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Kaohsiung Journal of Medical Sciences (2014) xx, 1e5
Available online at www.sciencedirect.com
ScienceDirect journal homepage: http://www.kjms-online.com
ORIGINAL ARTICLE
Severe pneumonia in mycophenolate mofetil combined with low-dose corticosteroid-treated patients with immunoglobulin A nephropathy Qi-Jun Wan, Hao-Fei Hu, Yong-Cheng He*, Shao-Dong Luan, Hong-Tao Chen, Hong-Ping Liu, Tong Li, Yi Xu, Hui-Li Xu, Ying Liao Department of Nephrology, Shenzhen Second People’s Hospital, Guangdong 518035, China Received 8 May 2014; accepted 27 August 2014
KEYWORDS Cytomegalovirus; IgA nephropathy; Mycophenolate mofetil; Pneumocystis pneumonia; Severe pneumonia
Abstract The tolerance of mycophenolate mofetil (MMF; Shanghai Roche, China) in Lee Classes III, IV, and V immunoglobulin A nephropathy (IgAN) remains unclear. This article reports nine cases of severe pneumonia (SP), including pneumocystis pneumonia (PCP) and cytomegalovirus (CMV) pneumonia, and its risk factors in MMF plus low-dose corticosteroid-treated patients with Lee Classes III, IV, and V IgAN. Fifty-three patients with IgAN were included in this single-center study. The treatment regimen was MMF (1e1.5 g/d) plus low-dose corticosteroids (0.5 mg/kg/d). SP was defined as diffuse bilateral lung infiltrate with respiratory failure. PCP was diagnosed by detecting the organisms in the sputum and bronchoalveolar lavage. CMV infection was diagnosed through serum screening for CMV-IgG and IgM antibodies and CMVDNA testing by a real-time polymerase chain reaction assay. The risk factors of SP were analyzed. Nine cases (16.9%) of SP occurred in this study. All SP developed at approximately the 10the14th week after the initiation of the regimen: PCP was diagnosed in four cases and CMV infection in two cases. Renal function impairing was more serious in patients with SP than in those without SP, as evidenced by estimated glomerular filtration rate (p Z 0.019) and serum creatinine level (p Z 0.016). Six of the nine SPs occurred in MMP plus low-dose methylprednisolone group, which was statistically higher than that in the MMF plus low-dose prednisone group (p Z 0.000). The incidence of SP in this study was 16.9%. Chronically impaired renal function and the use of methylprednisolone may be the risk factors for SP. Copyright ª 2014, Kaohsiung Medical University. Published by Elsevier Taiwan LLC. All rights reserved.
Conflicts of interest: All authors declare no conflicts of interest. * Corresponding author. Department of Nephrology, Shenzhen Second People’s Hospital, Number 3002 Sungang West Road Futian District, Shenzhen, Guangdong 518035, China. E-mail address: [email protected] (Y.-C. He). http://dx.doi.org/10.1016/j.kjms.2014.10.004 1607-551X/Copyright ª 2014, Kaohsiung Medical University. Published by Elsevier Taiwan LLC. All rights reserved.
Please cite this article in press as: Wan Q-J, et al., Severe pneumonia in mycophenolate mofetil combined with low-dose corticosteroidtreated patients with immunoglobulin A nephropathy, Kaohsiung Journal of Medical Sciences (2014), http://dx.doi.org/10.1016/ j.kjms.2014.10.004
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Introduction Mycophenolate mofetil (MMF; Shanghai Roche, China) has selective inhibitory effects on proliferative T- and B-lymphocytes [1]. Several prospective randomized, controlled trials have proven the effectiveness of MMF in immunoglobulin A nephropathy (IgAN) [2,3]. Most clinical trials have shown that MMF is well tolerated and possesses potent activity against pneumocystis pneumonia (PCP) [4]. Until this study, although one study [5] concerning the fact that severe infections, especially PCP, could occur following MMF administration has been reported, the tolerance of MMF combined with low-dose corticosteroids in Lee Classes III, IV, and V IgAN still remains unknown. To further evaluate the occurrence of severe pneumonia (SP) and the clinical characteristics in Chinese patients classified as having Lee Classes III, IV, and V IgAN and treated with MMF, this retrospective cohort study was performed in patients with IgAN who received either MMF plus low-dose methylprednisolone (MP) or MMF combined with low-dose prednisone during the same follow-up period from 2006 to 2012.
Materials and methods Patients and data This retrospective study evaluated 53 primary Chinese patients with IgAN, as determined by biopsy, who were registered for a follow-up examination in our renal center. Eighteen patients received MMF plus low-dose MP (0.5 mg/ kg/d), whereas the remaining 35 patients received MMF plus low-dose prednisone (0.5 mg/kg/d). MMF was initiated with 1e1.5 g/d for 6 months, 0.5e1.0 g/d for the next 6 months, and then 0.25e0.5 g/d for the previous 6 months. Prednisone was initiated with 0.5 mg/kg/d for 2 months, then slowly tapered by 5 mg every 2 weeks until discontinuation (the usage of MP was the same as that of prednisone in the current study). The records of the patients were reviewed from the start of the treatment through the time when the chart was reviewed, and until the drug was discontinued or severe infection appeared (final time point). Baseline characteristics including age, sex, 24-hour urine protein excretion, serum creatinine, and estimated glomerular filtration rate (eGFR; according to the modified Modification of Diet in Renal Disease (MDRD) equation for Chinese [6]) were recorded. SP was defined as diffused bilateral lung infiltrate with respiratory failure (PO2 < 60 mmHg). PCP was diagnosed by detecting the organism in the sputum and bronchoalveolar lavage (BAL) [7]. CMV infection was diagnosed through serum screening for CMV-IgG and IgM antibodies. CMV-DNA testing was carried out by a real-time polymerase chain reaction assay. This study was conducted in accordance with the Declaration of Helsinki and with approval from the Ethics Committee of Shenzhen Second People’s Hospital, Guangdong, China. Written informed consent was obtained from all participants.
Statistical analysis The clinical characteristics and occurrence of SP were compared between the MMF plus MP group and the MMF
Q.-J. Wan et al. plus prednisone group. The results are given as mean standard deviation for descriptive statistics. The baseline clinical variables were compared using the Student t test between groups, and the Chi-square test was used for the comparison of stratified data. SPSS version 13.0 software (SPSS Inc., Chicago, IL, USA) was used in all analyses. A p value < 0.05 was considered significant.
Results Baseline characteristics Fifty-three patients with IgAN were registered in our renal center, and received follow-up examinations from 2006 to 2012. Among these patients, 18 (34%) were treated with MMF plus low-dose MP, whereas 35 (66%) were treated with MMF combined with low-dose prednisone. The two groups did not differ in terms of their distribution of age, sex, serum creatinine, eGFR, and urine protein excretion at the baseline (Table 1).
Treatment efficacy MMF plus low-dose MP or MMF combined with low-dose prednisone reduced the urine protein excretion and preserved the renal function in the present study. At the 12th month of follow-up, urine protein excretion decreased greatly from 3.14 1.72 g/d to 0.96 0.32 g/day (p Z 0.000), and the renal function remained stable (serum creatinine was 232.16 103.9 mmol/L and 206.33 79.5 mmol/L prior to and after the treatment, respectively, p Z 0.245) in the MMF plus MP group. Meanwhile, urine protein excretion decreased greatly from 3.30 1.66 g/day to 0.31 0.23 g/d (p Z 0.000), and renal function remained stable (serum creatinine was 228.6 101.8 mmol/L and 201.3 99.3 mmol/L prior to and after the treatment, respectively, p Z 0.035) in the MMF plus prednisone group.
Table 1 Demographic and clinical data for patients with Lee Classes III, IV, V IgAN in the mycophenolate mofetil plus low-dose methylprednisolone and mycophenolate mofetil combined with low-dose prednisone groups. Characteristics
Age (y) Sex (M:F) SCr (mmol/L) eGFR (mL/min/ 1.73 m2) Urine protein excretion (g/d)
MMF þ MP group (n Z 18)
MMF þ prednisone group (n Z 35)
p
38.3 11.9 11:7 232.16 103.9 39.93 11.63
36.9 11.6 19:16 228.6 101.8 43.06 12.16
0.433 0.767 0.338 0.381
3.14 1.72
3.30 1.66
0.631
Values expressed as mean standard deviation. There were no significant differences in baseline characteristics between the groups. eGFR Z estimated glomerular filtration rate; IgAN, immunoglobulin A nephropathy; MMF Z mycophenolate mofetil; MP Z methylprednisolone; SCr Z serum creatinine.
Please cite this article in press as: Wan Q-J, et al., Severe pneumonia in mycophenolate mofetil combined with low-dose corticosteroidtreated patients with immunoglobulin A nephropathy, Kaohsiung Journal of Medical Sciences (2014), http://dx.doi.org/10.1016/ j.kjms.2014.10.004
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Occurrence, clinical characteristics, and prognosis Among the 53 patients treated with MMF and low-dose corticosteroids, nine developed SP around the 3rd month (10the14th week) after treatment. Six of these nine patients with SP occurred in the MMP plus low-dose MP group, which was statistically higher than that in the MMF plus low-dose prednisone group (33.3%% vs. 8.6%, p Z 0.000). The nine patients that developed delayed SP after MMF plus low-dose corticosteroid treatment had fevers > 38 C, dry cough, and progressive dyspnea, as outlined in (Table 2). Chest radiography and computed tomography demonstrated diffuse, bilateral interstitial, and alveolar infiltrates. All the nine patients had acute onset and progressed respiratory failure in 4e7 days. All patients had hypoxemia with arterial PO2 < 60 mmHg (range: 41e56 mmHg). Two patients died of respiratory failure after 7e10 days of fever, dry cough, and progressive dyspnea. The other seven patients recovered.
Table 3 Clinical characteristics of patients with and without severe pneumonia. Characteristics
Age (y) Sex (M:F) SCr (mmol/L) eGFR (mL/min/ 1.73 m2) Urine protein excretion (g/d) MMF dosage (g/d)
Patients with SP (n Z 9)
Patients without SP (n Z 44)
p
41.7 166 5:4 263.36 112.3 41.3 14.2
39.7 11.6 26:18 112.77 63.1 65.3 30.6
0.073 0.903 0.016 0.019
3.86 1.19
4.01 1.34
0.551
1.33 0.21
1.38 0.19
0.283
eGFR Z estimated glomerular filtration rate; MMF Z mycophenolate mofetil; PCP Z pneumocystis pneumonia; SCr Z serum creatinine; SP Z severe pneumonia.
Clinical characteristics
Discussion
Renal function impairing was more serious in patients with SP than in those without SP, as evidenced by eGFR (41.3 14.2 mL/min/1.73 m2 vs. 65.3 30.6 mL/min/ 1.73 m2, respectively, p Z 0.019) and serum creatinine (263.36 112.3 vs. 112.77 63.1, respectively, p Z 0.016; Table 3). The other index did not exhibit statistical difference.
IgAN is the most common type of glomerulonephritis in the world [8]. The course of IgAN is variable, and 15e40% of patients progress to end-stage renal disease over 10e20 years [9]. However, the effectiveness, especially the safety therapy, for IgAN remains uncertain and curative therapy is still unavailable [10]. MMF was introduced into clinical practice 10 years ago [11,12]. Until this report, SP, including PCP and MCV, followed with MMF, had rarely been reported in the treatment of primary renal diseases [13,14]. Many randomized, controlled studies of lupus glomerulonephritis have shown that MMF had a good tolerance compared with other immunosuppressants [15]. In four controlled human trials, none of the 1068 renal transplant recipients that received MMF developed PCP [16]. In a retrospective study, PCP and MCV did not occur in 272 renal transplant recipients treated with MMF [4]. MMF was first used to treat IgAN in 1997 [17]. To date, four randomized controlled trials have shown good safety profile in patients with IgAN [2,3,18,19]. However, in a retrospective study [5], six patients had SP in 32 MMFtreated patients with IgAN, (3 patients with PCP and 2 patients suspected of having PCP), compared with those
Microbial etiology Human immunodeficiency virus screening was negative in all the nine patients. Six of the nine patients with SP were transferred to Guangzhou Institute of Respiratory Disease, Guangzhou, China for further treatment. PCP was diagnosed in four patients through PCP screening of sputum, induced by hypertonic sodium chloride and BAL. BAL revealed an abundance of inflammatory cells, with a predominance of neutrophils (49e66%). CMV infection was diagnosed in two patients via serum screening for CMV-IgG and IgM antibodies and CMV-DNA testing by real-time polymerase chain reaction assay. The microbial etiology of the other three patients with SP was unclear.
Table 2 No. 1 2 3 4 5 6 7 8 9
Clinical data of patients with severe pneumonia.
Age (y)
Sex
eGFR (mL/min/1.73 m2)
MMF (g/d)
Time for SP after MMF (wk)
Onset
Cause of SP
Prognosis
37 29 45 47 32 49 36 39 61
Male Male Male Female Female Female Male Female Male
29.9 43.1 41.7 39.4 49.0 51.3 38.6 41.6 38.2
1.5 1.0 1.5 1.0 1.5 1.5 1.5 1.5 1.5
11 10 14 13 12 13 11 12 13
Acute Acute Acute Acute Acute Acute Acute Acute Acute
PCP PCP not clear CMV CMV not clear not clear PCP PCP
Survived Survived Died Survived Survived Survived Survived Survived Died
CMV Z cytomegalovirus; eGFR Z estimated glomerular filtration rate; MMF Z mycophenolate mofetil; PCP Z pneumocystis pneumonia; SP Z severe pneumonia.
Please cite this article in press as: Wan Q-J, et al., Severe pneumonia in mycophenolate mofetil combined with low-dose corticosteroidtreated patients with immunoglobulin A nephropathy, Kaohsiung Journal of Medical Sciences (2014), http://dx.doi.org/10.1016/ j.kjms.2014.10.004
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4 treated with cyclophosphamide and low-dose prednisone. Moreover, the patients with SP had a very poor prognosis; five of six patients presented with an abrupt onset that rapidly progressed to respiratory failure; three patients died despite receiving intensive trimethoprimsulfamethoxazole therapy. The authors of this retrospective study thought that the chronically impaired renal function may be a risk factor for SP in their patients with IgAN [5]. However, the safety of MMF combined with low-dose prednisone in IgAN remains unclear. In this study, the incidence of SP in patients with IgAN treated with MMF combined with low-dose corticosteroids was 16.9%, similar to that reported in the literature [5]. The microbial etiology of SP included PCP and CMV, which was a bit different from the article reported previously [5]. All the nine patients presented with an abrupt onset of symptoms that rapidly progressed to respiratory failure; Two patients died (mortality rate was 22.2%). The prognosis was even worse than that of AIDS patients with PCP [7]. To date, the related factors of SP in MMF combined with low-dose prednisone regimen in IgAN are still not well known. Reduced renal function has been strongly associated with the occurrence of SP [5]. In the current study, renal function impairing was also found to be more statistically serious in patients with SP than in those without SP, as evidenced by eGFR and serum creatinine. This finding may be due to the pharmacokinetic characteristics of MMF. The pharmacokinetics of MMF in patients with end-stage renal disease indicated that renal failure prolongs the half-life of glucuronide, causing the accumulation of the mycophenolic acid glucuronide (MPAG) and increasing the free non-protein-bound fraction of mycophenolic acid (MPA) (f-MPA) [18e21]. All of the instances of SP occurred on the 10the14th week of MMF treatment, suggesting that fMPA and MPAG accumulated in patients when renal function was damaged. Thus, pharmacokinetic analysis in different stages of renal damage deserves further evaluation in future studies. MMF may be prescribed by adjusting the dosage according to the renal function. The incidence of SP in MMP plus low-dose MP group was statistically higher than that in the MMF combined with lowdose prednisone group, which has not been previously reported. According to the literature [22], in vitro, the relative immunosuppressive potency of prednisone is zero, whereas the MP’s immunosuppressive function is 11. Thus, patients treated with MMF plus MP may be more susceptible to infection than patients treated with MMF combined with prednisone. Given the number of patients with SP is only nine in this study, the further analysis of the relationship between SP and prednisone or MP is needed. The immunosuppressive mechanisms of glucocorticoids are currently unclear, but the high T-cell sensitivity may indicate that glucocorticoids interact with the proliferation of activated T-lymphocytes [22]. According to the previous study [7], the decreased numbers of CD4 þ T cells is a strong risk factor for PCP infection and lymphopenia is associated with the susceptibility for PCP [5], so, the immune status should be monitored by testing lymphocytes and CD4 þ T cells. This retrospective study showed that chronically impaired renal function and MP are probably the two risk factors for SP. The microbial etiology mainly was PCP and
Q.-J. Wan et al. CMV. Based on this preliminary result, we recommended that caution should be taken in the administration of MMF combined with a steroid, especially with MP, in IgAN patients with renal insufficiencies. If needed, MMF plus prednisone is safer than MMF plus MP in Lee Class III-V IgAN patients.
References [1] Danovitch GM. Mycophenolate mofetil: a decade of clinical experience. Transplantation 2005;80:S272e4. [2] Tang S, Leung JC, Chan LY, Lui YH, Tang CS, Kan CH, et al. Mycophenolate mofetil alleviates persistent proteinuria in IgA nephropathy. Kidney Int 2005;68:802e12. [3] Xu G, Tu W, Jiang D, Xu C. Mycophenolate mofetil treatment for IgA nephropathy: a meta-analysis. Am J Nephrol 2009;29: 362e7. [4] Azevedo LS, Castro MC, Paula FJ, Ianhez LE, David-Neto E. Mycophenolate mofetil may protect against pneumocystis carinii pneumonia in renal transplanted patients. Rev Inst Med Trop Sao Paulo 2005;47:143e5. [5] Lv J, Zhang H, Cui Z, Su T, Zhang Y, Wang H. Delayed severe pneumonia in mycophenolate mofetil-treated patients with IgA nephropathy. Nephrol Dial Transplant 2008;23:2868e72. [6] Ma YC, Zuo L, Chen JH, Luo Q, Yu XQ, Li Y, et al. Modified glomerular filtration rate estimating equation for Chinese patients with chronic kidney disease. J Am Soc Nephrol 2006; 17:2937e44. [7] Thomas Jr CF, Limper AH. Current insights into the biology and pathogenesis of pneumocystis pneumonia. Nat Rev Microbiol 2007;5:298e308. [8] Donadio JV, Grande JP. IgA nephropathy. N Engl J Med 2002; 347:738e48. [9] D’Amcio G. Natural history of idiopathic IgA nephropathy: the role of clinical and histological prognostic factors. Am J Kidney Dis 2002;36:227e37. [10] Tan CH, Loh PT, Yang WS, Chan CM. Mycophenolate mofetil in the treatment of IgA nephropathy: a systematic review. Singapore Med J 2008;49:780e5. [11] Ciancio G, Miller J, Gonwa TA. Review of major clinical trials with mycophenolate mofetil in renal transplantation. Transplantation 2005;80:S191e200. [12] Appel GB, Radhakrishnan J, Ginzler EM. Use of mycophenolate mofetil in autoimmune and renal diseases. Transplantation 2005;80:S265e71. [13] Chan TM, Li FK, Tang CS, Wong RW, Fang GX, Ji YL, et al. Efficacy of mycophenolate mofetil in patients with diffuse proliferative lupus nephritis. Hong Kong-Guangzhou Nephrology Study Group. N Engl J Med 2000;343:1156e62. [14] Contreras G, Pardo V, Leclercq B, Lenz O, Tozman E, O’Nan P, et al. Sequential therapies for proliferative lupus nephritis. N Engl J Med 2004;350:971e80. [15] Iaccarino L, Rampudda M, Canova M, Della Libera S, SarziPuttinic P, Doria A. Mycophenolate mofetil: what is its place in the treatment of autoimmune rheumatic disease? Autoimmun Rev 2007;6:190e5. [16] Husain S, Singh N. The impact of novel immunosuppressive agents on infections in organ transplant recipients and the interactions of these agents with antimicrobials. Clin Infect Dis 2002;35:53e61. [17] Nowack R, Birck R, van der Woude FJ. Mycophenolate mofetil for systemic vasculitis and IgA nephropathy. Lancet 1997;349: 774. [18] Frisch G, Lin J, Rosenstock J, Markowitz G, D’Agati V, Radhakrishnan J, et al. Mycophenolate mofetil (MMF) vs placebo in patients with moderately advanced IgA nephropathy:
Please cite this article in press as: Wan Q-J, et al., Severe pneumonia in mycophenolate mofetil combined with low-dose corticosteroidtreated patients with immunoglobulin A nephropathy, Kaohsiung Journal of Medical Sciences (2014), http://dx.doi.org/10.1016/ j.kjms.2014.10.004
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Treatment of IgA nephropathy a double-blind randomized controlled trial. Nephrol Dial Transplant 2005;20:2139e45. [19] Maes BD, Oyen R, Claes K, Evenepoel P, Kuypers D, Vanwalleghem J, et al. Mycophenolate mofetil in IgA nephropathy: results of a 3-year prospective placebo-controlled randomized study. Kidney Int 2004;65:1842e9. [20] MacPhee IA, Spreafico S, Bewick M, Davis C, Eastwood JB, Johnston A, et al. Pharmacokinetics of mycophenolate mofetil in patients with end-stage renal failure. Kidney Int 2000;57: 1164e8.
5 [21] Gonza ´lez-Roncero FM, Gentil MA, Brunet M, Algarra G, Pereira P, Cabello V, et al. Pharmacokinetics of mycophenolate mofetil in kidney transplant patients with renal insufficiency. Transplant Proc 2005;37:3749e51. [22] Langhoff E, Olgaard K, Ladefoged J. The immunosuppressive potency in vitro of physiological and synthetic steroids on lymphocyte cultures. Int J Immunopharmacol 1987;9: 469e73.
Please cite this article in press as: Wan Q-J, et al., Severe pneumonia in mycophenolate mofetil combined with low-dose corticosteroidtreated patients with immunoglobulin A nephropathy, Kaohsiung Journal of Medical Sciences (2014), http://dx.doi.org/10.1016/ j.kjms.2014.10.004
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Kaohsiung Journal of Medical Sciences (2014) xx, 1e5
Available online at www.sciencedirect.com
ScienceDirect journal homepage: http://www.kjms-online.com
ORIGINAL ARTICLE
Severe pneumonia in mycophenolate mofetil combined with low-dose corticosteroid-treated patients with immunoglobulin A nephropathy Qi-Jun Wan, Hao-Fei Hu, Yong-Cheng He*, Shao-Dong Luan, Hong-Tao Chen, Hong-Ping Liu, Tong Li, Yi Xu, Hui-Li Xu, Ying Liao Department of Nephrology, Shenzhen Second People’s Hospital, Guangdong 518035, China Received 8 May 2014; accepted 27 August 2014
KEYWORDS Cytomegalovirus; IgA nephropathy; Mycophenolate mofetil; Pneumocystis pneumonia; Severe pneumonia
Abstract The tolerance of mycophenolate mofetil (MMF; Shanghai Roche, China) in Lee Classes III, IV, and V immunoglobulin A nephropathy (IgAN) remains unclear. This article reports nine cases of severe pneumonia (SP), including pneumocystis pneumonia (PCP) and cytomegalovirus (CMV) pneumonia, and its risk factors in MMF plus low-dose corticosteroid-treated patients with Lee Classes III, IV, and V IgAN. Fifty-three patients with IgAN were included in this single-center study. The treatment regimen was MMF (1e1.5 g/d) plus low-dose corticosteroids (0.5 mg/kg/d). SP was defined as diffuse bilateral lung infiltrate with respiratory failure. PCP was diagnosed by detecting the organisms in the sputum and bronchoalveolar lavage. CMV infection was diagnosed through serum screening for CMV-IgG and IgM antibodies and CMVDNA testing by a real-time polymerase chain reaction assay. The risk factors of SP were analyzed. Nine cases (16.9%) of SP occurred in this study. All SP developed at approximately the 10the14th week after the initiation of the regimen: PCP was diagnosed in four cases and CMV infection in two cases. Renal function impairing was more serious in patients with SP than in those without SP, as evidenced by estimated glomerular filtration rate (p Z 0.019) and serum creatinine level (p Z 0.016). Six of the nine SPs occurred in MMP plus low-dose methylprednisolone group, which was statistically higher than that in the MMF plus low-dose prednisone group (p Z 0.000). The incidence of SP in this study was 16.9%. Chronically impaired renal function and the use of methylprednisolone may be the risk factors for SP. Copyright ª 2014, Kaohsiung Medical University. Published by Elsevier Taiwan LLC. All rights reserved.
Conflicts of interest: All authors declare no conflicts of interest. * Corresponding author. Department of Nephrology, Shenzhen Second People’s Hospital, Number 3002 Sungang West Road Futian District, Shenzhen, Guangdong 518035, China. E-mail address: [email protected] (Y.-C. He). http://dx.doi.org/10.1016/j.kjms.2014.10.004 1607-551X/Copyright ª 2014, Kaohsiung Medical University. Published by Elsevier Taiwan LLC. All rights reserved.
Please cite this article in press as: Wan Q-J, et al., Severe pneumonia in mycophenolate mofetil combined with low-dose corticosteroidtreated patients with immunoglobulin A nephropathy, Kaohsiung Journal of Medical Sciences (2014), http://dx.doi.org/10.1016/ j.kjms.2014.10.004
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Introduction Mycophenolate mofetil (MMF; Shanghai Roche, China) has selective inhibitory effects on proliferative T- and B-lymphocytes [1]. Several prospective randomized, controlled trials have proven the effectiveness of MMF in immunoglobulin A nephropathy (IgAN) [2,3]. Most clinical trials have shown that MMF is well tolerated and possesses potent activity against pneumocystis pneumonia (PCP) [4]. Until this study, although one study [5] concerning the fact that severe infections, especially PCP, could occur following MMF administration has been reported, the tolerance of MMF combined with low-dose corticosteroids in Lee Classes III, IV, and V IgAN still remains unknown. To further evaluate the occurrence of severe pneumonia (SP) and the clinical characteristics in Chinese patients classified as having Lee Classes III, IV, and V IgAN and treated with MMF, this retrospective cohort study was performed in patients with IgAN who received either MMF plus low-dose methylprednisolone (MP) or MMF combined with low-dose prednisone during the same follow-up period from 2006 to 2012.
Materials and methods Patients and data This retrospective study evaluated 53 primary Chinese patients with IgAN, as determined by biopsy, who were registered for a follow-up examination in our renal center. Eighteen patients received MMF plus low-dose MP (0.5 mg/ kg/d), whereas the remaining 35 patients received MMF plus low-dose prednisone (0.5 mg/kg/d). MMF was initiated with 1e1.5 g/d for 6 months, 0.5e1.0 g/d for the next 6 months, and then 0.25e0.5 g/d for the previous 6 months. Prednisone was initiated with 0.5 mg/kg/d for 2 months, then slowly tapered by 5 mg every 2 weeks until discontinuation (the usage of MP was the same as that of prednisone in the current study). The records of the patients were reviewed from the start of the treatment through the time when the chart was reviewed, and until the drug was discontinued or severe infection appeared (final time point). Baseline characteristics including age, sex, 24-hour urine protein excretion, serum creatinine, and estimated glomerular filtration rate (eGFR; according to the modified Modification of Diet in Renal Disease (MDRD) equation for Chinese [6]) were recorded. SP was defined as diffused bilateral lung infiltrate with respiratory failure (PO2 < 60 mmHg). PCP was diagnosed by detecting the organism in the sputum and bronchoalveolar lavage (BAL) [7]. CMV infection was diagnosed through serum screening for CMV-IgG and IgM antibodies. CMV-DNA testing was carried out by a real-time polymerase chain reaction assay. This study was conducted in accordance with the Declaration of Helsinki and with approval from the Ethics Committee of Shenzhen Second People’s Hospital, Guangdong, China. Written informed consent was obtained from all participants.
Statistical analysis The clinical characteristics and occurrence of SP were compared between the MMF plus MP group and the MMF
Q.-J. Wan et al. plus prednisone group. The results are given as mean standard deviation for descriptive statistics. The baseline clinical variables were compared using the Student t test between groups, and the Chi-square test was used for the comparison of stratified data. SPSS version 13.0 software (SPSS Inc., Chicago, IL, USA) was used in all analyses. A p value < 0.05 was considered significant.
Results Baseline characteristics Fifty-three patients with IgAN were registered in our renal center, and received follow-up examinations from 2006 to 2012. Among these patients, 18 (34%) were treated with MMF plus low-dose MP, whereas 35 (66%) were treated with MMF combined with low-dose prednisone. The two groups did not differ in terms of their distribution of age, sex, serum creatinine, eGFR, and urine protein excretion at the baseline (Table 1).
Treatment efficacy MMF plus low-dose MP or MMF combined with low-dose prednisone reduced the urine protein excretion and preserved the renal function in the present study. At the 12th month of follow-up, urine protein excretion decreased greatly from 3.14 1.72 g/d to 0.96 0.32 g/day (p Z 0.000), and the renal function remained stable (serum creatinine was 232.16 103.9 mmol/L and 206.33 79.5 mmol/L prior to and after the treatment, respectively, p Z 0.245) in the MMF plus MP group. Meanwhile, urine protein excretion decreased greatly from 3.30 1.66 g/day to 0.31 0.23 g/d (p Z 0.000), and renal function remained stable (serum creatinine was 228.6 101.8 mmol/L and 201.3 99.3 mmol/L prior to and after the treatment, respectively, p Z 0.035) in the MMF plus prednisone group.
Table 1 Demographic and clinical data for patients with Lee Classes III, IV, V IgAN in the mycophenolate mofetil plus low-dose methylprednisolone and mycophenolate mofetil combined with low-dose prednisone groups. Characteristics
Age (y) Sex (M:F) SCr (mmol/L) eGFR (mL/min/ 1.73 m2) Urine protein excretion (g/d)
MMF þ MP group (n Z 18)
MMF þ prednisone group (n Z 35)
p
38.3 11.9 11:7 232.16 103.9 39.93 11.63
36.9 11.6 19:16 228.6 101.8 43.06 12.16
0.433 0.767 0.338 0.381
3.14 1.72
3.30 1.66
0.631
Values expressed as mean standard deviation. There were no significant differences in baseline characteristics between the groups. eGFR Z estimated glomerular filtration rate; IgAN, immunoglobulin A nephropathy; MMF Z mycophenolate mofetil; MP Z methylprednisolone; SCr Z serum creatinine.
Please cite this article in press as: Wan Q-J, et al., Severe pneumonia in mycophenolate mofetil combined with low-dose corticosteroidtreated patients with immunoglobulin A nephropathy, Kaohsiung Journal of Medical Sciences (2014), http://dx.doi.org/10.1016/ j.kjms.2014.10.004
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Treatment of IgA nephropathy
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Occurrence, clinical characteristics, and prognosis Among the 53 patients treated with MMF and low-dose corticosteroids, nine developed SP around the 3rd month (10the14th week) after treatment. Six of these nine patients with SP occurred in the MMP plus low-dose MP group, which was statistically higher than that in the MMF plus low-dose prednisone group (33.3%% vs. 8.6%, p Z 0.000). The nine patients that developed delayed SP after MMF plus low-dose corticosteroid treatment had fevers > 38 C, dry cough, and progressive dyspnea, as outlined in (Table 2). Chest radiography and computed tomography demonstrated diffuse, bilateral interstitial, and alveolar infiltrates. All the nine patients had acute onset and progressed respiratory failure in 4e7 days. All patients had hypoxemia with arterial PO2 < 60 mmHg (range: 41e56 mmHg). Two patients died of respiratory failure after 7e10 days of fever, dry cough, and progressive dyspnea. The other seven patients recovered.
Table 3 Clinical characteristics of patients with and without severe pneumonia. Characteristics
Age (y) Sex (M:F) SCr (mmol/L) eGFR (mL/min/ 1.73 m2) Urine protein excretion (g/d) MMF dosage (g/d)
Patients with SP (n Z 9)
Patients without SP (n Z 44)
p
41.7 166 5:4 263.36 112.3 41.3 14.2
39.7 11.6 26:18 112.77 63.1 65.3 30.6
0.073 0.903 0.016 0.019
3.86 1.19
4.01 1.34
0.551
1.33 0.21
1.38 0.19
0.283
eGFR Z estimated glomerular filtration rate; MMF Z mycophenolate mofetil; PCP Z pneumocystis pneumonia; SCr Z serum creatinine; SP Z severe pneumonia.
Clinical characteristics
Discussion
Renal function impairing was more serious in patients with SP than in those without SP, as evidenced by eGFR (41.3 14.2 mL/min/1.73 m2 vs. 65.3 30.6 mL/min/ 1.73 m2, respectively, p Z 0.019) and serum creatinine (263.36 112.3 vs. 112.77 63.1, respectively, p Z 0.016; Table 3). The other index did not exhibit statistical difference.
IgAN is the most common type of glomerulonephritis in the world [8]. The course of IgAN is variable, and 15e40% of patients progress to end-stage renal disease over 10e20 years [9]. However, the effectiveness, especially the safety therapy, for IgAN remains uncertain and curative therapy is still unavailable [10]. MMF was introduced into clinical practice 10 years ago [11,12]. Until this report, SP, including PCP and MCV, followed with MMF, had rarely been reported in the treatment of primary renal diseases [13,14]. Many randomized, controlled studies of lupus glomerulonephritis have shown that MMF had a good tolerance compared with other immunosuppressants [15]. In four controlled human trials, none of the 1068 renal transplant recipients that received MMF developed PCP [16]. In a retrospective study, PCP and MCV did not occur in 272 renal transplant recipients treated with MMF [4]. MMF was first used to treat IgAN in 1997 [17]. To date, four randomized controlled trials have shown good safety profile in patients with IgAN [2,3,18,19]. However, in a retrospective study [5], six patients had SP in 32 MMFtreated patients with IgAN, (3 patients with PCP and 2 patients suspected of having PCP), compared with those
Microbial etiology Human immunodeficiency virus screening was negative in all the nine patients. Six of the nine patients with SP were transferred to Guangzhou Institute of Respiratory Disease, Guangzhou, China for further treatment. PCP was diagnosed in four patients through PCP screening of sputum, induced by hypertonic sodium chloride and BAL. BAL revealed an abundance of inflammatory cells, with a predominance of neutrophils (49e66%). CMV infection was diagnosed in two patients via serum screening for CMV-IgG and IgM antibodies and CMV-DNA testing by real-time polymerase chain reaction assay. The microbial etiology of the other three patients with SP was unclear.
Table 2 No. 1 2 3 4 5 6 7 8 9
Clinical data of patients with severe pneumonia.
Age (y)
Sex
eGFR (mL/min/1.73 m2)
MMF (g/d)
Time for SP after MMF (wk)
Onset
Cause of SP
Prognosis
37 29 45 47 32 49 36 39 61
Male Male Male Female Female Female Male Female Male
29.9 43.1 41.7 39.4 49.0 51.3 38.6 41.6 38.2
1.5 1.0 1.5 1.0 1.5 1.5 1.5 1.5 1.5
11 10 14 13 12 13 11 12 13
Acute Acute Acute Acute Acute Acute Acute Acute Acute
PCP PCP not clear CMV CMV not clear not clear PCP PCP
Survived Survived Died Survived Survived Survived Survived Survived Died
CMV Z cytomegalovirus; eGFR Z estimated glomerular filtration rate; MMF Z mycophenolate mofetil; PCP Z pneumocystis pneumonia; SP Z severe pneumonia.
Please cite this article in press as: Wan Q-J, et al., Severe pneumonia in mycophenolate mofetil combined with low-dose corticosteroidtreated patients with immunoglobulin A nephropathy, Kaohsiung Journal of Medical Sciences (2014), http://dx.doi.org/10.1016/ j.kjms.2014.10.004
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4 treated with cyclophosphamide and low-dose prednisone. Moreover, the patients with SP had a very poor prognosis; five of six patients presented with an abrupt onset that rapidly progressed to respiratory failure; three patients died despite receiving intensive trimethoprimsulfamethoxazole therapy. The authors of this retrospective study thought that the chronically impaired renal function may be a risk factor for SP in their patients with IgAN [5]. However, the safety of MMF combined with low-dose prednisone in IgAN remains unclear. In this study, the incidence of SP in patients with IgAN treated with MMF combined with low-dose corticosteroids was 16.9%, similar to that reported in the literature [5]. The microbial etiology of SP included PCP and CMV, which was a bit different from the article reported previously [5]. All the nine patients presented with an abrupt onset of symptoms that rapidly progressed to respiratory failure; Two patients died (mortality rate was 22.2%). The prognosis was even worse than that of AIDS patients with PCP [7]. To date, the related factors of SP in MMF combined with low-dose prednisone regimen in IgAN are still not well known. Reduced renal function has been strongly associated with the occurrence of SP [5]. In the current study, renal function impairing was also found to be more statistically serious in patients with SP than in those without SP, as evidenced by eGFR and serum creatinine. This finding may be due to the pharmacokinetic characteristics of MMF. The pharmacokinetics of MMF in patients with end-stage renal disease indicated that renal failure prolongs the half-life of glucuronide, causing the accumulation of the mycophenolic acid glucuronide (MPAG) and increasing the free non-protein-bound fraction of mycophenolic acid (MPA) (f-MPA) [18e21]. All of the instances of SP occurred on the 10the14th week of MMF treatment, suggesting that fMPA and MPAG accumulated in patients when renal function was damaged. Thus, pharmacokinetic analysis in different stages of renal damage deserves further evaluation in future studies. MMF may be prescribed by adjusting the dosage according to the renal function. The incidence of SP in MMP plus low-dose MP group was statistically higher than that in the MMF combined with lowdose prednisone group, which has not been previously reported. According to the literature [22], in vitro, the relative immunosuppressive potency of prednisone is zero, whereas the MP’s immunosuppressive function is 11. Thus, patients treated with MMF plus MP may be more susceptible to infection than patients treated with MMF combined with prednisone. Given the number of patients with SP is only nine in this study, the further analysis of the relationship between SP and prednisone or MP is needed. The immunosuppressive mechanisms of glucocorticoids are currently unclear, but the high T-cell sensitivity may indicate that glucocorticoids interact with the proliferation of activated T-lymphocytes [22]. According to the previous study [7], the decreased numbers of CD4 þ T cells is a strong risk factor for PCP infection and lymphopenia is associated with the susceptibility for PCP [5], so, the immune status should be monitored by testing lymphocytes and CD4 þ T cells. This retrospective study showed that chronically impaired renal function and MP are probably the two risk factors for SP. The microbial etiology mainly was PCP and
Q.-J. Wan et al. CMV. Based on this preliminary result, we recommended that caution should be taken in the administration of MMF combined with a steroid, especially with MP, in IgAN patients with renal insufficiencies. If needed, MMF plus prednisone is safer than MMF plus MP in Lee Class III-V IgAN patients.
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Please cite this article in press as: Wan Q-J, et al., Severe pneumonia in mycophenolate mofetil combined with low-dose corticosteroidtreated patients with immunoglobulin A nephropathy, Kaohsiung Journal of Medical Sciences (2014), http://dx.doi.org/10.1016/ j.kjms.2014.10.004
