1. INTRODUCTION:

The treatment of “end-stage kidney disease” was transformed by “kidney transplantation”, which gave patients the chance of long-term survival and liberated them from the need for ongoing dialysis. With the creation of novel immunosuppressive drugs, protection against acute rejection was crucial.¹

Tacrolimus, Mycophenolate mofetil (MMF), and prednisolone are frequently used for new kidney transplant patients and have excellent clinical outcomes compared to other treatments. This combination has been shown to improve “graft function”, increase “patient survival rates”, and reduce the occurrence of “acute rejection episodes”.^1,2

Following three pivotal clinical trials demonstrating that mycophenolate mofetil (“MMF, CellCept ®, Hoffmann-La Roche, Basel, Switzerland”) reduced the incidence of “acute rejection” within the year post-kidney transplantation, the “US Food and Drug Administration” (FDA) endorsed MMF as the preferred anti-metabolite in 1995. Consequently, numerous medical centres rapidly embraced MMF as their “anti-metabolite of choice” in both developed and developing countries. The enzyme “inosine monophosphate dehydrogenase (IMPDH)”, which catalyses the conversion of “inosine monophosphate” to “guanine monophosphate (GMP)”, the principal progenitor for the DNA nucleotide guanine, is reversibly inhibited by MMF, a pro-drug of the active compound “mycophenolic acid (MPA)”. This may lead to extensive “T-cell suppression” and assist in diminishing acute rejection in solid organ transplantation when combined with other agents that limit “T-cell receptor activation”, such as calcineurin inhibitors. Despite the similar mechanisms of action of MMF and Azathioprine (AZA), interest in MMF has surged because of its more refined mode of action and minimised drug interactions compared to AZA. It was anticipated that MMF would surpass AZA in avoiding acute rejection and prolonging patient and transplant survival.^3–5

Traditionally, MMF is used as a fixed dose without therapeutic drug monitoring in most of the transplant centers across India due to the cumbersome method of MMF level estimation. The initial MMF dosage for renal transplant is 2g/day based on “dose-finding studies in cyclosporine-treated patients”.^6,7 It is important to highlight that tacrolimus is linked with significantly greater levels of MPA exposure compared to cyclosporine. This is primarily because tacrolimus less effectively inhibits “MPA enterohepatic recirculation”. Consequently, patients who are receiving tacrolimus may require reduced doses of MMF. Nevertheless, most studies, although not all, that compared the incidence of rejection in tacrolimus-treated patients to a lower to intermediate dose (1-1.5g) of MMF daily to 2g/day found a surge in the incidence of rejection with the lower dose.^8–11

Currently, there is a lack of research directly comparing the effectiveness and potential negative impacts of a transitional MMF starting at the dose of 1.5g/day versus 2g/day, specifically in the Indian population over the long term. It is important to note that MMF has been linked with various side effects, such as gastrointestinal problems, bone marrow suppression, and nonspecific immunosuppressive effects. As a result, reducing drug exposure is a valuable goal.¹² We propose, drawing from existing literature, that a daily dosage of 1.5g of MMF would demonstrate efficacy comparable to that of 2g/day, while the higher dosage may be linked to an amplified incidence of adverse events. This study observed the outcomes correlated to the occurrence of “acute rejection episodes” for efficacy, leukopenia, and infection episodes for adverse events, as well as “graft and patient survival” one-year post-transplant. The aim was to compare the influence of the two dosing regimens on graft function, providing insights into the outcomes associated with various MMF dosing strategies in Indian renal transplant recipients.¹³

2. MATERIALS AND METHODS:

This retrospective study comprised 62 adult (aged >18 years) “live-related kidney transplant” recipients at a tertiary care hospital between January 2018 and December 2022. Patients who began on immunosuppressive regimens other than “Tacrolimus+ MMF+ Prednisolone” and who underwent cadaveric kidney transplantations were excluded. This study was conducted in accordance with the principles of the “Declaration of Helsinki” and was approved by the Institutional Ethics Committee (IEC). Data on patient demographics, baseline characteristics, MMF dose, and post-transplant outcomes (leukopenia, infections, rejection) were collected from electronic medical records. Among them, 20 patients received 1.5g MMF (Group 1), and 42 received 2g MMF (Group 2). Patients received Basiliximab, Anti-thymocyte globulin (ATG), or Grafalon induction based on individual characteristics, along with pulse methylprednisolone as per the nephrologist's discretion on risk assessment. Tacrolimus was given orally at a 0.08 mg/kg/day starting dose and titrated to trough levels on twice daily dosing. Given trough levels, the maintenance dosage was adjusted to 8–12 ng/mL for months 0–3, 6–8 ng/mL for months 3–6, and 4–6 ng/mL after 6 months post-transplant. Prednisolone was tapered over 6 months to 5-7.5 mg/day after transplant. The two groups of MMF were compared for leukopenia, rejection events, infections, and one-year post-transplant implant function and mortality.

2.1 Definitions used:

· Leukopenia was termed as “a total white blood cell count < 4 × 10⁹ cells/L”.

· The "standard Banff criteria" were employed to evaluate all rejection episodes that were biopsy-proven.

· The graft function was evaluated using the “CKD EPI (Chronic Kidney Disease Epidemiology Collaboration)” formula to calculate “Estimated Glomerular Filtration Rate” (eGFR).

In accordance with established practice, all patients were given oral valganciclovir (400 mg) for 6 months as CMV prophylaxis and cotrimoxazole (400 mg/80 mg) for at least 1 year to prevent infection. As per institutional protocol, pulse methylprednisolone pulses and higher baseline immunosuppression were used to treat acute cellular rejection. Pulse methylprednisolone + plasma exchange ± anti-thymocyte globulin/Rituximab were used to treat acute antibody-mediated rejection.

2.2 Outcomes:

The primary outcomes analyzed were the incidence of leukopenia, infections, and rejection episodes across the groups within one-year post-transplantation, whereas the secondary outcomes were the graft and patient survival comparison between the groups at the end of one-year post-transplantation.

2.3 Statistical Analysis:

The “Mann-Whitney U-test” for non-parametric data and the “Student’s t-test” for parametric data were used to compare groups. Chi-square analysis was employed to compare proportions. The “p < 0.05” was set as the level of statistical significance. All analyses were performed using the statistical software, “Jamovi,” to ensure robust and reliable results.

3. RESULTS:

As shown in Figure 1 and detailed in Table 1, the study included 62 adult live-related kidney transplant recipients, with 20 patients in the MMF 1.5g/day group and 42 in the 2 g/day group. Baseline recipient and donor characteristics, including immunological characteristics (HLA mismatches), were comparable between groups. The distribution of native kidney diseases and nadir renal function parameters also showed no significant difference. Induction agents (Basiliximab, ATG, ATG-F) were used based on risk profiles and were comparable among the groups. In our cohort, there were no patients who underwent second or third kidney transplants. The incidence of BKV in the 1500mg group was 0% while in the 2000mg group, it was 4.8% (n=2).

3.1 Primary outcomes (Table 2):

3.1.1 Leukopenia: Overall, 21 patients (41.2%) developed leukopenia, with a significantly higher incidence in the 2g group (47.6%) compared to the 1.5g group (20 %) (p = 0.04). Leukopenia occurred at a mean of 160 and 162 days after transplant among the 1.5g and 2g groups, respectively, and the response to leukopenia was by MMF dose reduction in all cases at the discretion of the treating transplant nephrologist, in whom leukopenia persisted despite stopping valganciclovir and cotrimoxazole. Colony-stimulating factors were not routinely used. The median duration of leukopenia was 32 days. Additionally, 69% of patients in the 2g group required a dose reduction of MMF within the first year of transplantation.

Figure 1: CONSORT diagram

3.1.2 Infection:

Infections were also more recurrent in the higher dose group, affecting 34.3% compared to 10.5% in the lower dose group (p = 0.03). Notably, infections occurred earlier in the 2 g group (mean 183 days) than in the 1.5g group (mean 332 days). The commonest infection seen in our cohort was urinary tract infections (UTI) and bronchopneumonia.

3.1.3 Rejection: Rejection episodes (including borderline and subclinical) were observed in 56.9% of the total cohort. Although more frequent in the 2g group (54.8%) than the 1.5g group (45 %), with a p-value of 0.49, the disparity did not reach statistical significance.

Table 2: Primary outcomes

Characteristics	MMF 1.5 g/day (n=20)	MMF 2g/day (n=42)	p-value
Leukopenia (n, %)	4 (20 %)	20 (47.6 %)	0.04
Infection (n, %)	2 (10 %)	15 (35.7 %)	0.03
Rejection (n, %)	9 (45 %)	23 (54.8 %)	0.47

3.2 Secondary outcomes:

3.2.1 eGFR at 1 Year post-transplant (Figure 2): eGFR at 1 Year post-transplant in the 1.5g/day group was 68.2± 22.8ml/min/1.73m² and 69.3±23.2/min/1.73m²in the 2g/day group, however there was no statistically significant difference in the mean between the two groups receiving different doses of MMF (p=0.86).

Figure 2: Graft Survival at 1-year post-transplantation

3.2.2 Mortality rate at 1-year post-Transplant: Patients who received MMF 1.5g/day (n=2; 10%) and those who received MMF 2g/day (n=3; 7%) did not have a statistically significant difference in mortality (p=0.87), and death was due to sepsis.

4. DISCUSSION:

In the early 1990s, MMF was incorporated into the range of anti-rejection medications. Considering that MMF exposure is greater with tacrolimus compared to cyclosporine, a reduced initial dose of MMF may suffice, especially in live related renal transplant recipients. About 90% of adult kidney transplant recipients are on maintenance immunosuppressive treatment consisting of tacrolimus (TAC) and MMF, either with or without steroids. There are studies proving the best tacrolimus trough targets to prevent alloimmune reactions, but there is little information available regarding the best MMF dosage and when to lower doses after transplantation to lower the risk of infectious and malignant sequelae, as mentioned in the “Kidney Disease: Improving Global Outcomes (KDIGO) Transplant Work Group” guidelines^7,14–20 .

Research comparing 1g and 2g/day in patients treated with tacrolimus has shown decreased rejection rates with the larger dose; however, this is not always the case, since other studies have found the lower amount to be either superior or equivalent. Reduced early rejection is linked to increased mean exposure of “area under the concentration-time curve” (AUC), which is correlated with higher MMF dosages. Higher dosing techniques, however, also raise the percentage of individuals with potential extra toxicities who are over the desired AUC values. Additionally, whereas greater doses are linked to higher AUCs, there is no proof that this results in better long-term graft function for the patient or graft. 1 g of MMF daily is not a sufficient starting dose to reduce rejection in patients treated with tacrolimus, although this is not acknowledged. However, evidence comparing the efficacy of 1.5g/day versus 2g/day remains limited.^{8,9,11,21–27}

Leukopenia was a prevalent finding in this trial, and the greater MMF dose was substantially linked to its development. Prior research has documented leukopenia rates ranging from 18 to 36% after a year, with variations among trials probably related to the usage of concurrent drugs, for instance, cotrimoxazole and antiviral valganciclovir prophylaxis.^9,11,24–29 Leukopenia in our study peaked five months post-transplant, coinciding with reduced prednisolone. It was generally short-lived and managed by adjusting MMF or other marrow-suppressive drugs, without increasing hospitalizations for severe infection. Unlike earlier reports, leukopenia showed no association with rejection or renal dysfunction. This likely reflects our strategy of reducing rather than stopping MMF, which increased the need for monitoring and dose adjustments, causing patient discomfort and added costs, but not adverse clinical outcomes.^30,31

Furthermore, our study revealed that infection rates were significantly higher in the 2g MMF group when compared to the 1.5g/day group [n=12;34.2% vs 2 (10.5%)]. This finding underscores the multifaceted impact of MMF dosage on post-transplant outcomes, with higher dosages potentially increasing the susceptibility to infections, thereby necessitating more stringent monitoring and management strategies. Our research supports the conclusions of the Datrino et al. meta-analysis of thirty studies, revealing infection (36%; 95% CI: 26%-46%) and leukopenia (18%; 95%CI: 3%-33%) being strongly associated with TAC+MMF. MMF has been utilized to strengthen TAC's effectiveness, which may lower the dosage needed and, consequently, its adverse effects because of the synergistic effect through many mechanisms of action.³² Along with minimizing side effects, the immunosuppressant combination seeks to maximize effectiveness in reducing rejection and mortality as well as lessen the need for corticosteroids. As a result, MMF and TAC together have emerged as one of the most popular immunosuppressive regimens in kidney transplant clinical practice.^10,33,34 Our results are also consistent with the retrospective study conducted by Hosohata et al., which examined 10,272 adults and found that the most common adverse events brought on by MMF were polyomavirus-associated nephropathy, urinary tract infections, and cytomegalovirus infections.³⁵ MMF disrupts leukocyte adhesion and endothelial function, reducing immune cell recruitment. While essential for preventing rejection, this mechanism compromises host defences, increasing susceptibility to infections, particularly CMV.³⁶

Our study revealed that the rejection rates of the two groups did not differ significantly in the first year following transplantation [2g/day: n=23 (54.8%) vs. 1.5g/day: n=9 (45%); p=0.49]. This is surprising. In a study similar to that of Dave et al., which analysed 125 recipients of de novo renal transplants, 60 of whom were initiated on MMF 1.5g/day and 65 of whom were initiated on 2g/day, it was determined that, despite the fact that rejection episodes were more prevalent in the first year following transplantation in the MMF 1.5 g group (31 of 60, 51.7%) than in the 2g group (25 of 65, 38.5%), the unadjusted outcome was not statistically significant (p=0.09). This suggests that there is no disparity in graft survival or renal function after transplantation, demonstrating that these initial doses are similarly effective in the long run.¹³

There was no significant distinction in the graft outcomes at one year after transplantation between the two groups, despite the fact that the graft function (eGFR by CKD-EPI equation) was slightly better in the 2g/day MMF group [eGFR at 1 year in 2g MMF/day: 69.3±23.2ml/min/1.73m² vs. 1.5gMMF/day: 68.2± 22.8ml/min/1.73m²; p=0.86]. This is comparable to a study by Dave et al. that compared the eGFR of 125 adult renal transplant recipients who received 1.5g/day and 2g/day MMF. Although the eGFR of the 2g/day MMF group was lower than that of the 1.5g/daily group at 1 month [1.5g/day MMF: 63.9±24.9ml/min/1.73m² vs. 2g/day MMF: 54.9±23.2ml/min/1.73m²; p=0.03], the eGFR was comparable at the end of a year after transplantation [1.5g/day MMF: 64.0±22.7 ml/min/1.73m² vs 2g/day MMF: 61.0±21.6 ml/min/1.73m²; p=0.47] and continued for up to 7 years (study period). This could be because the 2g/day MMF group had a higher proportion of donation after circulatory death donor (DCD) transplants, and the 2g/day MMF group had a higher frequency of delayed graft function.¹³

In this study, a statistically non-significant difference in mortality rate between patients receiving MMF 1.5g/day (n=2; 10%) and those receiving MMF2g/day (n=3; 7%) was found, and the major cause was refractory septic shock due to microbiologically proven bloodstream infections. The impact of immunosuppression predisposes transplant recipients to infections, even if allograft survival has improved recently. Bloodstream infections (BSI) continue to be a foremost source of morbidity, graft failure, and post-transplant mortality. Septic shock can increase mortality to as much as 50%.^37–40 In the initial six months, infections are typically associated with postoperative complications, urinary tract manipulation, or viral reactivation, with urinary tract infections (UTI) serving as the primary source of BSI.^37–40 Perioperative antibiotic prophylaxis should be guided by colonization status, risk factors, and local epidemiology. Despite standard prophylaxis reducing infections, multidrug-resistant bacteraemia remains a major threat, causing worse outcomes and higher mortality than other etiologies.⁴¹ Clinicians can make the best treatment decisions by having knowledge of the immunosuppressive burden, both past and present, and the duration of infectious episodes following transplantation.

5. LIMITATIONS:

· Use of different induction agents in our study may have influenced the incidence of both leukopenia and rejection.

· MMF levels were not performed due to decreased availability and the cumbersome nature of the test.

· Lack of matching for immunological risk between the two groups could have confounded the outcomes.

· The generalizability of our findings may be restricted by the small sample size in our study.

6. CONCLUSION:

This study indicated that the initial high dose of 2g/day MMF is linked with a higher risk of infection and leukopenia, with no difference in the rejection episodes. The best starting mycophenolate dosage for renal transplant recipients receiving tacrolimus is still up for debate, as neither dose results in better graft nor patient survival one year after transplantation. Future research with larger sample sizes and more rigorous patient matching protocols is warranted to validate our findings and explore potential underlying mechanisms.

7. ACKNOWLEDGEMENT:

The final manuscript was read and approved by all the authors.

8. DATA AVAILABILITY STATEMENT:

Data available on request due to privacy/ethical restrictions.

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Received on 21.07.2025 Revised on 12.11.2025

Accepted on 23.01.2026 Published on 01.07.2026

Available online from July 04, 2026

Research J. Pharmacy and Technology. 2026;19(7):2947-2953.

DOI: 10.52711/0974-360X.2026.00420

This work is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International License. Creative Commons License.

Characteristic	MMF 1.5 g/day (n=20)	MMF 2g /day (n=42)
Recipient age, mean ± SD	30.95±9.88	35.79±10.69
Recipient gender (males), (n, %)	17 (85%)	39 (92.8%)
Donor age, mean ± SD	41± 9.7	50.7± 8.3
Donor gender (females), (n, %)	14 (70%)	30 (71%)
HLA mismatches, mean ± SD	3.1± 1.2	3.2± 1.4
Nadir Creatinine, mean ± SD	1.32±0.76	1.34±0.7
Nadir eGFR, mean ± SD	80.46±23.48	76.19±23.58
Native Kidney Disease (n, %)
Chronic Glomerulonephritis (CGN)	7 (35%)	11 (26.2%)
Chronic Tubulointerstitial Nephritis (CTIN)	3 (15%)	7 (16.7%)
Diabetic Kidney Disease (DKD)	2 (10%)	4 (9.5%)
Focal Segmental Glomerulosclerosis (FSGS)	0 (0.0%)	2 (4.8%)
Immunoglobulin A Nephropathy (IgAN)	4 (20%)	12 (28.6%)
Unknown	4 (20%)	6 (14.3%)
Induction Agents (n, %)
Anti-Thymocyte Globulin (ATG)	2 (10%)	8 (19%)
Anti-Thymocyte Globulin-Fresenius (ATG-F)	4 (20%)	10 (24%)
Basiliximab	14 (70%)	24 57%)