Tacrolimus combined with low-dose corticosteroids is an effective and safe therapeutic option for refractory IgA nephropathy

Wan,Qi‑Jun; Hu,Hao‑Fei; He,Yong‑Cheng; Luan,Shao‑Dong; Chen,Hong‑Tao; Li,Tong; Xu,Yi; Xu,Hui‑Li; Liao,Ying

doi:10.3892/etm.2016.3523

Tacrolimus combined with low-dose corticosteroids is an effective and safe therapeutic option for refractory IgA nephropathy

Authors:
- Qi‑Jun Wan
- Hao‑Fei Hu
- Yong‑Cheng He
- Shao‑Dong Luan
- Hong‑Tao Chen
- Tong Li
- Yi Xu
- Hui‑Li Xu
- Ying Liao
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Affiliations: Department of Nephrology, Shenzhen Second People's Hospital, Shenzhen, Guangdong 518035, P.R. China
Published online on: July 14, 2016 https://doi.org/10.3892/etm.2016.3523
Pages: 1934-1938

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Abstract

Tacrolimus (TAC) has been shown to improve remission from proteinuria in patients with refractory IgA nephropathy (IgAN); however, the efficacy and safety of TAC in such patients have not been fully explored. Therefore, the present study was conducted to evaluate the tolerance to and efficacy of TAC combined with low-dose corticosteroids in patients with refractory IgAN. This was a single‑center retrospective study. A total of 28 patients with refractory IgAN were randomly included and received TAC plus corticosteroid; 26 patients received TAC and prednisone, and 2 patients received TAC and methylprednisolone. In addition, all patients were treated with an angiotensin inhibitor. Total urinary protein excretion, serum albumin, blood glucose, complete remission (CR), partial remission (PR), cholesterol, low‑density lipoprotein (LDL), serum creatinine (Scr) and estimated GFR (eGFR) were tested at baseline and at 3, 6 and 12 months after the initiation of treatment in all patients. The primary endpoints were CR and PR. Secondary endpoints included changes of Scr, eGFR, clinical data and adverse events. After 12 months, CR was achieved in 40.1% of patients and PR in 43.4%, yielding a total response rate of 83.5%, and the total urinary protein excretion, serum albumin, cholesterol and LDL results were improved significantly compared with those at baseline. Proteinuria and serum albumin results were significantly improved by month 3 of treatment. Two patients relapsed during months 3‑6 of follow‑up. At the 12‑month follow‑up, renal function was improved compared with the baseline level as evidenced by eGFR and Scr, respectively. The blood glucose level was stable. One case of pneumococcal pneumonia developed in a patient treated with TAC plus low‑dose methylprednisolone and one case of upper gastrointestinal hemorrhage was found in a patient treated with TAC plus low‑dose prednisone; both cases completely recovered after treatment. In conclusion, TAC combined with low‑dose corticosteroids may be an effective and safe therapeutic option for the treatment of refractory IgAN. However, given the small number of patients in this study, further prospective randomized controlled trials are required with a larger sample of participants and longer follow-up period.

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1	Karnib HH, Gharavi AG, Aftimos G, Mahfoud Z, Saad R, Gemayel E, Masri B, Assaad S, Badr KF and Ziyadeh FN: A 5-year survey of biopsy proven kidney diseases in Lebanon: Significant variation in prevalence of primary glomerular diseases by age, population structure and consanguinity. Nephrol Dial Transplant. 25:3962–3969. 2010. View Article : Google Scholar : PubMed/NCBI
2	Goto M, Wakai K, Kawamura T, Ando M, Endoh M and Tomino Y: A scoring system to predict renal outcome in IgA nephropathy: A nationwide 10-year prospective cohort study. Nephrol Dial Transplant. 24:3068–3074. 2009. View Article : Google Scholar : PubMed/NCBI
3	Kiryluk K, Li Y, Sanna-Cherchi S, Rohanizadegan M, Suzuki H, Eitner F, Snyder HJ, Choi M, Hou P, Scolari F, et al: Geographic differences in genetic susceptibility to IgA nephropathy: GWAS replication study and geospatial risk analysis. PLoS Genet. 8:e10027652012. View Article : Google Scholar : PubMed/NCBI
4	Chacko B: IgA nephropathy in India: What we do know. Ren Fail. 33:102–107. 2011. View Article : Google Scholar : PubMed/NCBI
5	Yamamoto R, Nagasawa Y, Shoji T, Inoue K, Uehata T, Kaneko T, Okada T, Yamauchi A, Tsubakihara Y, Imai E, et al: A candidate gene approach to genetic prognostic factors of IgA nephropathy-a result of polymorphism research to distinguish genetic factors contributing to progression of IgA nephropathy (PREDICT-IgAN). Nephrol Dial Transplant. 24:3686–3694. 2009. View Article : Google Scholar : PubMed/NCBI
6	Kaartinen K, Syrjänen J, Porsti I, Harmoinen A, Pasternack A, Huhtala H, Niemelä O and Mustonen J: Insulin resistance and the progression of IgA glomerulonephritis. Nephrol Dial Transplant. 22:778–783. 2007. View Article : Google Scholar : PubMed/NCBI
7	Bonnet F, Deprele C, Sassolas A, Moulin P, Alamartine E, Berthezène F and Berthoux F: Excessive body weight as a new independent risk factor for clinical and pathological progression in primary IgA nephritis. Am J Kidney Dis. 37:720–727. 2001. View Article : Google Scholar : PubMed/NCBI
8	Chen W, Liu Q, Liao Y, Yang Z, Chen J, Fu J, Zhang J, Kong Y, Fu P, Lou T, et al: Outcomes of tacrolimus therapy in adults with refractory membranous nephrotic syndrome: A prospective, multicenter clinical trial. Am J Med Sci. 345:81–87. 2013. View Article : Google Scholar : PubMed/NCBI
9	Loeffler K, Gowrishankar M and Yiu V: Tacrolimus therapy in pediatric patients with treatment-resistant nephrotic syndrome. Pediatr Nephrol. 19:281–287. 2004. View Article : Google Scholar : PubMed/NCBI
10	Girman P, Lipar K, Koznarova R, Boucek P, Kriz J, Kocik M, Havrdova T, Adamec M and Saudek F: Similar early complication rate in simultaneous pancreas and kidney recipients on tacrolimus/mycophenolate mofetil versus tacrolimus/sirolimus immunosuppressive regimens. Transplant Proc. 42:1999–2002. 2010. View Article : Google Scholar : PubMed/NCBI
11	Naesens M, Kuypers DR and Sarwal M: Calcineurin inhibitor nephrotoxicity. Clin J Am Soc Nephrol. 4:481–508. 2009.PubMed/NCBI
12	Flechner SM, Kobashigawa J and Klintmalm G: Calcineurin inhibitor-sparing regimens in solid organ transplantation: Focus on improving renal function and nephrotoxicity. Clin Transplant. 22:1–15. 2008.PubMed/NCBI
13	Wierzbicka A, Pawłowska J, Socha P, Jankowska I, Skorupa E, Teisseyre M, Ismail H, Czubkowski P and Socha J: Lipid, carbohydrate metabolism and antioxidant status in children after liver transplantation. Transplant Proc. 39:1523–1525. 2007. View Article : Google Scholar : PubMed/NCBI
14	Noto T, Furuichi Y, Ishiye M, Matsuoka N, Aramori I, Mutoh S and Yanagihara T: Tacrolimus (FK506) limits accumulation of granulocytes and platelets and protects against brain damage after transient focal cerebral ischemia in rat. Biol Pharm Bull. 30:313–317. 2007. View Article : Google Scholar : PubMed/NCBI
15	Aomatsu T, Imaeda H, Takahashi K, Fujimoto T, Kasumi E, Yoden A, Tamai H, Fujiyama Y and Andoh A: Tacrolimus (FK506) suppresses TNF-α-induced CCL2 (MCP-1) and CXCL10 (IP-10) expression via the inhibition of p38 MAP kinase activation in human colonic myofibroblasts. Int J Mol Med. 30:1152–1158. 2012.PubMed/NCBI
16	Faul C, Donnelly M, Merscher-Gomez S, Chang YH, Franz S, Delfgaauw J, Chang JM, Choi HY, Campbell KN, Kim K, et al: The actin cytoskeleton of kidney podocytes is a direct target of the antiproteinuric effect of cyclosporine A. Nat Med. 14:931–938. 2008. View Article : Google Scholar : PubMed/NCBI
17	Mathieson PW: Proteinuria and immunity-an overstated relationship? N Engl J Med. 359:2492–2494. 2008. View Article : Google Scholar : PubMed/NCBI
18	Rostaing L, Cantarovich D, Mourad G, Budde K, Rigotti P, Mariat C, Margreiter R, Capdevilla L, Lang P, Vialtel P, et al: Corticosteroid-free immunosuppression with tacrolimus, mycophenolate mofetil and daclizumab induction in renal transplantation. Transplantation. 79:807–814. 2005. View Article : Google Scholar : PubMed/NCBI
19	Zhang Q, Shi SF, Zhu L, Lv JC, Liu LJ, Chen YQ, Zhang H and Wang HY: Tacrolimus improves the proteinuria remission in patients with refractory IgA nephropathy. Am J Nephrol. 35:312–320. 2012. View Article : Google Scholar : PubMed/NCBI
20	Bayrak O, Seckiner I, Erturhan SM, Mizrak S and Erbagci A: Analysis of changes in the glomerular filtration rate as measured by the Cockroft-Gault formula in the early period after percutaneous nephrolithotomy. Korean J Urol. 53:552–555. 2012. View Article : Google Scholar : PubMed/NCBI
21	Lee HS, Lee MS, Lee SM, Lee SY, Lee ES, Lee EY, Park SY, Han JS, Kim S and Lee JS: Histological grading of IgA nephropathy predicting renal outcome: Revisiting H. S. Lee's glomerular grading system. Nephrol Dial Transplant. 20:342–348. 2005. View Article : Google Scholar : PubMed/NCBI
22	Lee SM, Rao VM, Franklin WA, Schiffer MS, Aronson AJ, Spargo BH and Katz AI: IgA nephropathy: Morphologic predictors of progressive renal disease. Hum Pathol. 13:314–322. 1982. View Article : Google Scholar : PubMed/NCBI
23	Ma YC, Zuo L, Chen JH, Luo Q, Yu XQ, Li Y, Xu JS, Huang SM, Wang LN, Huang W, et al: Modified glomerular filtration rate estimating equation for Chinese patients with chronic kidney disease. J Am Soc Nephrol. 17:2937–2944. 2006. View Article : Google Scholar : PubMed/NCBI
24	Ferraro PM, Ferraccioli GF, Gambaro G, Fulignati P and Costanzi S: Combined treatment with renin-angiotensin system blockers and polyunsaturated fatty acids in proteinuric IgA nephropathy: A randomized controlled trial. Nephrol Dial Transplant. 24:156–160. 2009. View Article : Google Scholar : PubMed/NCBI
25	Reich HN, Troyanov S, Scholey JW and Cattran DC: Toronto Glomerulonephritis Registry: Remission of proteinuria improves prognosis in IgA nephropathy. J Am Soc Nephrol. 18:3177–3183. 2007. View Article : Google Scholar : PubMed/NCBI
26	Manno C, Torres DD, Rossini M, Pesce F and Schena FP: Randomized controlled clinical trial of corticosteroids plus ACE-inhibitors with long-term follow-up in proteinuric IgA nephropathy. Nephrol Dial Transplant. 24:3694–3701. 2009. View Article : Google Scholar : PubMed/NCBI
27	Lv J, Zhang H, Chen Y, Li G, Jiang L, Singh AK and Wang H: Combination therapy of prednisone and ACE inhibitor versus ACE-inhibitor therapy alone in patients with IgA nephropathy: A randomized controlled trial. Am J Kidney Dis. 53:26–32. 2009. View Article : Google Scholar : PubMed/NCBI
28	Aliabadi AZ, Pohanka E, Seebacher G, Dunkler D, Kammerstätter D, Wolner E, Grimm M and Zuckermann AO: Development of proteinuria after switch to sirolimus-based immunosuppression in long-term cardiac transplant patients. Am J Transplant. 8:854–861. 2008. View Article : Google Scholar : PubMed/NCBI
29	Skytte DM, Jaroszewski JW, Johansen KT, Hansen SH, Hansen L, Nielsen PG and Frydenvang K: Some transformations of tacrolimus, an immunosuppressive drug. Eur J Pharm Sci. 48:514–522. 2013. View Article : Google Scholar : PubMed/NCBI
30	Westhoff TH and van der Giet M: Tacrolimus in the treatment of idiopathic nephrotic syndrome. Expert Opin Investig Drugs. 16:1099–1110. 2007. View Article : Google Scholar : PubMed/NCBI
31	Chen M, Li H, Li XY, Lu FM, Ni ZH, Xu FF, Li XW, Chen JH and Wang HY: Chinese Nephropathy Membranous Study Group: Tacrolimus combined with corticosteroids in treatment of nephrotic idiopathic membranous nephropathy: A multicenter randomized controlled trial. Am J Med Sci. 339:233–238. 2010. View Article : Google Scholar : PubMed/NCBI
32	Roberti I and Vyas S: Long-term outcome of children with steroid-resistant nephrotic syndrome treated with tacrolimus. Pediatr Nephrol. 25:1117–1124. 2010. View Article : Google Scholar : PubMed/NCBI
33	Li X, Li H, Ye H, Li Q, He X, Zhang X, Chen Y, Han F, He Q, Wang H and Chen J: Tacrolimus therapy in adults with steroid- and cyclophosphamide-resistant nephrotic syndrome and normal or mildly reduced GFR. Am J Kidney Dis. 54:51–58. 2009. View Article : Google Scholar : PubMed/NCBI
34	van Hooff JP, Christiaans MH and van Duijnhoven EM: Tacrolimus and posttransplant diabetes mellitus in renal transplantation. Transplantation. 79:1465–1469. 2005. View Article : Google Scholar : PubMed/NCBI
35	Dittrich K, Knerr I, Rascher W and Dötsch J: Transient insulin-dependent diabetes mellitus in children with steroid-dependent idiopathic nephrotic syndrome during tacrolimus treatment. Pediatr Nephrol. 21:958–961. 2006. View Article : Google Scholar : PubMed/NCBI
36	Sarkar S, Mondal R, Nandi M and Das AK: Tacrolimus induced diabetic ketoacidosis in nephrotic syndrome. Indian J Pediatr. 80:596–597. 2013. View Article : Google Scholar : PubMed/NCBI