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NDT Advance Access published online on May 7, 2008
Nephrology Dialysis Transplantation, doi:10.1093/ndt/gfn161
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© The Author [2008]. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved. For Permissions, please e-mail: journals.permissions@oxfordjournals.org


Delayed severe pneumonia in mycophenolate mofetil-treated patients with IgA nephropathy

Jicheng Lv, Hong Zhang, Zhao Cui, Tao Su, Yimiao Zhang and Haiyan Wang

Renal Division, Department of Medicine, Peking University First Hospital, Institute of Nephrology, Peking University and Key Laboratory of Renal Disease, Ministry of Health of China, Beijing, People's Republic of China

Correspondence and offprint requests to: Hong Zhang, Renal Division, Department of Internal Medicine, Peking University First Hospital, Institute of Nephrology, Peking University, No. 8, Xishiku St. Xicheng District, Beijing 100034, People's Republic of China. Tel: +86-10-66551122 Ext 2388; Fax: +86-10-66551055; E-mail: hongzh{at}bjmu.edu.cn



   Abstract
Top
 Abstract
Introduction
 Patients and methods
 Results
 Discussion
 References
 
Background. Mycophenolate mofetil (MMF), a relatively new immunosuppressant, is widely used in the field of transplantation and also for autoimmune diseases with good tolerance. It has been reported that MMF possesses potent activity against pneumocystis pneumonia (PCP). This study investigated the effects of this treatment on the occurrence of severe pneumonia (SP) including PCP and its risk factors.

Methods. This was a retrospective cohort study. Of 850 IgA nephropathy (IgAN) patients that were followed up in our renal centre, 32 received MMF (1–1.5 g/day) and 47 were treated with cyclophosphamide (CTX; 50–100 mg/day). All the patients also received prednisone. SP was defined as diffuse bilateral lung infiltrate with respiratory failure, and PCP was diagnosed by detecting organisms in sputum and bronchoalveolar lavage.

Results. Patients given MMF or CTX did not differ in their distribution of age, sex, renal function or prednisone dosage. However, 6 of the 32 patients developed SP around the third month after the initiation of MMF administration: 3 were diagnosed with PCP, 2 with suspected PCP and in the other PCP could not be excluded. SP did not occur in patients treated with CTX. Most SP cases (five of six) presented with abrupt onset and rapidly progressed to respiratory failure, from which four died. The deterioration of renal function was strongly associated with the occurrence of SP. Six patients (6 of 16) with chronic renal function impairment (eGFR < 60 ml/min/1.73 m2) developed SP while none of the patients with eGFR > 60 ml/min/1.73 m2 did. Absolute lymphocyte counts decreased significantly in patients with eGFR < 60 ml/min/1.73 m2 after 3 months of MMF treatment compared to the counts before MMF was initiated (1.71 ± 0.23 versus 2.43 ± 0.17 x 109/l, P = 0.04). This effect was more pronounced in patients with SP, which had significantly lower counts than patients without SP (0.22 ± 0.04 versus 1.91 ± 0.20 x 109/l, P = 0.001). The occurrence of SP or PCP in patients with chronically impaired renal function was also associated with lymphopenia.

Conclusions. This study is the first report of delayed SP including PCP following MMF plus corticosteroids in patients with IgAN. Chronically impaired renal function might be a risk factor for severe infection, and lymphocyte counts may serve as useful and convenient tools for monitoring the intendance of the occurrence of PCP. This finding and its risk factors need to be further evaluated.

Keywords: IgA nephropathy; lymphopenia; mycophenolate mofetil; pneumocystis pneumonia; severe pneumonia



   Introduction
Top
 Abstract
 Introduction
Patients and methods
 Results
 Discussion
 References
 
Mycophenolate mofetil (MMF) has selective inhibitory effects on proliferative T- and B-lymphocytes and has been used widely in transplantation and successfully reduced the incidence of acute rejection in renal allograft recipients [1–4]. Moreover, a few well-controlled prospective trials have proved the effectiveness of MMF in autoimmune renal diseases including severe lupus nephritis [5–9], membranous nephropathy [10], minimal change renal disease and focal segmental glomerulosclerosis [11]. Most clinical trials have shown that MMF is well tolerated. It has been reported that MMF possesses potent activity against PCP [12–14]. Until this study, few reports existed concerning the fact that severe infections, especially pneumocystis pneumonia (PCP), could occur following MMF administration.

In a pilot study of the effects of MMF in potentially progressing IgA nephropathy (IgAN), a few cases of severe pneumonia (SP), including PCP, were diagnosed which exceeded our expectations. To further evaluate the occurrence of SP and clinical characteristics in IgAN patients treated with MMF, a retrospective cohort study was performed in IgAN patients who received either MMF or cyclophosphamide (CTX) combined with prednisone during the same follow-up period (from 2001 to 2007). This study revealed that delayed SP, including PCP infection, occurred in patients treated with MMF plus corcoticosteroids, especially in those with advanced renal function impairment and lymphopenia.



   Patients and methods
Top
 Abstract
 Introduction
 Patients and methods
Results
 Discussion
 References
 
Patients and data collection
This retrospective study evaluated 850 primary IgAN patients, as determined via biopsy, who were registered for a follow-up examination in our renal centre and the data were entered in our standard registry computer database (http://www.renal-online.org). Seventy-nine patients with potential progressive IgAN received either MMF (n = 32) or CTX (n = 47); both of these groups were initiated with prednisone 40–60 mg/day simultaneously, which was tapered after 6–8 weeks

Indications for treatment with MMF or CTX were as follows: (1) impaired renal function (serum creatinine >1.5 mg/dl); (2) persistent proteinuria (>3.5 g/day) regardless of the RAS blockage with ACEI/ARB; (3) renal histology lesions of segmental glomerular necrotizing or focal and small crescent formation. MMF or CTX was selected according to the patients’ intension. MMF was initiated with 1.0–1.5 g/day for 6 months and then reduced to 0.5– 1.0 g/day in the following 6 months; CTX was prescribed with 100 mg/day (if eGFR < 30 ml/min/1.73 m2, it was adjusted to 50 mg/day [15]) and the accumulated dose was 6–8 g. Patients’ records were reviewed from the start of MMF/CTX (baseline) 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, disease duration, blood pressure, 24-h urine protein excretion, serum creatinine and estimated GFR (according to the modified MDRD equation for Chinese [16]) were recorded.

SP was defined as diffuse bilateral lung infiltrate with respiratory failure (PO2 < 60 mmHg). PCP was diagnosed by detecting the organism in sputum and bronchoalveolar lavage (BAL) [17]. Acute bronchitis was diagnosed by persistent cough, sputum production for >5 days but no evidence of pneumonia on the chest X-ray [18].

The study was approved by the Peking University First Hospital Review Board and the patients gave written and informed consent at the beginning of their registration for follow-up at our renal centre.

Statistical analyses
The clinical characteristics and occurrence of infection, especially SP, were compared between the MMF and CTX groups. For descriptive statistics, results are given as mean ± SD. The baseline clinical variables were compared using the t-test between groups, and for the comparison of stratified data, the chi-square test was used. In all analyses, SPSS 10.0 software was used and a P-value <0.05 was considered significant.



   Results
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 Abstract
 Introduction
 Patients and methods
 Results
Discussion
 References
 
Baseline characteristics
Eight hundred and fifty IgAN patients were registered in our renal centre and received follow-up examinations from 2001 to 2007. Of these patients, 32 were (3.8%) treated with MMF (16 patients with eGFR < 60 ml/min/1.73 m2), with a mean follow-up of 13.8 months (range: 3–72), and 47 (5.5%) were treated with CTX (19 patients with eGFR < 60 ml/min/1.73 m2), with a mean follow-up 25.0 months (range: 3–70). The MMF and CTX groups did not differ in terms of their distribution of age, gender, blood pressure, proteinuria, serum creatinine and dose of prednisone at the baseline (Table 1).


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  		Table 1 Demographic and clinical data for patients with chronically impaired renal function (eGFR < 60 ml/min/1.73 m2) in the MMF and CTX groups

 
Efficacy of MMF treatment
MMF plus corticosteroids reduced proteinuria and preserved renal function in this group of patients with IgAN. At the 12th month of follow-up, urine protein excretion decreased greatly from 4.1 ± 3.1 to 2.0 ± 2.7 g/day (P = 0.01), and renal function remained stable (serum creatinine was 2.1 ± 1.7 and 2.1 ± 1.3 mg/dl before and after treatment, respectively, P = 0.96).

Occurrence of SP
Of the 32 patients given MMF and prednisone, 6 developed SP at the third month (12th to 13th weeks) after treatment started and 1 developed acute bronchitis. In the CTX group, only two patients developed acute bronchitis. None of the patients in the CTX group developed SP, nor did they progress to respiratory failure.

Clinical characteristics of SP
As illustrated in Table 2, the six patients that developed delayed SP after MMF and corticosteroid treatment had fevers above 38°C, dry cough and progressive dyspnea. Chest radiography and computed tomography demonstrated diffuse, bilateral interstitial and alveolar infiltrates. Five of these six patients had acute onset and progressed respiratory failure in 3–12 days; another patient had a gradual onset and developed respiratory failure in 1 month. All patients had hypoxaemia with arterial PO2 <60 mmHg (range: 34–57 mmHg).


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  		Table 2 Clinical data of patients with SP

 
Microbial aetiology of SP.
The five patients who were treated in our hospital received PCP screening of sputum, induced by hypertonic sodium chloride and BAL; three of them were diagnosed with PCP. BAL revealed an abundance of inflammatory cells, with a predominance of neutrophils (56–71%). The other two cases had clinical and radiographic characteristics that accorded with PCP and responded well to a 3-week treatment with intravenous trimethoprim–sulfamethoxazole (TMP–SMX; TMP: 20 mg/kg/day; SMZ: 100 mg/kg/day), but were negative for PCP in sputum and BAL which were performed 2 and 7 days after TMP–SMX therapy. Thus, PCP was suspected in these two patients. Serum screening for cytomegalovirus (CMV)-IgG and IgM antibodies and CMV-DNA testing by a real-time polymerase chain reaction assay were negative in these five patients. HIV screening was negative in all the six patients.

Risks of SP
As illustrated in Table 3, renal function impairing was more serious in patients with SP than in those without SP as evidenced by eGFR (33.5 ± 16.0 versus 85.5 ± 52.5 ml/min/1.73 m2, respectively, P = 0.024) and serum creatinine (3.6 ± 1.2 versus 1.7 ± 0.2 mg/dl, respectively, P = 0.012). Of the 16 patients with eGFR < 60 ml/min/ 1.73 m2, 6 developed SP, while none of the patients with eGFR > 60 ml/min/1.73 m2 did (P = 0.018). Patients with or without SP did not differ in daily dosage of MMF (1.3 ± 0.26 versus 1.4 ± 0.22 g/day, respectively, P = 0.29) or prednisone (48.3 ± 7.5 versus 46.7 ± 15.4 mg/day, respectively, P = 0.80), nor did they differ in their accumulated dosage of prednisone at the end of the third month (3826.7 ± 590 versus 23748.2 ± 1061.5 mg, respectively, P = 0.863).


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  		Table 3 Clinical characteristics of patients with and without SP

 
Before MMF treatment, the lymphocyte count was lower in patients with eGFR < 60 ml/min/1.73 m2 compared to those with a higher eGFR (2.81 ± 0.26 versus 2.21 ± 0.15 x 109/l, respectively; P = 0.04), (Figure 1). In patients with eGFR < 60 ml/min/1.73 m2 (without SP), the absolute lymphocyte count was significantly lower after 3 months of MMF therapy (after: 1.71 ± 0.23 versus before: 2.43 ± 0.17 x 109/l, P = 0.024); this decrease was more pronounced in patients with SP (after MMF treatment: 0.22 ± 0.04 versus before: 1.91 ± 0.20 x 109/l, P = 0.001). No difference in lymphocyte number was seen before and after MMF treatment in patients with eGFR > 60 ml/min/ 1.73 m2 (2.81 ± 0.26 versus 2.90 ± 0.20 x 109/l, respectively; P = 0.801).


Figure 1
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  		Fig. 1 Absolute lymphocyte counts before and after 3 months of MMF treatment in patients with IgAN. Note: Group 1: patients with eGFR > 60 ml/min/1.73 m2; Groups 2 and 3: patients with eGFR < 60 ml/min/1.73 m2 with or without SP, respectively. In Groups 2 and 3, lymphocytes decreased significantly after MMF and prednisone treatment, P < 0.05. MMF: mycophenolate mofetil; (a) after MMF treatment; (b) before MMF treatment.

 
Clinical course and prognosis of SP.
One patient died of respiratory failure after 3 days of fever, dry cough and progressive dyspnea in a community hospital. In the other five patients, even with intravenous TMP–SMX treatment under the support of mechanical ventilation and corticosteroids as adjunctive therapy (prednisone 80 mg/day), three of the five patients died of respiratory failure in 3–21 days; the other two recovered.



   Discussion
Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
References
 
MMF was introduced into clinical practice ~10 years ago and since then it has been shown to be very well tolerated in the field of renal transplantation and autoimmune renal diseases [3,4,19,20]. Moreover, in randomized, controlled studies of lupus glomerulonephritis, MMF showed a good safety profile compared to other immunosuppressants [19].

Until this report, PCP followed with MMF had rarely been documented in renal transplantation [3,14] or in the treatment of native renal diseases [5–9,20–23]. In four controlled human trials, none of the 1068 renal transplant recipients that received MMF developed PCP [14]. In a retrospective study, PCP did not occur in 272 renal transplant recipients treated with MMF, despite the absence of TMP–SMX prophylaxis [12]. Even more, MMF was documented to potentially act against P. jiroveci in animal experiments [13]. However, in our retrospective study, it was unexpectedly found that SP occurred in MMF-treated IgAN patients including three PCP and two suspected PCP, compared to those treated with CTX and same dosage of 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 TMP–SMZ therapy. This prognosis was worse than that of AIDS patients with PCP, in which the mortality rate was usually 10–20% [17]. In our patients, the BAL fluid smear revealed abundant neutrophils compared to the predominance of lymphocytes seen in AIDS patients [17], which might account for the dramatic progression of severe lung injury.

Until now there was no report about PCP followed by MMF in native renal disease. However, most trials of MMF in glomerular diseases [5–11,20–25] mainly involved patients with normal or mildly reduced renal function, or with rapid recovery of renal function after immunosuppressant therapy, such as in lupus nephritis patients. In fact, the safety of MMF in patients with chronic renal function impairment (eGFR < 60 ml/min/1.73 m2) was not well known. The present study demonstrated that reduced renal function was strongly associated with the occurrence of SP. Pharmacokinetics of MMF in kidney transplant with renal insufficiencies and ESRD patients indicated that renal failure prolongs the half-life of glucuronide, causes accumulation of the glucuronide metabolite (MPAG) and increases the free non-protein-bound fraction of MPA (f-MPA) [26,27]. That all of the instances of SP occurred in the third month of MMF treatment might suggest that f-MPA and MPAG accumulated in patients when renal function was damaged. Pharmacokinetic analysis in different stages of renal damage deserves further evaluation. It might be advisable to prescribe MMF, adjusting the dosage according, and to prescribe PCP prophylaxis.

This study also demonstrated that before MMF treatment, lymphocyte counts were lower in patients with chronic renal function impairment. The lymphocyte count was even lower after 3 months of MMF treatment in patients with eGFR < 60 ml/min/1.73 m2. In patients with SP, lymphocytes decreased by nearly 90%, while patients with nearly normal renal function had lymphocyte counts that remained within a safe range. It is well documented that decreased numbers of CD4+ T cells is a strong risk factor for PCP infection [17]; however, the high cost of CD4+ detection limited its clinical application. The present study suggests that lymphopenia is associated with the susceptibility for PCP, and further investigation may be helpful to find the threshold number of lymphocytes for the safe use of MMF without serious infection including PCP.

In the present retrospective study we have observed that MMF reduced the proteinuria greatly and at the same time the renal function remained stable, which was coordinated with the other two reports of the efficacy of MMF in Chinese IgAN patients [24,25]. However, the occurrence of severe pneumonia in patients with renal insufficiencies suggests that the risk–benefit balance should be carefully evaluated during application of MMF in patients with impaired renal function.

This retrospective study is the first to report delayed SP, including PCP, associated with MMF combined with corticoidsteroid treatment in a cohort of IgAN patients. Chronically impaired renal function might be a risk factor for severe infection, and lymphocyte counts may serve as useful and convenient tools for monitoring the intendance of the occurrence of PCP. However, these findings are valuable for further evaluation. From this preliminary result, it is recommended that caution should be taken in administration of MMF combined with a steroid in patients with renal insufficiencies.



   Acknowledgments
 
This work was funded by the Foundation of Ministry of Education, People's Republic of China (grant number 985-2-2007-113), the National Natural Science Foundation of China (grant number 30670981) to H.Z.

Conflict of interest statement. None declared.



   References
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 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 

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Received for publication: 21. 9.07
Accepted in revised form: 28. 2.08


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