Effect of MMF Immunosuppression Based on CNI Reduction on CNI-Related Renal Damage after Lung Transplantation.

In this paper, numerous effects of immunosuppressive regimen of mycophenolate mofetil (MMF) on CNI-related renal damage after lung transplantation are evaluated thoroughly. For this purpose, 110 lung transplant recipients who were treated in our hospital from March 2016 to January 2018 were randomly selected. All patients took prednisone acetate tablets or rapamycin at the same time or not at the same time. MMF is 1 g every time, twice a day, and adjusted according to the re-examination. According to the different drugs taken by 110 patients, they were divided into cyclosporine A group and tacrolimus group. Among them, 92 patients in cyclosporine A group took cyclosporine A; 18 patients in tacrolimus group took tacrolimus. The clinical data of age and gender of the two groups were collected, To observe and compare the occurrence of CNI-related renal damage in lung transplant recipients and different immunosuppressants. The CNI dosage of tacrolimus group and cyclosporine A group was compared before and after MMF. The changes of serum creatinine level and serum creatinine clearance rate were measured before MMF administration and 30, 60, and 90 days after MMF administration, to observe the complications of CNI-related renal damage after lung transplantation. Experimental results showed that there were 16 cases (14.55%) of CNI-related renal damage in lung transplant recipients and different immunosuppressants, including 10 cases (11.36%) in males, 6 cases (27.27%) in females, 11 cases (12.09%) in tacrolimus group, and 5 cases (26.32%) in cyclosporine A group. There was no significant difference between the two groups (P > 0.05). Compared with MMF before and after administration, CNI dosage of cyclosporine A group and tacrolimus group decreased significantly (P < 0.01). Compared with MMF before administration, serum creatinine level decreased and serum creatinine clearance rate increased significantly (P < 0.05). In the follow-up, 16 patients with CNI-related renal damage were found to be immune rejection before the adjustment of immunosuppression program, no complications such as immune rejection, myelosuppression, and infection occurred within 15 months after the adjustment of immunosuppression program, blood glucose increased in 3 patients within 2 years after operation, blood lipid increased in 1 patient, urea increased in 1 patient, and uric acid increased in 1 patient. MMF immunosuppressive therapy based on CNI reduction is a safe and effective immunosuppressive therapy, which can significantly reduce immune rejection, improve renal function, and play an important role in improving CNI-related renal damage after lung transplantation.

1. Introduction

Terminal lung disease is the progressive and irreversible decline of lung function caused by various lung diseases. According to statistics, chronic lung diseases in China account for about 11% of the total prevalence rate and have become an important problem in the world that seriously endangers human health and aggravates social and economic burden [1]. With the development of social science and technology, lung transplantation has been applied more and more clinically, and the first successful lung allotransplantation was achieved in 1983 [2]. Lung transplantation is one of the most important methods for the treatment of end-stage lung diseases. Studies have found that kidney injury is the most common complication after lung transplantation with a high incidence, and immunosuppressive therapy after lung transplantation is the key to the successful suppression and long-term survival of lung transplantation recipients [3]. At present, immunosuppressive drugs play an important role in the successful implementation of lung transplantation. However, there are many methods of immunosuppressive treatment with different curative effects. It also brings related adverse reactions while resisting rejection, which is a major clinical problem. Therefore, finding a safer immunosuppressive therapy is of great significance to improve the long-term survival rate of lung transplantation recipients [4]. With the continuous deepening of research on immunosuppressive drugs, studies have found that safe and effective immunosuppressive drug reduction programs can achieve the same transplantation effect while significantly reducing the side effects and adverse reactions caused by immunosuppressive drugs [5]. Calcineurin inhibitor (CNI) is the only serine/threonine protein phosphatase that is regulated by calmodulin so far. It is a routine immunosuppressive drug after lung transplantation and is considered to be one of the main causes of kidney injury in patients after lung transplantation [2, 6]. At present, the two most widely used immunosuppressants in clinical practice are cyclosporine A and tacrolimus. In the related studies of kidney transplantation, it was found that the kidney survival rate of renal transplant patients who used cyclosporin A and tacrolimus was significantly increased, but post-transplant pneumonia and drug-induced severe liver injury were prone to many postoperative complications [7]. The triple immunosuppressive regimen of MMF combined with cyclosporine A and tacrolimus is a classic triple immunotherapy, but currently, there are few reports on its use in lung transplantation. To investigate the effect of MMF immunosuppression program based on CNI reduction on CNI-related renal damage after lung transplantation, the following experiment is designed:

In this paper, numerous effects of immunosuppressive regimen of mycophenolate mofetil (MMF) on CNI-related renal damage after lung transplantation are evaluated thoroughly. For this purpose, 110 lung transplant recipients who were treated in our hospital from March 2016 to January 2018 were randomly selected. All patients took prednisone acetate tablets or rapamycin at the same time or not at the same time. MMF is 1 g every time, twice a day, and adjusted according to the re-examination. According to the different drugs taken by 110 patients, they were divided into cyclosporine A group and tacrolimus group. Among them, 92 patients in cyclosporine A group took cyclosporine A; 18 patients in tacrolimus group took tacrolimus. The clinical data of age and gender of the two groups were collected. In the follow-up, 16 patients with CNI-related renal damage were found to be immune rejection before the adjustment of immunosuppression program, no complications such as immune rejection, myelosuppression, and infection occurred within 15 months after the adjustment of immunosuppression program, blood glucose increased in 3 patients within 2 years after operation, blood lipid increased in 1 patient, urea increased in 1 patient, and uric acid increased in 1 patient. MMF immunosuppressive therapy based on CNI reduction is a safe and effective immunosuppressive therapy, which can significantly reduce immune rejection, improve renal function, and play an important role in improving CNI-related renal damage after lung transplantation.

The remaining paper is arranged as given described in the following paragraph.

In section Material and Methods, a detailed description of the numerous effects of immunosuppressive regimen of mycophenolate mofetil (MMF) on CNI-related renal damage after lung transplantation is presented. Then, how the proposed mechanism is effective in resolving this issue is described in detail. Experimental results of the proposed study are presented in Section 3 of the paper which is followed by a detailed and comprehensive discussion. Lastly, concluding remarks along with references, specifically those which are used in this paper, is presented.

2. Materials and Methods

2.1. Basic Information

From March 2016 to January 2018, 110 patients receiving lung transplantation in our hospital were randomly selected. Among them, 88 cases were male and 22 cases were female. The mean age was 58.72 ± 5.16. The postoperative time was 0.25∼3.25 years, with an average of 1.67 ± 0.21 years. Inclusion criteria were as follows: (1) white blood cell (WBC) count above 4 × 109/L; (2) patients did not take mycophenolate mofetil (MMF) for the first two months of the study; (3) the research was approved by the ethics committee of the hospital; (4) patients were diagnosed as CNI-related renal damage; (5) patients and their families give informed consent and sign informed consent; (6) patients with complete medical records can cooperate with treatment; (7) serum creatinine (Scr) levels were detected once a week for three consecutive times, and Scr levels were all greater than 106 mol/L; and (8) the patients had normal lung function and no related renal dysfunction before the study. Exclusion criteria were as follows: (1) patients with severe liver and kidney dysfunction; (2) with cardiac dysfunction; (3) those with infectious diseases; (4) the patient has a history of severe drug allergies; and (5) patients who have incomplete clinical data or withdraw halfway through. The basic information of the patients is shown in Table 1.

Table 1

Basic information.

Group	Base information
Average age (years)	58.72 ± 5.16
Gender (n)
Male	88
Female	22
Postsurgery duration (years)	1.67 ± 0.21

2.2. Proposed Methods

All patients should take prednisone acetate tablet (Zhejiang Xianju Pharmaceutical Co., Ltd., batch no.: 33021207, specification: 5 mg ∗ 100 s) or (and) rapamycin [Wyeth Pharmaceuticals Company (USA), batch no: 20160483]. Take it with or without it. Prednisone was given at a dose of 5 mg per dose, and rapamycin was given in doses of 2 mg once a day. All patients should take MMF (Shanghai Roche pharmaceutical Co., Ltd., batch number: 20151277, specification: 0.5 g ∗ 20 s) 1 g each time, twice a day, and the dosage shall be adjusted according to the review.

The 110 patients were divided into the cyclosporine A group and the tacrolimus group according to the different types of drugs they took. Among them, 92 patients in the cyclosporine A group took cyclosporine A (Xianle Health Technology Co., Ltd., batch no.: 20158147, specification: 25 mg × 50 s), 5 mg each time, twice a day, and started taking the drug within 12 h before surgery. Astellas Ireland Co., Ltd. (Ireland, batch no.: 20160195, specification: 0.5 mg ∗ 50 s) took tacrolimus in 18 patients, 0.2 mg/kg daily, twice orally, and started taking it within 6 h after surgery. Reduce the starting dose by 5% per week.

2.3. Observation Indexes

Clinical data collection: Collect statistics on 110 patients undergoing immunotherapy after lung transplantation in our hospital, and collect basic clinical data of patients. Including age (≤55 years old, >55 years old), gender (male, female), surgical method (double lung transplantation, single lung transplantation), residence (urban, rural), occupation (civil servant, worker, farmer, other), and education level (junior high school and below, high school and above).

CNI-related renal damage: observe and compare the occurrence of CNI-related renal damage in lung transplant recipients and in different immunosuppressive agents

Changes in CNI doses: compare the changes of CNI doses in the tacrolimus group and cyclosporine A group before and after MMF plus administration

Serum creatinine level and serum creatinine clearance rate: follow up before and 30d, 60d, and 90d after the addition of MMF to determine the changes in serum creatinine level and serum creatinine clearance rate

Complications: to observe the occurrence of complications in patients with CNI-related renal damage after lung transplantation

2.4. Statistical Methods

Chi-square test was used for comparison of enumeration data in this study. Independent sample t test was used to compare the measurement data. If the statistical result is P < 0.05, it is statistically significant. SPSS17.0 software package was used for statistical analysis in this study.

3. Results of the Various Experiments

3.1. Analysis of Basic Data of 110 Immunotherapy Patients after Lung Transplantation

The proportions of males and females in 110 immunotherapy patients after lung transplantation were 80.00% (88/110) and 20.00% (22/110), respectively. Among the ages ≤55 years old and >55 years old accounted for 35.45% (39/110) and 65.55% (71/110), respectively. The proportions of double lung transplantation and single lung transplantation were 59.09% (65/110) and 40.91% (45/110), respectively. The proportions of urban and rural areas of residence are 40.91% (45/110) and 59.09% (65/110), respectively. The proportions of civil servants, workers, and farmers in occupations were 17.27% (19/110), 11.82% (13/110), and 35.45% (39/110). The proportions of junior high school and below, high school and above in educational level are 23.64% (26/110) and 76.36% (84/110) respectively, respectively. See Table 2.

Table 2

Analysis of basic data of 110 immunotherapy patients after lung transplantation.

Factors	Cases	Percentage
Gender
Male	88	80.00
Female	22	20.00
Age (years)
≤55	39	35.45
>55	71	65.55
Surgical approach
Double lung transplantation	65	59.09
Single lung transplantation	45	40.91
Place of residence
City	45	40.91
Rural area	65	59.09
Profession
Civil servants	19	17.27
Worker	13	11.82
Farmer	39	35.45
Others	39	35.45
Education
Junior high school and below	26	23.64
High school and above	84	76.36

3.2. Changes of CNI Dose in Tacrolimus Group and Cyclosporine A Group after MMF Administration

Compared with before MMF, CNI dose in both cyclosporine A group and tacrolimus group decreased significantly after MMF administration (P < 0.01). See Table 3.

Table 3

Changes in the CNI dose of patients with renal impairment in the tacrolimus group and cyclosporine A group before and after the addition of MMF (, mg/d).

Group	Cases (n)	Before adding MMF	After adding MMF	t	P
Cyclosporine A group	5	370.17 ± 179.26	105.33 ± 27.39	4.484	0.001
Tacrolimus group	9	2.61 ± 1.15	1.11 ± 0.23	3.898	0.002

3.3. MMF Was Followed Up before and 30 Days, 60 Days, and 90 Days after Administration, and the Changes of Serum Creatinine Level and Serum Creatinine Clearance Rate Were Measured

Before and after the addition of MMF, the CNI doses of patients in the tacrolimus group and cyclosporine A group with related renal impairment were, respectively, (2.61 ± 1.15) mg/d vs (1.11 ± 0.23) mg/d, (370.17 ± 179.26) mg/d vs (105.33 ± 27.39) mg/d.

Compared with before MMF, serum creatinine levels were significantly decreased and serum creatinine clearance was significantly increased on 30 d, 60 d, and 90 d after MMF administration (P < 0.05). See Table 3.

3.4. Follow-Up before and 30 d, 60 d, and 90 d after the Addition of MMF, and the Serum Creatinine Level and the Changes of Serum Creatinine Clearance Rate Were Measured

Compared with before MMF addition, 30 d, 60 d, and 90 d after MMF addition, the serum creatinine level decreased significantly with the increase of time, and the serum creatinine clearance rate increased significantly (P < 0.05). See Table 4.

Table 4

Follow-up before adding MMF and 30 d, 60 d, and 90 d after adding MMF, and the changes of serum creatinine level and serum creatinine clearance rate of patients were measured ()

Group	Cases (n)	Serum creatinine level (μmol/L)	Serum creatinine clearance (ml/min)
Before adding MMF	14	139.25 ± 19.36	52.38 ± 10.33
30 d after taking MMF	14	125.14 ± 16.53a	63.42 ± 11.17a
60 d after taking MMF	14	112.18 ± 12.44ab	72.39 ± 9.56ab
90 d after taking MMF	14	91.23 ± 16.35abc	81.48 ± 13.45abc

Note. a P < 0.05 compared with before taking MMF, bP < 0.05 compared with 30 d after taking MMF, and cP < 0.05 compared with 60 d after taking MMF.

3.5. Complications in Patients with CNI-Related Renal Damage after Lung Transplantation

Follow-up found that before the adjustment of the immunosuppression regimen, 16 patients with CNI-related renal damage were found to have immune rejection. After the adjustment of the immunosuppression regimen, there were no complications such as immune rejection, bone marrow suppression, and infection. There were 3 patients with elevated blood sugar within 2 years after operation, 1 patient with elevated blood lipids, 1 patient with elevated urea, and 1 patient with elevated uric acid.

4. Discussion

Lung transplantation is the most effective kidney replacement treatment for patients with end-stage lung disease. With the continuous development of lung transplantation technology, immune rejection after lung transplantation is often the biggest problem facing transplantation. It can significantly reduce the long-term survival of the transplanted lung of the patient, and it is also the most important factor causing the failure and loss of the transplanted lung of the patient. The higher the compatibility of human leukocyte antigens between donors and recipients of organ transplantation, the higher the probability of survival of the transplanted organ, which makes it necessary for patients to use immunosuppressants for a long time to fight rejection [8]. Hormones are currently routinely used drugs in immunosuppressive programs after transplantation, and their adverse reactions are more common. However, some scholars have found that the adverse reactions caused by the use of hormones may cause the transplanted organ intolerance symptoms in the suppressed recipients. The intolerance of transplanted organs may significantly increase the incidence of rejection of transplanted organs, which in turn will cause the transplanted organs to lose function [9]. In addition, the risk of vascular complications in transplant recipients may be significantly related to the cumulative use of hormones [10].

CNI has been involved in the field of transplantation to treat rejection since the early 1980s and has significantly prolonged the survival time of patients and transplanted organs in a short period of time. Studies have found that the survival rate of kidney transplant recipients within 1 year after CNI use is more than 90% [11]. Up to now, CNI is still the most commonly used immunosuppressant after transplantation, and it is also the basic drug for immunosuppressive therapy after lung transplantation. It can effectively reduce the incidence of acute rejection and improve the short-term efficacy of lung transplantation [12]. At present, CNI mainly includes cyclosporine A and tacrolimus. Among them, cyclosporin A is a cyclic polypeptide composed of 11 amino acids, and it is also a potent immunosuppressant that selectively acts on T lymphocytes. It can bind to intracellular immunophilin cyclophilin and inhibit the activation of helper T cells and the reactivity to interleukin-2 (interleukin-2, IL-2) [13]. According to reports, cyclosporine A is used to prevent graft-versus-host reaction after transplantation or to treat a variety of autoimmune diseases, which may be related to the transcription and secretion of cytokines caused by calcineurin transplantation. It is important to block T cell activation and differentiation. Kidney injury is an important adverse reaction of cyclosporin A [14]. Haam et al. found that the use of cyclosporin A itself can cause renal toxicity, chronic injury, and long-term loss of function of the transplanted kidney [15]. In the study of Nankivell et al., through the acquisition of multiple kidney transplant puncture specimens, there were the analysis and discovery of the cyclosporin A nephrotoxicity indicators such as transparent deformation of transplanted kidney tubules, cord-like fibrosis, and renal tubular calcification. The peak of nephrotoxicity of cyclosporine A was 6 months after transplantation and 3 years after transplantation. The nephrotoxicity caused by cyclosporin A is reversible at 6 months after transplantation, and the renal damage caused by cyclosporin A is often irreversible at 3 years after transplantation [16]. Tacrolimus is a powerful immunosuppressive newly discovered in recent years, and it is also a basic drug for the prevention and treatment of rejection after organ transplantation. It has a high affinity for plasma proteins. Neurotoxicity is one of the most serious adverse reactions of tacrolimus. According to statistics, the incidence of neurotoxic adverse reactions after organ transplantation is about 8% to 47%. The incidence of neurotoxic side effects is highest within 3 months after organ transplantation [17]. Studies have found that CNI can inhibit the dephosphorylation of calcineurin by binding to the corresponding receptor to form a receptor protein complex, inhibit the proliferation of lymphocytes, prevent the occurrence of rejection, and promote the short-term survival of patients and transplanted lungs [6]. However, studies have found that CNI has more toxic and side effects. It has obvious nephrotoxicity while exerting immunosuppressive effects and can cause related kidney damage. It can cause the renal glomerular artery to contract, thicken the wall of the renal arterioles, narrow the lumen, and cause impaired renal function [18, 19]. In addition, CNI can also cause adverse reactions such as new diabetes, hypertension, and hyperlipidemia after transplantation, and eventually lead to transplant failure.

At present, the most commonly used immunosuppressive treatment for lung transplant recipients is the classic triple immunosuppressive therapy based on CNI, that is, cyclosporin A, tacrolimus combined with an antiproliferative drug [12]. MMF is an ester derivative of mycophenolic acid and an antimetabolism and proliferation immunosuppressant. MMF is also the most commonly used immunosuppressant for patients after heart transplantation (HTX) [20]. MMF has the advantages of simple use, no monitoring, no obvious liver and kidney toxicity, bone marrow suppression, and other adverse reactions. In the classic lymphocyte guanine nucleotide synthesis process, it can block hypoxanthine mononucleotide dehydrogenase, thereby inhibiting lymphocyte proliferation and antibody production [21]. Due to renal arteriole and tubular remodeling, interstitial fibrosis, and glomerulosclerosis, CNI-based immunosuppressants are associated with irreversible renal damage. Some scholars have found in the related studies of kidney transplantation that the use of CNI combined with MMF immunosuppressive therapy after kidney transplantation can increase the possibility of macrophage infection of the virus, which may be an important reason for the failure of kidney transplantation [22]. Therefore, by maintaining CNI treatment, a further deterioration of renal function parameters is usually observed.

According to reports, the occurrence of CNI-related renal damage after lung transplantation is closely related to the dosage of CNI. Reducing the dosage of CNI and controlling the blood concentration within a certain range play an important role in reducing the occurrence of nephrotoxicity [23]. Previous studies have found that CNI has obvious and clear nephrotoxicity in kidney transplantation [24]. Some scholars have found that everolimus combined with low-dose tacrolimus is used in clinical trials for kidney transplant recipients. It was found that it cannot only maintain good renal function, but also effectively reduce the occurrence of rejection and improve the survival rate of patients and transplanted kidneys [25]. Sawinski et al. [26] conducted a meta-analysis of CNI reduction, conversion, removal, and complete avoidance, and conducted a meta-analysis of a number of randomized controlled experiments. In order to evaluate its clinical effect, it was found that compared with the standard dose regimen, the CNI reduction regimen can significantly improve the renal function of patients without increasing the incidence of acute rejection. Although the CNI conversion and withdrawal program can improve renal function, it will increase the incidence of acute rejection. In the study of Jiang et al. [27], after organ transplantation, patients were randomly divided into MMF + low-dose cyclosporine A + hormone group according to their postoperative medication, MMF + cyclosporin A (gradually reduced at 4 months and completely removed at 6 months) + hormone group, MMF + conventional dose cyclosporin A + hormone group, followed up to 12 months after surgery. It was found that the acute rejection reaction of the complete withdrawal group was significantly higher than that of the other two groups, but the safety of complete withdrawal was lower. The reasonable and healthy use of it can not only maintain good transplant organ function, but also not increase the incidence of acute rejection. Cyclosporine A and tacrolimus have similar reaction mechanisms. Some scholars have found in vivo experiments that it has a better effect on liver and kidney transplantation [28]. Although the two CNIs suppress the immune system through similar mechanisms, differences in their side effects can be observed. Studies believe that an important reason for the improvement of renal function parameters in tacrolimus immunosuppressed patients may be that the serum concentration of tacrolimus is reduced by 100 times [29]. Therefore, the CNI reduction program plays an important role in improving renal function after transplantation.

In this group of studies, 16 patients (14.55%) had CNI-related renal damage among lung transplant recipients and different immunosuppressive agents. Among them, 10 cases (11.36%) occurred in men, 6 cases (27.27%) occurred in women, and 11 cases (12.09%) occurred in the tacrolimus group. There were 5 cases (26.32%) in the cyclosporine A group, and there was no significant difference between the groups (P > 0.05). Compared with before MMF plus administration, after MMF plus administration, both the cyclosporine A group and the tacrolimus group had significantly reduced CNI doses (P < 0.01). Compared with before MMF addition, 30 d, 60 d, and 90 d after MMF addition, the serum creatinine level decreased significantly with the increase of time, and the serum creatinine clearance rate increased significantly (P < 0.05). Follow-up found that before the adjustment of the immunosuppression regimen, 16 patients with CNI-related renal damage were found to have immune rejection. After the adjustment of the immunosuppression regimen, no immune rejection, bone marrow suppression, or infection occurred within about 15 months. There were 3 patients with elevated blood sugar within 2 years after operation, 1 patient with elevated blood lipids, 1 patient with elevated urea, and 1 patient with elevated uric acid. It is suggested that the use of MMF immunosuppressive regimen on the basis of CNI reduction can effectively reduce immune rejection and improve renal function.

In summary, the MMF immunosuppressive regimen based on CNI reduction is a safe, effective, and more optimized immunosuppressive treatment regimen. It can significantly reduce immune rejection, improve renal function, and play an important role in improving CNI-related renal damage after lung transplantation.

5. Conclusion

In this paper, numerous effects of immunosuppressive regimen of mycophenolate mofetil (MMF) on CNI-related renal damage after lung transplantation are evaluated thoroughly. For this purpose, 110 lung transplant recipients who were treated in our hospital from March 2016 to January 2018 were randomly selected. All patients took prednisone acetate tablets or rapamycin at the same time or not at the same time. MMF is 1 g every time, twice a day, and adjusted according to the re-examination. According to the different drugs taken by 110 patients, they were divided into cyclosporine A group and tacrolimus group. Among them, 92 patients in cyclosporine A group took cyclosporine A; 18 patients in tacrolimus group took tacrolimus. Compared with MMF before and after administration, CNI dosage of cyclosporine A group and tacrolimus group decreased significantly (P < 0.01). Compared with MMF before administration, serum creatinine level decreased and serum creatinine clearance rate increased significantly (P < 0.05). In the follow-up, 16 patients with CNI-related renal damage were found to be immune rejection before the adjustment of immunosuppression program, no complications such as immune rejection, myelosuppression, and infection occurred within 15 months after the adjustment of immunosuppression program, blood glucose increased in 3 patients within 2 years after operation, blood lipid increased in 1 patient, urea increased in 1 patient, and uric acid increased in 1 patient. MMF immunosuppressive therapy based on CNI reduction is a safe and effective immunosuppressive therapy, which can significantly reduce immune rejection, improve renal function, and play an important role in improving CNI-related renal damage after lung transplantation.