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Saudi Journal of Kidney Diseases and Transplantation
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LETTER TO THE EDITOR  
Year : 2014  |  Volume : 25  |  Issue : 3  |  Page : 661-666
Effect of cyclosporine a in the treatment of proteinuric patients with immunoglobulin a nephropathy


1 Department of Medicine, Nephrology Section, Hasheminejad Kidney Center, Iran University of Medical Sciences, Tehran, Iran
2 Student Scientific Research Center, Iran University of Medical Sciences, Tehran, Iran

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Date of Web Publication9-May-2014
 

How to cite this article:
Ossareh S, Madadi B, Joodat R. Effect of cyclosporine a in the treatment of proteinuric patients with immunoglobulin a nephropathy. Saudi J Kidney Dis Transpl 2014;25:661-6

How to cite this URL:
Ossareh S, Madadi B, Joodat R. Effect of cyclosporine a in the treatment of proteinuric patients with immunoglobulin a nephropathy. Saudi J Kidney Dis Transpl [serial online] 2014 [cited 2019 Nov 11];25:661-6. Available from: http://www.sjkdt.org/text.asp?2014/25/3/661/132231
To the Editor,

Immunoglobulin A nephropathy (IgAN) is now the most common type of primary glomerulonephritis in most countries of the world. [1],[2],[3] Clinically, it presents with macroscopic hematuria in about 40-45% of patients, with microscopic hematuria and proteinuria in about 35-40% of patients and with nephrotic syndrome or acute renal failure in the remainder. [3] Histologically, it may vary from a mild mesangial proliferation to severe crescentic glomerulonephritis. [4] Although IgAN was first considered to have a benign course, it is now known to slowly progress to end-stage renal disease (ESRD). [5] Systolic hypertension, proteinuria, hypoproteinemia, azotemia and a high histological grade at initial renal biopsy, have been shown to be the main predictors of progression to ESRD. [6]

Accordingly, in mild cases, conservative (non-immunosuppressive) therapy can be considered beneficial to decrease proteinuria and the rate of decline in glomerular filtration rate (GFR), as may tonsillectomy and fish oil therapy. [7],[8],[9] Patients with more severe proteinuria and/or acute decline in renal function are conventionally being subjected to treatment with various immunosuppressive regimens, including steroids, cyclophosphamide, azathioprine and mycophenolate mofetil/sodium, with conflicting results. [10],[11] However, there is still a strong debate regarding the use of cyclosporine A (CsA) for the treatment of proteinuria in IgAN, mainly due to concerns about the possible increase in serum creatinine caused by CsA. This debate is based on old clinical trials with CsA carried out on small numbers of patients, [12],[13] although it is being used as one of the main immunosuppressive agents in various other proteinuric glomerulonephritides.

In Hasheminejad Kidney Center, a referral kidney center in Iran, 11% of renal biopsies were diagnosed as IgAN between the years 1998 and 2010. [14] A retrospective case series study was performed to evaluate the results of administration of CsA in the group of proteinuric IgAN patients as the primary treatment or after failure to respond to other treatment modalities. The criteria for administration of CsA had been proteinuria more than 1000 mg/day and serum creatinine ≤2 mg/dL. Of 120 patients with biopsy-proven IgAN, 13 patients who had received CsA alone or with angiotensin-converting enzyme inhibitors (ACE-I), prednisolone or a combination of the latter two medications, and had a follow-up of at least two months, were included in the study. More than half of the patients had nephrotic syndrome (proteinuria ≥3500 mg/day) at base-line and only two patients had a serum creatinine higher than 1.4 mg/dL. CsA was started at a dose of 4 mg/kg/day.

Data including demographic characteristics, serum creatinine, GFR and 24 h urine protein value before administration of CsA, and during the treatment course till the last follow-up date, were collected from records retrospectively Complications of CsA and the reason for stopping the drug were also recorded. Partial response to treatment was defined as a decrease in proteinuria to half of the baseline value with no increase in serum creatinine, and complete response was defined as decrease of proteinuria to less than 1000 mg/day, without increase in serum creatinine.

Data were analyzed using Statistical Package for the Social Sciences (SPSS), version 18. Quantitative variables were expressed as mean ± standard deviation. A paired T test was used for the comparison of the variables before and after treatment. Statistical significance was considered as a P-value <0.05.

Among the 13 patients, six (46.2%) were male and seven (53.8%) were female, with a mean age of 33.46 ± 14.64 years. Mean proteinuria, serum creatinine and GFR before treatment were 4027 ± 1964 mg/24h (1250-8100), 1.2 ± 0.7 mg/dL (0.5-3.3) and 88.23 ± 28.50 mL/min, respectively [Table 1]. At the end of the treatment course with CsA, there was a significant decrease in mean proteinuria (2493 ± 2146, P = 0.03) [Figure 1], with no significant decrease in GFR [Figure 2] or increase in serum creatinine [Figure 3].
Figure 1: Changes in proteinuria of 13 patients during treatment with cyclosporine A (CsA) and in the last follow-up.

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Figure 2: Changes in glomerular filtration rate (GFR) of 13 patients during treatment with cyclosporine A (CsA) and in the last follow-up.

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Figure 3: Changes in serum creatinine (Cr) of 13 patients during treatment with cyclosporine A (CsA) and in the last follow-up.

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Table 1: Comparison of laboratory values before and after treatment with CsA.

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[Table 2] shows the baseline characteristic and the response to treatment in each patient. As the table shows, at baseline, six patients had sub-nephrotic proteinuria and seven had nephrotic range proteinuria. Serum creatinine was 2.4 in patient 12 and 3.3 in patient 6, which was decreased to 1.1 mg/dL with pulse methylprednisolone and mycophenolate mofetil before starting CsA for resistant proteinuria. Complete remission was seen in eight patients (patients 1-8), with unresponsive relapse in two of them (patients 7 and 8). Four patients had no response to CsA and in one patient the drug was stopped due to non-tolerance (complaints of dizziness, headache and tremor) (patient 9). From the four unresponsive patients, one was non-compliant to different drug regimens and the other three had relentless disease with resistant proteinuria to other immunosuppressive agents, one of whom progressed to ESRD within seven years (patient 13). In two patients, CsA had to be stopped after rise in serum creatinine from 2.4 to 3.1 (patient 12) and 0.9 to 1.4 (patient 10), which reversed to the baseline level in two to four months.
Table 2: Basic clinical characteristics and response to treatment in 13 IgA nephropathy patients.

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Our study shows that more than half of our patients had complete remission with no serious complications caused by CsA. There are only a few studies regarding the use of CsA in IgAN, mainly affected by the very first report that discouraged the use of this medication in IgAN due to an increase in serum creatinine, although the complication was reversible. In that study, Lai and colleagues compared the effect of CsA (5 mg/kg/day) in nine IgAN patients with placebo in ten patients for a duration of 12 weeks. In the CsA-treated group, significant decrease in proteinuria was observed; however, the serum creatinine level rose in this group, which decreased to the previous level in eight weeks after discontinuation of the drug. [11] In spite of the beneficial effect of CsA in the treatment of proteinuria in IgAN patients, the authors discouraged the use of this drug because of the risk of rise in serum creatinine. Actually, based on this single study and due to the lack of other controlled clinical trials, other authors have not suggested the use of CsA in IgAN. [12],[13],[15],[16]

However, there are a few other studies that have successfully used CsA in resistant IgAN patients. In a non-randomized study, Chabova and colleagues administered 5 mg/kg/day of CsA plus alternate day 5-10 mg prednisolone to six IgAN patients with nephrotic range proteinuria and normal serum creatinine, who were resistant to three months of glucocorticoid therapy. [17] They aimed a trough serum cyclosporine level of 70-150 ng/mL and continued the regimen for one year. After one month of treatment, proteinuria reduced from 4.66 ± 0.43 g/day to 1.38 ± 0.29 g/day and after one year to 0.59 ± 0.14 g/day. GFR was not different significantly from the baseline in two years. In a retrospective study by Shin and colleagues on 14 children with IgAN, a significant decrease in proteinuria and increase in serum albumin concentration without any rise in serum creatinine level was observed. [18] A decrease in histologic grade of IgAN was seen in a follow-up biopsy of 50% of the patients. These researchers suggested that CsA has a significant role in decreasing proteinuria and reversing kidney pathology in children with IgAN. Also, in two other studies from Korea by the same group, on children with Henoch-Schönlein purpura and nephrotic syndrome and in a case report of a nephrotic four-year-old girl with Henoch-Schönlein purpura from Greece, complete clinical remission together with improvement in histologic grade of the disease have been reported. [19],[20],[21] In an interesting recent study by Zhang and colleagues, remission of nephrotic range proteinuria could be induced in nine of 11 IgAN patients with the use of Tacrolimus, which was explained through the effect of the drug in podocyte cytoskeleton stabilization through inhibition of calcineurin expression. [22]

In our retrospective case series of 13 adult patients with IgAN and significant proteinuria, more than half of the patients did respond to CsA therapy with or without steroids, with long-term remission in some. A rise in serum creatinine was observed only in two patients, which was mild and reversible. Thus, this complication should not preclude the use of CsA. [23]

Although there are no randomized controlled trials studying the effect of CsA on proteinuric IgAN, we believe that the results of our case series, as well as the above-mentioned studies, can help to prevent the discouragement of the use of this medication for an idiopathic immunologic disease with not many therapeutic choices. The fear from increase in serum creatinine seems to have prevented the researchers from designing clinical trials to study this valuable immunosuppressive agent in the treatment of IgAN, and we suggest to start such trials for a better long-term judgment.

Conflict of interest: None

 
   References Top

1.Yoshikawa N, Iijima K, Ito H. IgA nephropathy in children. Nephron 1999;83:1-12.  Back to cited text no. 1
    
2.Kawasaki Y, Suzuki J, Sakai N, et al. Efficacy of prednisolone and mizoribine therapy for diffuse IgA nephropathy. Am J Nephrol 2004; 24:147-53.  Back to cited text no. 2
    
3.Galla JH. IgA nephropathy. Kidney Int 1995; 47:377-87.  Back to cited text no. 3
    
4.Lemley KV, Lafayette RA, Safai M, et al. Podocytopenia and disease severity in IgA nephropathy. Kidney Int 2002;61:1475-85.  Back to cited text no. 4
    
5.Geddes CC, Rauta V, Gronhagen-Riska C, et al. A tricontinental view of IgA nephropathy. Nephrol Dial Transplant 2003;18:1541-8.  Back to cited text no. 5
    
6.Wakai K, Kawamura T, Endoh M, et al. A scoring system to predict renal outcome in IgA nephropathy: From a nationwide prospective study. Nephrol Dial Transplant 2006;21:2800-8.  Back to cited text no. 6
    
7.Remuzzi A, Perticucci E, Ruggenenti P, Mosconi L, Limonta M, Remuzzi G. Angiotensin converting enzyme inhibition improves glomerular size-selectivity in IgA nephropathy. Kidney Int 1991;39:1267-73.  Back to cited text no. 7
    
8.Appel GB, Waldman M. The IgA nephropathy treatment dilemma. Kidney Int 2006;69:1939-44.  Back to cited text no. 8
    
9.Barratt J, Feehally J. Treatment of IgA nephropathy. Kidney Int 2006;69:1934-8.  Back to cited text no. 9
    
10.Strippoli GF, Manno C, Schena FP. An "evidence-based" survey of therapeutic options for IgA nephropathy: Assessment and criticism. Am J Kidney Dis 2003;41:1129-39.  Back to cited text no. 10
    
11.Lai KN, Lai FM, Li PK, Vallance-Owen J. Cyclosporin treatment of IgA nephropathy: A short term controlled trial. Br Med J (Clin Res Ed) 1987;295:1165-8.  Back to cited text no. 11
    
12.Cattran DC. Current status of cyclosporin A in the treatment of membranous, IgA and membranoproliferative glomerulonephritis. Clin Nephrol 1991;35 Suppl 1:S43-7.  Back to cited text no. 12
    
13.Nolin L, Courteau M. Management of IgA nephropathy: Evidence-based recommendations. Kidney Int Suppl 1999;70:S56-62.  Back to cited text no. 13
    
14.Ossareh S, Asgari M, Abdi E, et al. Renal biopsy findings in Iran: Case series report from a referral Kidney Center. Int Urol Nephrol 2010;42:1031-40.  Back to cited text no. 14
    
15.Thomas M. The CARI Guidelines - Caring for Australasians with Renal Impairment Prevention of Progression of Kidney Disease. Specific Management of IgA Nephropathy: Role of Cyclosporin and Other Therapies (April 2006). Available from: http://www.cari.org.au. [Last accessed on 14 April 2014]  Back to cited text no. 15
    
16.Samuels JA, Strippoli GF, Craig JC, Schena FP, Molony DA. Immunosuppressive treatments for immunoglobulin A nephropathy: A meta-analysis of randomized controlled trials. Nephrology (Carlton) 2004;9:177-85.  Back to cited text no. 16
    
17.Chábová V, Tesar V, Zabka J, et al. Long term treatment of IgA Nephropathy With Cycloporine A. Ren Fail 2000;22:55-62.  Back to cited text no. 17
    
18.Shin JI, Lim BJ, Kim PK, Lee JS, Jeong HJ, Kim JH. Effects of cyclosporine A therapy combined with steroids and angiotensin converting enzyme inhibitors on childhood IgA nephropathy. J Korean Med Sci 2010;25:723-7.  Back to cited text no. 18
    
19.Shin JI, Park JM, Shin YH, et al. Cyclosporin A therapy for severe Henoch-Schönlein nephritis with nephrotic syndrome. Pediatr Nephrol 2005;20:1093-7.  Back to cited text no. 19
    
20.Park JM, Won SC, Shin JI, Yim H, Pai KS. Cyclosporin A therapy for Henoch-Schönlein nephritis with nephrotic-range proteinuria. Pediatr Nephrol 2011;26:411-7.  Back to cited text no. 20
    
21.Georgaki-Angelaki E, Kostaridou S, Lourida A, Petraki C, Lagona E. Abrupt and durable remission of Henoch-Schӧnlein purpura nephritis with cyclosporine A. NDT Plus 2008;1: 300-2.  Back to cited text no. 21
    
22.Zhang Q, Shi SF, Zhu L, et al. Tacrolimus improves the proteinuria remission in patients with refractory IgA nephropathy. Am J Nephrol 2012;35:312-20.  Back to cited text no. 22
    
23.Vercauteren SB, Bosmans JL, Elseviers MM, Verpooten GA, De Broe ME. A meta-analysis and morphological review of cyclosporine-induced nephrotoxicity in auto-immune diseases. Kidney Int 1998;54:536-45.  Back to cited text no. 23
    

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Correspondence Address:
Dr. Shahrzad Ossareh
Department of Medicine, Nephrology Section, Hasheminejad Kidney Center, Iran University of Medical Sciences, Tehran
Iran
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DOI: 10.4103/1319-2442.132231

PMID: 24821173

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