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Saudi Journal of Kidney Diseases and Transplantation
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ORIGINAL ARTICLE  
Year : 2021  |  Volume : 32  |  Issue : 1  |  Page : 128-136
Impact of Therapeutic Dose Monitoring of Mycophenolic Acid on the Outcome of Live-Donor Kidney Transplant Recipients - A Prospective Controlled Study


1 Urology and Nephrology Center, Nephrology Unit, Mansoura University, Mansoura, Egypt
2 Department of Nephrology, Zagazig University, Zagazig, Egypt
3 Urology and Nephrology Center, Immunology Unit, Mansoura University, Mansoura, Egypt

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Date of Web Publication16-Jun-2021
 

   Abstract 


Immunosuppressive therapy is the backbone to renal transplantation. Although an adequate level of immunosuppression is required to dampen the immune response to the allograft, the level of chronic immunosuppression is slowly decreased over time (as the risk of acute rejection decreases) to help lower the overall risk of infection and malignancy. Several studies have discussed the clinical use of therapeutic drug monitoring of mycophenolic acid (MPA) in kidney transplant recipients. This prospective single-center study included 88 patients with end-stage renal disease who were transplanted in Mansoura Urology and Nephrology Center from living related donors, from the beginning of February 2016 to the end of December 2016. Eight patients were excluded, the remaining 80 patients were divided into two groups; the study group (40 patients) who were followed up using therapeutic trough level monitoring of MPA and, control group (40 patients) who were followed up using the fixed-dose of Mycophenolate according to our local immunosuppressive protocol. These patients were followed up for one year posttransplantation with regard to graft function, rejection episodes, gastrointestinal (GI), and hematological side effects, the incidence of infection or malignancy, patient survival, and graft survival. Fifteen patients from the study group (37.5%) needed dose reduction of MPA, no patients needed to increase the dose. Our study showed insignificant differences regarding the patients’ characteristics and demographic data. Significantly higher incidence of GI manifestations was noted in the control group (P = 0.001). Although the higher frequency of incidence of infection, anemia, leukopenia and thrombocytopenia was seen in the fixed- dose group, the difference was statistically insignificant. Regarding proteinuria and post-transplant diabetes mellitus, comparable data were obtained. Significantly higher percentage of recipients in the study group is still having normally functioning grafts (P = 0.02). Furthermore, higher percent of recipients in the control group died with functioning graft after one year of follow-up (P = 0.04). There were insignificant differences as regarding patient and graft survival. The decrease in the dose of MPA reduced the annual cost by around six thousand US dollars. Our results suggest that adopting therapeutic dose monitoring strategy during follow-up of kidney transplant recipients is adequate. Longer-term studies with a larger sample size may be needed to support this policy.

How to cite this article:
Denewar AA, Mohamed EM, M. Ismael MI, Ismail AM, Refaie AF. Impact of Therapeutic Dose Monitoring of Mycophenolic Acid on the Outcome of Live-Donor Kidney Transplant Recipients - A Prospective Controlled Study. Saudi J Kidney Dis Transpl 2021;32:128-36

How to cite this URL:
Denewar AA, Mohamed EM, M. Ismael MI, Ismail AM, Refaie AF. Impact of Therapeutic Dose Monitoring of Mycophenolic Acid on the Outcome of Live-Donor Kidney Transplant Recipients - A Prospective Controlled Study. Saudi J Kidney Dis Transpl [serial online] 2021 [cited 2021 Jul 31];32:128-36. Available from: https://www.sjkdt.org/text.asp?2021/32/1/128/318514



   Introduction Top


Marked improvements in early graft survival and long-term graft function have made kidney transplantation a more cost-effective alternative to dialysis.[1] The main goal for kidney transplantation to be successful is to avoid acute and chronic allograft rejection, thereby preventing allograft loss, without increasing the risk of infections and/or de novo malignancies.[2] Mycophenolate is recommended as first-line antiproliferative agent in maintenance immunosuppression in renal transplantation.[3] It is an inactive prodrug, with mycophenolic acid (MPA) being its active component. MPA is a selective, reversible inhibitor of inosine monophosphate dehydrogenase mainly type II isoform, which is predominately expressed in activated lymphocytes which is the rate-limiting enzyme in the de novo synthesis of purines.[4] After an oral dose, Mycophenolate in quickly disappears in the systemic circulation and the plasma concentration of MPA rises rapidly, reaching its maximum concentration within 1 h. Food intake can delay the rate of mycophenolate absorption but does not affect the extent. Co-administration of antacids, ferrous sulfate, cholestyramine or calcium carbonate decreases the extent of absorption by approximately 20%–40%.[5]

Cyclosporine also causes impaired enterohepatic cycling of MPA.[6] Corticosteroids interfere with mycophenolate mofetil (MMF) bioavailability enhanced glucuronidation.[7] MPA, due to enterohepatic circulation, shows a secondary peak in its plasma concentration profile at about 6 h after intravenous or oral dosing. The liver is the major organ of MPA elimination, kidney and intestine also contribute. Factors that may influence this include protein binding of MPA, the intrinsic enzymatic activity of the liver, and the blood flow to the liver.[8] Ethnic variability exists in the efficacy of mycophenolate when used in renal transplant patients. Black patients were shown to require higher dosages of mycophenolate compared with white patients to achieve a similar extent of prevention from early acute rejection when combined with cyclosporin A (CsA).[9] There is evidence that MPA level shows substantial inter- and intra-patient variability.[10] Regarding toxicity relationship with drug concentration, while the majority of studies confirmed the concentration-efficacy relationship, the correlation between MPA exposure and toxicity is less convincing. The gastrointestinal side effects of MPA do not seem to be related to MPA plasma concentrations. Hematological toxicity in a number of studies was found to be related to the nonprotein bound MPA concentrations.[11]

Common adverse drug reactions (≥1% of patients) associated with mycophenolate therapy include diarrhea, nausea, vomiting, joint pain, infections, leukopenia, and/or anemia reflecting the immunosuppressive and myelosuppressive nature of the drug.[12] Other rare but serious complications include progressive multifocal leukoencephalopathy; it attacks the brain and is usually fatal,[13] reversible bronchiectasis and pulmonary fibrosis, inflammatory bowel diseases like crypt distortion, and graft versus host like gut affection.[14]

In the comparison of measured MPA C0 levels and 12-h MPA area under the curves (AUCs) estimated by a limited-sampling strategy in stable transplant patients receiving chronic maintenance immunosuppressive therapy with CsA/MMF or rapamycin/MMF, abbreviated AUC estimation predicted drug exposure more accurately than did measure C0 levels. Thus, MPA AUCs obtained by limited sampling may be useful in guiding clinical management and dosing. However, further study is required, including validation of these findings in clinical outcome studies.[15]


   Patients and Methods Top


Eighty-eight patients with end-stage renal disease, who underwent live-donor renal allo-transplantation at the Urology and Nephrology Center, Mansoura University between February 2016 and December 2016, were enrolled into this prospective controlled study and followed up for one year post-transplantation. Eight patients were excluded (4 children, 2 foreigners who were lost to follow-up, and 2 were re-transplanted). The 80 patients studied received their grafts from living related donors, were maintained on Prednisolone, prograf, and MMF as primary immunosuppression. They were randomly divided into two groups (stratified randomization), study group (40 patients) and control group who were age- and sex-matched (40 patients). The study group of patients underwent trough level monitoring of MPA MMF performed by Thermo Scientific CEDIA MPA Immunoassay using Indico analyzer, Thermoscientific, Part of Thermofisher scientific, USA. A minimum of 1 mL blood sample is collected and centrifuged at 2000 rpm for 10 min and then 300 μl from separated plasma was used to measure MPA trough level. This was done on day-14 post-transplantation before discharge with a target trough level 1–3.5 μg/ml and then repeated twice with one month interval to confirm attaining satisfactory MMF level. The control group of patients received mycophenolate in a fixed-dose according to our local protocol. Both groups of patients were followed up for 12 months posttransplantation regarding graft function, incidence of rejection, incidence of toxic side effects of MPA like hematological side effects, gastrointestinal (GI) toxicity, infection episodes, condition at last follow-up, patient and graft survival.

Bivariate techniques were used for the initial evaluation of contrasts. Thus, the chi-square and Fisher’s exact tests were used for comparisons of frequencies of qualitative variables; the Mann-Whitney test and the unpaired t-test were used for comparisons of means of two quantitative variables. A P <0.05 was considered significant. Graft and patient survival rates were assessed using the Kaplan-Meier method. All analyses were carried out using the Statistical Package for the Social Sciences (SPSS) for windows version 16.0 (SPSS Inc. Chicago, IL, USA).


   Results Top


This study was adopted to identify the impact of therapeutic dose monitoring of MPA on the outcome of live-donor renal allo-transplantation regarding the incidence of graft rejection, mean serum creatinine at certain time points, incidence of proteinuria and its degree, hematological and GI toxic side effects, incidence of infection, posttransplant diabetes mellitus as well as its impact on patient and graft survival. Patients who were transplanted at Mansoura urology and nephrology center in the period between February 2016 and December 2016 were included in this study and divided into study group (40 patients) and control groups (40 patients) according to either using trough level monitoring of MPA or using fixed dose. These two groups were followed up and compared prospectively for one year posttransplantation.

[Table 1] shows patients’ characteristics and demographic differences between both groups of renal allograft recipients at the time of transplantation that were insignificant with respect to age, gender, donor age, gender and consanguinity.
Table 1: Pretransplant characteristics of all recipients included in the study.

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The overall frequencies of acute rejection episodes among both groups of recipients were statistically comparable [Table 2]. Also, mean serum creatinine levels at comparable time points were statistically insignificant [Table 3].
Table 2: Frequency of acute rejection episodes in all recipients according to mycophenolic acid therapeutic drug monitoring.

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Table 3: Mean serum creatinine levels in all renal allograft recipients according to mycophenolic acid therapeutic drug monitoring.

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Despite apparently higher incidence of anemia, leukopenia, and/or thrombocytopenia among fixed-dose recipients, the difference was not statistically significant [Table 4]. Comparable results were obtained regarding overall episodes of infection as well as the type of infection between both groups studied [Table 5]. GI manifestations including dyspepsia, food-related abdominal distension, loose stool, mild diarrheal episodes, or recurrent abdominal pain that were traced through subjective assessment were significantly higher in those with fixed-dose MMF than those who underwent therapeutic level monitoring [Table 6]. Posttransplant complications including diabetes mellitus and hypertension were comparable between both groups of patients at the studied time point [Table 7].
Table 4: Impact of mycophenolic acid therapeutic drug monitoring on incidence of its hematological side effects.

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Table 5: Impact of mycophenolic acid therapeutic drug monitoring on incidence of posttransplant infection episodes.

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Table 6: Impact of mycophenolic acid therapeutic drug monitoring on incidence of gastrointestinal manifestations.

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Table 7: Frequency of posttransplant diabetes mellitus and hypertension in all recipients according to mycophenolic acid therapeutic drug monitoring.

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Significantly higher percentage of recipients in the study group still have perfectly functioning graft. Furthermore, recipients in the control group showed inferior patient survival after one year follow-up. Out of the 40 patients in the control group, one patient lost his graft due to self-stoppage of immuno-suppressive medications and died of invasive pulmonary aspergillosis. Four other patients from the control group died with functioning graft, one of them with acute hemorrhagic pancreatitis, one died at home of unknown cause, one with extensive bronchopneumonia and respiratory failure and the 4th one died with bacterial meningitis [Table 8].
Table 8: Condition at last follow-up of patients with or without mycophenolic acid therapeutic drug monitoring.

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Regard graft and patient survival, insignificant data were obtained as shown in [Figure 1] and [Figure 2], respectively.
Figure 1: Kaplan–Meier curve for demonstrating graft survival.

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Figure 2: Kaplan–Meier curve for demonstrating patient survival.

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   Discussion Top


Immunosuppression management is not a one-size-fits-all practice. Many factors influence the selection of a given regimen, the principal goal being to balance the benefit of rejection prevention against the risk of over immuno-suppression.[16] Mycophenolate is recommended as a first-line anti-proliferative agent for initial maintenance therapy in kidney transplant recipients.[3] MPA is the active metabolite responsible for the immunosuppressive effects of the mycophenolates. MPA, a noncompetitive reversible inhibitor of inosine mono-phosphate dehydrogenase, produces a reduction in intracellular guanine nucleotide pools resulting in the arrest of lymphocyte proliferation. MMF and enteric-coated mycophenolate sodium have both been approved for use at a fixed dose in kidney transplantation. During the last few years, several large clinical trials and numerous pharmacokinetic studies have been reported that bring new insights to the debate of the clinical use of therapeutic drug monitoring (TDM) of MPA in kidney transplant recipients.[17]

In this prospective randomized trial, we tried to shed light on the importance of therapeutic dose monitoring of MPA through comparing two groups, the study group (40 patients), and the control group (40 patients); both groups were followed up one year posttransplantation.

In our study, there were no statistically significant results were detected regarding incidence of acute rejection. Same results were obtained by others.[11],[18] On the other hand, other studies logically documented lower incidence of acute rejection in patients who had MPA levels higher than the predetermined target range.[19],[20] This difference may be attributed to different ethnicity, different induction, and maintenance immuno-suppressive protocols, or difference in MPA starting dose.

In our study, despite apparently higher incidence of anemia, leukopenia and/or throm-bocytopenia among fixed-dose recipients, the difference was not high enough to reach statistical significance. Similar results were obtained by Van Gelder et al and Gourishankar et al.[21],[22] In disagreement to these results, many authors documented significantly higher incidence of leukopenia and/or anemia in patients receiving MMF with fixed dose.[23],[24] The difference may be attributed to the presence of other co-factors which may cause myelosuppression other than MPA including induction agent (thymoglobin or basiliximab), the cause of end-stage kidney disease, iron indices, baseline hemoglobin before starting MPA or associated viral infection including CMV or parvovirus B19.

This study showed that episodes of infection including infective gastroenteritis, pneumonia, acute bronchitis, and CMV disease were statistically comparable between the two studied groups of patients. In concordance with our results,[20],[22],[25] many other studies have reported comparable results. In contrast, many other studies have documented higher incidence of infection in recipients receiving MMF with a fixed dose.[26] Discrepancies may be attributed to potential differences in the sampling strategies either AUC or trough level monitoring used for estimating MPA level and/or the reluctance of study physicians to modify MPA dosing according to study protocol in the concentration-controlled arm.

In our study, we found that GI manifestations including dyspepsia, abdominal distension postmeals, loose stool, mild diarrheal episodes or recurrent abdominal pain that were traced through subjective assessment were significantly higher in those with fixed-dose MMF than those who underwent therapeutic level monitoring. Many other studies showed same significant differences in the incidence of distressing GI manifestations with higher MMF levels.[24],[25] Conversely, many other studies have documented insignificant variations between both groups.[21],[22],[26]

Regarding the financial impact of changing MPA dose according to trough level monitoring with adopting the TDM strategy on 40 transplanted patients for one year, 15 patients needed dose reduction with 250, 500 or 750 mg reduction in dose. Consequently, about 6000 US dollars were saved without increasing the incidence of rejection episodes and with decreasing toxic side effects of MPA like infection, GI intolerance, and hematological side effects.

Regarding patient and graft survival, there were comparable differences between both groups studied. Many other documents report similar insignificant data.[20],[22],[26] Some other authors have reported lower patient and graft survival in patients treated with MMF in a fixed dose.[27]


   Conclusion Top


The careful clinician is still left with uncertainty regarding routine MPA monitoring and its clinical utility. Can greater efficacy be achieved without increased toxicity or conversely, can efficacy be maintained with a reduction in adverse effects?

In conclusion, this study, unfortunately, cannot give a sharp answer to this most fundamental question. So, should MPA be monitored? Given the results to date the answer is still not clear. Thus, in theory, TDM of MPA is logical, makes sense and could potentially improve the balance of safety and efficacy in an individual patient.

Conflict of interest: None declared.



 
   References Top

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Matas AJ, Smith JM, Skeans MA, Thompson B, Gustafson SK, Schnitzler MA, et al. OPTN/ SRTR 2012 Annual Data Report: Kidney. Am J Transplant 2014;14 Suppl 1:11-44.  Back to cited text no. 1
    
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Nashan B. Is acute rejection the key predictor for long-term outcomes after renal transplanttation when comparing calcineurin inhibitors? Transplant Rev (Orlando) 2009;23:47-52.  Back to cited text no. 2
    
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Kidney Disease: Improving Global Outcomes (KDIGO) Transplant Work Group. KDIGO clinical practice guideline for the care of kidney transplant recipients. Am J Transplant 2009;9 Suppl 3:S1-155.  Back to cited text no. 3
    
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Langone AJ, Chan L, Bolin P, Cooper M. Enteric-coated mycophenolate sodium versus mycophenolate mofetil in renal transplant recipients experiencing gastrointestinal intolerance: A multicenter, double-blind, randomized study. Transplantation 2011;91:470-8.  Back to cited text no. 4
    
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Bullingham RE, Nicholls AJ, Kamm BR. Clinical pharmacokinetics of mycophenolate mofetil. Clin Pharmacokinet 1998;34:429-55.  Back to cited text no. 5
    
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Hesselink DA, van Hest RM, Mathot RA, et al. Cyclosporine interacts with mycophenolic acid by inhibiting the multidrug resistance-associated protein 2. Am J Transplant 2005;5:987-94.  Back to cited text no. 6
    
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Shihab FS, Lee ST, Smith LD, et al. Effect of corticosteroid withdrawal on tacrolimus and mycophenolate mofetil exposure in a randomized multicenter study. Am J Transplant 2013;13:474-84.  Back to cited text no. 7
    
8.
Noreikaitė A, Saint-Marcoux F, Marquet P, Kaduševičius E, Stankevičius E. Influence of cyclosporine and everolimus on the main mycophenolate mofetil pharmacokinetic parameters: Cross-sectional study. Medicine (Baltimore) 2017;96:e6469.  Back to cited text no. 8
    
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Neylan JF. Immunosuppressive therapy in high-risk transplant patients: Dose-dependent efficacy of mycophenolate mofetil in African-American renal allograft recipients. U.S. Renal Transplant Mycophenolate Mofetil Study Group. Transplantation 1997;64:1277-82.  Back to cited text no. 9
    
10.
Filler G, Lepage N. To what extent does the understanding of pharmacokinetics of myco-phenolate mofetil influence its prescription. Pediatr Nephrol 2004;19:962-5.  Back to cited text no. 10
    
11.
Atcheson BA, Taylor PJ, Mudge DW, et al. Mycophenolic acid pharmacokinetics and related outcomes early after renal transplant. Br J Clin Pharmacol 2005;59:271-80.  Back to cited text no. 11
    
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Opelz G, Döhler B, Collaborative Transplant Study. Influence of immunosuppressive regimens on graft survival and secondary outcomes after kidney transplantation. Transplantation 2009;87:795-802.  Back to cited text no. 12
    
13.
FDA Issues Second CellCept Warning. Available from: http://www.newsinferno.com. [Last accessed on 2008 May 18].  Back to cited text no. 13
    
14.
Rook M, Postma DS, van der Jagt EJ, et al. Mycophenolate mofetil and bronchiectasis in kidney transplant patients: A possible relationship. Transplantation 2006;81:287-9.  Back to cited text no. 14
    
15.
Dösch AO, Ehlermann P, Koch A, Remppis A, Katus HA, Dengler TJ. A comparison of measured trough levels and abbreviated AUC estimation by limited sampling strategies for monitoring mycophenolic acid exposure in stable heart transplant patients receiving cyclosporin A-containing and cyclosporin A-free immunosuppressive regimens. Clin Ther 2006;28:893-905.  Back to cited text no. 15
    
16.
Lim MA, Kohli J, Bloom RD. Immunosuppression for kidney transplantation: Where are we now and where are we going? Transplant Rev (Orlando) 2017;31:10-7.  Back to cited text no. 16
    
17.
Le Meur Y, Borrows R, Pescovitz MD, et al. Therapeutic drug monitoring of mycophenolates in kidney transplantation: Report of The Transplantation Society consensus meeting. Transplant Rev (Orlando) 2011;25:58-64.  Back to cited text no. 17
    
18.
Flechner SM, Feng J, Mastroianni B, et al. The effect of 2-gram versus 1-gram concentration controlled mycophenolate mofetil on renal transplant outcomes using sirolimus-based calcineurin inhibitor drug-free immunosuppression. Transplantation 2005;79:926-34.  Back to cited text no. 18
    
19.
Le Meur Y, Büchler M, Lavaud S, et al. Therapeutic drug monitoring of Mmf: A randomized multicenter study comparing concentration controlled versus fixed dose in kidney transplant recipients. Transplantation 2006;82:343-4.  Back to cited text no. 19
    
20.
Gaston RS, Kaplan B, Shah T, et al. Fixed- or controlled-dose mycophenolate mofetil with standard - or reduced-dose calcineurin inhibitors: The Opticept trial. Am J Transplant 2009;9:1607-19.  Back to cited text no. 20
    
21.
van Gelder T, Silva HT, de Fijter JW, et al. Comparing mycophenolate mofetil regimens for de novo renal transplant recipients: The fixed-dose concentration-controlled trial. Transplantation 2008;86:1043-51.  Back to cited text no. 21
    
22.
Gourishankar S, Houde I, Keown PA, et al. The CLEAR study: A 5-day, 3-g loading dose of mycophenolate mofetil versus standard 2-g dosing in renal transplantation. Clin J Am Soc Nephrol 2010;5:1282-9.  Back to cited text no. 22
    
23.
Kuypers DR, Claes K, Evenepoel P, Maes B, Vanrenterghem Y. Clinical efficacy and toxicity profile of tacrolimus and mycophenolic acid in relation to combined long-term pharmacokinetics in de novo renal allograft recipients. Clin Pharmacol Ther 2004;75:434-47.  Back to cited text no. 23
    
24.
Borrows R, Chusney G, Loucaidou M, et al. Mycophenolic acid 12-h trough level monitoring in renal transplantation: Association with acute rejection and toxicity. Am J Transplant 2006;6:121-8.  Back to cited text no. 24
    
25.
Sarangi SC, Reeta KH, Agarwal SK, Kaleekal T, Guleria S, Gupta YK. A pilot study on area under curve of mycophenolic acid as a guide for its optimal use in renal transplant recipients. Indian J Med Res 2012;135:84-91.  Back to cited text no. 25
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26.
Fu L, Huang Z, Song T, et al. Short-term therapeutic drug monitoring of mycophenolic acid reduces infection: A prospective, single-center cohort study in Chinese living-related kidney transplantation. Transpl Infect Dis 2014;16:760-6.  Back to cited text no. 26
    
27.
Burton ME. Applied Pharmacokinetics & Pharmacodynamics: Principles of Therapeutic Drug Monitoring. Lippincott Williams & Wilkins; 2006.  Back to cited text no. 27
    

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Correspondence Address:
Ahmed Abdelfattah Denewar
Urology and Nephrology Center, Nephrology Unit, Mansoura
Egypt
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DOI: 10.4103/1319-2442.318514

PMID: 34145122

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