidney biopsy is mandatory in adults with NS since MCD represents only 15% of cases, while other C-resistant glomerulopathies are more common, especially membranous ones (40%) [2] . Maltreated MCD is associated with high morbidity and mortality as well as poor quality of life due to its symptomatic anasarca, bacterial infections, venous and arterial thromboembolism as well as the inherent complications of immunosuppressive therapy. Historically, C was its mainstay of therapy, yet nearly 50% of C-responsive patients manifest C-refractoriness viz. frequent relapses and C-dependency [4] . In those patients, previous long-term C-use resulted in acne, hirsutism, peptic disease, infections, psychosis, obesity, growth retardation, hypertension, diabetes mellitus, osteoporosis and adrenal suppression [5] . Moreover, the second-line steroid-sparing immunosuppressants viz. antiproliferative, levamisole, calcineurin inhibitors and mycophenolate mofetil had limited long-term success and were associated with various side effects viz. infertility, interstitial fibrosis and infections [6] . Recently, yearly Rituximab use proved to be the most practical treatment for such forms of MCD [7] . Unfortunately, being a murine monoclonal antibody, hypersensitivity reactions were common. They include type I, cytokine-release, mixed type, and delayed-type IV reactions with a prevalence of 63, 13, 21, and 3% respectively. Of those 10% severe and limited R-use [8] . In an attempt to fill the gap in the treatment of such patients, we conducted the present study to assess the efficacy and safety of a new protocol of Cyclosporin A (Cy) therapy that consisted of an adequate therapeutic dose of only for 3 months (induction-phase) followed by a limited maintenance dose for 4-years only.

Over the past 10 years, patients were included in the study if they had a) nephrotic syndrome due to biopsy-proven, MCD, b) negative previous kidney and liver diseases as well as disorders requiring drugs interfering with Cy-blood levels viz. epilepsy, hypertension, and chronic infections, c) negative history, clinical examination, radiological scans as well as laboratory and serological tests for autoimmune diseases, infections, malignancy and drugs-side effect, d) C-refractoriness over > 2 years, e) severe allergy to R-infusions limiting its use, f) adequate follow up for > 5 years.

A total of 35 patients fulfilled the study inclusion criteria. The patient’s demographic characteristics and response to Cy-therapy are summarized in Table 1 . Eleven patients were children (<14 years) and 21 (60%) were females. All patients had confirmed NS with C-refractoriness for > 2 years and follow up of > year after discontinuation of Cy-therapy.

In our study, we provided a new protocol of Cy-therapy for the treatment of patients with NS due to SRIM that could not tolerate R for severe infusional reactions. It proved to be an effective treatment that a) induced complete remission in all the 35 patients, b) maintained such remission for 4 years despite dose-decrement, and c) prevented relapse of NS, in 89% of those patients, for 1 year without Cy-use. Moreover, such therapy was a) well-tolerated without patient fallout, and b) safe without inducing biochemical markers of significant and/or permanent kidney disease. Cy selection was based on the current knowledge of the pathogenesis of MCD and the mechanism of action Cy. MCD is a form of autoimmune podocytopathies. Its presumed etiology of primary ones is a T-cell induction of permeability plasma-factors viz. soluble urokinase plasminogen activator receptor (suPAR), cardiotrophin-like cytokine factor-1 (CLCF-1), and CD40 antibodies. They act on negative charges at different adhesion molecules between the podocyte and glomerular basement membrane leading to albumin leak [9] . On the other hand, Cy is a) a potent anti-T cell agent, and b) a stabilizer for the actin cytoskeleton in kidney podocytes; therefore, it is beneficial for treating proteinuric kidney diseases [10] . Cy immunosuppression acts via two pathways, a) the calcineurin/Nuclear factor of activated T cells (NFAT) pathway and, b) the c-Jun N-terminal kinases (JNK) and p38 signaling pathway. The first prevents calcineurin-mediated dephosphorylation, which leads to inhibition of the nuclear translocation of NFAT family members and subsequent gene expression in activated T-cells [11] . The other pathway involves inhibition of the mitogen-activated protein kinase (MAPK) pathway, which has significant roles in cellular activities such as proliferation, stress reactions, apoptosis, and immunological defense via blockage of interleukin-2 (IL-2) gene, promoting the transcription of IL-2 [12] [13] . Moreover, leukin T-B lymphocyte (LT-B) co-operation which is essential for activation of B-lymphocytes is inhibited [14] . Cy-efficacy has been shown in multiple autoimmune disorders viz. solid organ transplantation, rheumatoid arthritis, psoriasis, amyotrophic lateral sclerosis as well as graft vs. host, Behcet, posterior uveitis and glomerular diseases [14] . Unfortunately, chronic interstitial fibrosis limited its long-term maintenance use [15] . In our study, we used adequate therapeutic-doses to induce remission only for 3 months. Subsequently, a smaller dosage was used to maintain remission for a minimum of 4 years. The decrement in Cy-dose was gradual and efficacious. Moreover, it was associated with low Cy-levels, which were essential to avoid the induction of long-term interstitial fibrosis [16] . The choice of such duration was based on our previous experience with R-therapy for MCD [17] . Potent anti-T cell therapy may abolish memory cell leading to tolerance for up to 6 years [18] .

4-years-treatment with Cy offers a safe and effective alternative to R allergic patients with SRIM.

Prof/ Kamel El-Reshaid conceived the study, participated in its design, and drafted the manuscript. Dr. Shaikha Al-Bader and Dr. Hossameldin Tawfik Sallam participated in the study design, follow up of patients and data collection and tabulated the data. Dr John Madda participated in the study design, and was responsible for histological diagnosis, data collection and tabulation of histological data.

The data provided in the current review are available from the references.