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- Patients and Methods
We report our experience with calcineurin inhibitor (CNI) withdrawal and MMF monotherapy in 50 adult liver transplant (OLT) recipients with CNI-related toxicity. Thirty-four patients had chronic renal dysfunction (CRD) associated with arterial hypertension, 11 had only CRD and other five patients had hypertension. The mean time between OLT and introduction of MMF was 81 months. After the introduction of MMF, CNI was progressively reduced and withdrawn if possible. At the end of the follow up (mean time: 18 months) CNI was withdrawn in 39 patients (78%), and there was a significant decrease from baseline in serum creatinine (1.81–1.49 mg/dL; p < 0.0001), BUN (76.6–52.8 mg/dL; p < 0.0001) and uric acid (9–7.5 mg/dL; p < 0.0001) levels, and an increase in creatinine clearance (44.7–55.1 mL/min; p < 0.0001). Excluding patients who developed graft rejection and two patients who died, CRD improved in 32 of 40 patients (80%), and arterial hypertension improved in 22 of 29 patients (76%). Five patients (10%) developed acute rejection, and one patient (2%) chronic rejection. Twenty-six patients (52%) experienced side-effects, with asthenia, herpes virus infection, and diarrhea being the most common. Only eight patients (16%) required MMF dose reduction. In conclusion, MMF monotherapy late after OLT improves CRD and hypertension in most patients, is safe and well tolerated.
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- Patients and Methods
Calcineurin inhibitors (CNIs) are currently the key components of immunosuppressive therapy in liver transplant recipients. However, CNIs exhibit a broad spectrum of nonimmunological side-effects, including chronic renal dysfunction, arterial hypertension, diabetes mellitus and hyperuricemia (1–11), which are frequent causes of long-term morbidity and mortality after surgery. With the aim of reducing the incidence and severity of CNI side-effects, progressive CNI dose reduction and withdrawal, with or without additional immunosuppression, has been attempted in transplant recipients with different results (12–19).
Mycophenolate mofetil (MMF) is a potent immunosuppressive agent which does not cause chronic renal dysfunction, arterial hypertension or hyperuricemia. Previous reports support the use of MMF in combination with CNI reduction (14–17) or withdrawal (16,18–19) in the management of patients with CNI-related chronic renal dysfunction (14–17) with good results in terms of improvement of renal function. However, there are few reports on CNI withdrawal and MMF monotherapy, and these were in small series with a short follow up (16,18–19). In the present study, we report our experience with CNI withdrawal and MMF monotherapy in liver transplant recipients with CNI-related toxicity.
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- Patients and Methods
Fifty patients meeting all inclusion criteria were consecutively enrolled in the study during the period February 1997 to December 2002. There were 39 males (78%) and 11 females (22%), with an average of 55 years (median: 56; SD: 10, range 34–73 years). Liver transplantation had been performed in these patients during the period March 1986 to December 2001. The mean time that elapsed from transplantation to enrollment in the study was 81 months (median: 82; SD: 39; range: 13–169 months). The reason for liver transplantation was alcoholic cirrhosis in 18 patients (36%), hepatitis C virus (HCV) cirrhosis in 14 (28%), primary biliary cirrhosis in four (7.8%), hepatocellular carcinoma in four (8%), hepatitis B virus (HBV) cirrhosis in four (8%), cryptogenic cirrhosis in two (4%), and other hepatic diseases (sarcoidosis, Caroli's disease, ductular hyperplasia, alpha-1 antitrypsin deficiency) in the remaining four patients (8%). The immunosuppressive therapy that patients were receiving at the time of enrollment in the study was cyclosporine monotherapy in 44 patients (88%) and tacrolimus monotherapy in the remaining six patients (12%).
Calcineurin inhibitor-related adverse toxicity at the beginning of the study was chronic renal dysfunction and hypertension in 34 patients (68%), chronic renal dysfunction alone in 11 patients (22%), and arterial hypertension alone in five patients (10%).
Baseline mean serum creatinine, BUN and creatinine clearance values were 1.74 mg/dL (SD: 0.46; range: 1–3.70 mg/dL), 48.3 mL/min (SD: 16.7; range: 21.6–108 mL/min) and 73.5 mg/dL (29.7; range: 26–195 mg/dL), respectively. Baseline mean systolic and diastolic blood pressures were 139.6 mmHg (SD: 14.3; range: 120–170 mmHg), and 84.7 mmHg (SD: 7.3; range: 70–105 mmHg), respectively. The mean number of antihypertensive drugs used per patient was 0.94 (median: 1; SD: 0.7; range: 0–2). Mean uric acid level on enrollment in the study was 8.8 mg/dL (SD: 1.8; range: 4.3–13.1 mg/dL).
Mean cyclosporine and tacrolimus daily doses on enrollment in the study were 141 mg (median: 125; SD: 64; range: 25–400 mg) and 4.9 mg (median: 5; SD: 3.2; range: 0.5–10 mg), respectively. Mean baseline whole blood levels of cyclosporine and tacrolimus were 93 ng/mL (median: 88; SD: 30; range: 34–164 ng/mL) and 6.5 ng/mL (median: 6.4; SD: 2.7; range: 2.6–10 ng/mL), respectively.
Mean follow up after introduction of MMF was 18 months (median: 17; SD: 11; range: 3–55 months). Complete withdrawal of CNI was achieved in 39 of 50 patients (78%), with an average time between MMF introduction and CNI withdrawn of 5 months (median: 3; SD: 4; range: 1–21 months). At the end of the follow up, the average follow-up time on MMF monotherapy was 12 months (median: 12; SD: 9; range: 1–41 months). One patient (2%) died owing to recurrent alcoholic cirrhosis. In four patients (8%) CNI dose was reduced but not withdrawn owing to loss in the follow up (one case) and intolerance to full dose of MMF (three cases, two under tacrolimus and one under cyclosporine). In the remaining six patients (12%), CNI could not be withdrawn owing to graft rejection.
Excluding patients who developed rejection and the patient who died, chronic renal dysfunction improved in 32 of the 40 patients (80%) (Tables 1 and 2). In patients with chronic renal dysfunction and arterial hypertension, renal function improved in 24 of 29 patients (82.8%), and in patients with chronic renal dysfunction alone it improved in eight of 11 patients (72.7%) (NS). Creatinine levels were normal at the end of the follow up in 15 patients (37.5%). The characteristics of patients with chronic renal dysfunction are shown in Table 3. In patients with chronic renal dysfunction, serum creatinine levels decreased significantly during the study from 1.81 mg/dL (n = 40; SD: 0.44; range: 1.5–3.70 mg/dL) at baseline to 1.61 mg/dL (n = 34; SD: 0.6; range: 1.1–4.5 mg/dL; p < 0.0001) after 12 months, and to 1.49 mg/dL (n = 26; SD: 0.3; range: 1.1–2.1 mg/dL; p < 0.0001) after 18 months of MMF therapy (Figure 1). The change in the mean creatinine value during follow up in patients with and without arterial hypertension is shown in Table 4. Blood urea nitrogen levels also decreased significantly from 76.6 mg/dL (n = 40; SD: 29.2; range: 33–195 mg/dL) at baseline to 58.9 mg/dL (n = 34; SD: 28.9; range: 32–193 mg/dL; p < 0.0001) after 12 months, and to 52.8 mg/dL (n = 26; SD: 16; range: 30–85 mg/dL; p < 0.0001) after 18 months of MMF therapy. For both values, the most significant change occurred in the first 3 months from enrollment in the study (p < 0.0001). Moreover, this group of patients showed a statistically significant increase in mean creatinine clearance (estimated using the Cockcroft-Gault formula) from 44.7 mL/min (n = 40; SD: 11.9; range: 21.6–70.9 mL/min) at baseline to 50 mL/min (n = 34; SD: 13.8; range: 15.4–86.4 mL/min; p = 0.004) after 12 months, and to 55.1 mL/min (n = 26; SD: 13.5; range: 29.6–85.6 mL/min; p < 0.0001) after 18 months from the start of treatment with MMF (Figure 2).
Table 1. Number and percentage of patients with calcineurin inhibitor-related chronic renal dysfunction (alone or with hypertension) at baseline and at the end of follow up (excluding patients who developed graft rejection or died)
|Reason for inclusion in the study||Patients||Status at the end of follow up: renal function improvement|
|All n (%)||Yes n (%)||No n (%)|| p-value|
|CRD + hypertension||29 (72 5)||24 (82.8)||5 (17.2)||NS|
|CRD alone||11 (27 5)||8 (72.7)||3 (27.3)||NS|
|All||40 (100)||32 (80)||8 (20)||NS|
Table 2. Status at the end of follow up (excluding patients who developed graft rejection or died)
|CNI-related toxicity||Patients||Status at the end of follow up|
|Hyper-tension||32||7 (21.9%)||17 (53.1%)||8 (25%)|
|CRD||40||15 (37.5%)||17 (42.5%)||8 (20%)|
Table 3. Change in renal function in the different patient subgroups with chronic renal dysfunction (excluding patients who developed graft rejection or died)
| ||Status of renal function at the end of follow up|
|Normalization n = 15||Improvement n = 17||No improvement n = 8|
| Baseline creatinine (mg/dL)||1.55||1.97||1.65|
| End-of-study (18 m) creatinine (mg/dL)||1.3||1.6||1.65|
| Time after LTX (months)||73||83||91|
| MMF monotherapy (months)||13||14||11|
Table 4. Change in serum creatinine levels during follow up (excluding patients who developed graft rejection or died)
|Reason for inclusion in the study||n||Serum creatinine level (mg/dL)|
| Baseline|| 18 months|| p-value|
|CRD + hypertension||29||1.86 ± 0.48||1.54 ± 0.25|| |
|CRD alone||11||1.65 ± 0.29||1.36 ± 0.32|| |
|All||40||1.74 ± 0.46||1.50 ± 0.3||0.004|
In patients with hyperuricemia, there was a statistically significant decrease in the mean value of uric acid from 9 mg/dL (n = 44; SD: 1.7; range: 7.1–13.1 mg/dL) at baseline to 7.5 mg/dL (n = 36; SD: 1.5; range: 6.6–10.7 mg/dL; p < 0.0001) after 12 months, and 7.5 mg/dL after 18 months from the start of MMF (n = 26; SD: 1.3; range: 4.9–9.4 mg/dL; p < 0.0001). Three out of seven patients (42.9%) taking uric acid-lowering drugs were able to continue without any drug at the end of the study.
Excluding patients who developed graft rejection and the patient who died, arterial hypertension improved in 24 of the 32-hypertensive patients (75%) at the end of the follow up (Tables 2 and 5). In patients with chronic renal dysfunction and arterial hypertension, arterial hypertension improved in 22 of the 29 patients (75.9%), and in patients with arterial hypertension alone, it improved in two of the three patients (66.7%). In hypertensive patients, there was a significant decrease in the number of antihypertensive drugs used from 1.2 (n = 32; SD: 0.6; range: 0–2; p = 0.04) at baseline to 1.1 after 12 months (n = 29; SD: 0.7; range: 0–2), and to 1 (n = 21; SD: 0.8; range: 0–2; p = 0.008) after 18 months. Seven (21.9%) of the 32 hypertensive patients remained normotensive at the end of the follow up without antihypertensive drugs. There was no significant difference in mean systolic blood pressure at 12 months [134.1 mmHg (n = 29; SD = 18.1; range: 120–180 mmHg; p = 0.286] but the difference at 18 months did reach statistical significance (130.3 mmHg n = 21; SD: 12.7; range: 100–150 mmHg; p = 0.037) from baseline (142.1 mmHg, n = 32; SD: 14.6; range: 140–170 mmHg). There was no change in mean diastolic blood pressure at any time during the study (from 85.4 mmHg (n = 32; SD: 7.7; range: 70–105 mmHg) to 82.1 (n = 29; SD: 11.7; range: 60–110 mmHg; p = 0.826) after 12 months, and to 81.1 (n = 21; SD = 10.1; range: 50–90 mmHg; p = 0.301) after 18 months from the start of MMF.
Table 5. Number and percentage of patients with calcineurin inhibitor-related hypertension (alone or with chronic renal dysfunction) at baseline and at the end of follow up (excluding patients who developed graft rejection or died)
|Reason for inclusion in the study||Patients n (%)||Status at the end of follow up: arterial hypertension improvement|
|Yes n (%)||No n (%)|| p-value|
|CRD + hypertension||29 (90.6)||22 (75.9)||7 (24.1)||NS|
|Hypertension alone||3 (9.4)||2 (66.7)||1 (33.3)||NS|
|All||32 (100)||24 (75)||8 (25)||NS|
At the end of the mean follow up of 18 months, there were no significant changes in the mean values of liver function tests, serum cholesterol, glucose, platelets, hemoglobin or white blood cell count.
Five patients (10%) developed acute rejection episodes (two moderate and three mild) and one other patient developed chronic rejection (2%). One acute rejection episode developed during cyclosporine dose reduction, two episodes 1 month after CNI withdrawal, and in the remaining two patients 3 months after withdrawal. Chronic rejection appeared 1 month after CNI withdrawal. Acute rejection episodes were controlled by adding tacrolimus (four patients) or by increasing the level of tacrolimus (one patient). None of the five patients needed steroids. The patient with chronic rejection was under cyclosporine, rejection was not controlled by adding tacrolimus to MMF and the patient died waiting for retransplantation. This patient received liver transplantation owing to alcoholic cirrhosis and resumed alcohol consumption while he was under MMF monotherapy and did not have strict adherence to treatment and visits of follow up. Two of the six patients who developed graft rejection during CNI reduction or withdrawal did not have a previous history of graft rejection, three other patients had had one episode (including the one who developed chronic rejection) and the remaining patient had had two acute rejection episodes early after liver transplantation. The etiology of liver disease was alcoholic cirrhosis in four patients and primary biliary cirrhosis in the other two patients.
Age, time elapsed since transplantation until the beginning of MMF, etiology of liver disease, and history of previous rejection episodes were similar in the six patients who developed graft rejection and in the 44 patients who did not (Table 6). Nevertheless, we found that patients younger than 50 years, who began MMF monotherapy earlier than 6 years after OLT, and who had had previous rejection episodes had a greater risk of developing graft rejection during MMF monotherapy (50%) than patients without these three characteristics (8.7%; p = 0.06; RR: 5.7; CI: 1.5–22.2).
Table 6. General data of patients who developed rejection or not during calcineurin inhibitor reduction or withdrawal
| ||All n (%) 45 (100)||Rejection|
|Yes n (%) 6 (13.3)||No n (%) 39 (86.7)|
|Gender (male/female)||36/9 (80/20)||5/1(83.3/16.7||31/8 (79.5/20.5)|
| AC||18 (40)||4 (66.7)||14 (35.9)|
| HCV||13 (28.9)||0 (0)||13 (33.3)|
| PBC||3 (6.7)||2 (33.3)||1 (2.6)|
| Others||11 (24.4)||0 (0)||11(28.2)|
|Previous rejection||25 (55.6)||4 (66.6)||21 (53.8)|
|Median number of rejection episodes||1.4||1.3||1.4|
|Time elapsed since OLT (months)||82||63||84|
|P under tacrolimus/cyclosporine||4/41(8.9/91.1)||1/5 (16.7/83.3)||3/36 (7.7/92.3)|
Twenty-six patients (52%) had adverse effects. The most frequent adverse effects were asthenia in 13 patients (26%), human herpes virus 1 (HHV-1) infection in eight (16%), diarrhea in seven (14%), nausea and vomiting in seven (14%), abdominal pain in six (12%), leukocytopenia in six (12%), anemia in five (10%) and thrombocytopenia in four (8%). Nevertheless, only eight of the 50 patients (16%) required MMF dose reduction (four owing to recurrent HHV-1 infection, three because of GI intolerance, and the remaining one owing to anemia).
Two patients died during the study at 12 and 19 months, respectively. Both were waiting for liver retransplantation. The first patient died owing to a septic complication of his pre-existing graft liver cirrhosis and the second patient developed chronic rejection and died owing to massive esophageal variceal bleeding. The remaining 48 (96%) patients were alive and had stable graft function at the end of the follow up.
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Renal dysfunction during CNI-based immunotherapy after liver transplantation is a significant problem, which can be classified into an acute and a chronic form (2,3). The incidence of acute nephrotoxicity ranges between 21 and 94% (2,4–13). It is frequently associated with high blood levels of the drugs and is mainly observed in the early postoperative period when levels are kept particularly high. This type of renal dysfunction is detectable by a sudden increase in the creatinine level and is most likely caused by vasospasm of afferent arterioles. In general, acute toxicity is rapidly and completely reversible after CNI dose reduction. Calcineurin inhibitor-related chronic renal dysfunction (CRD) appears in 50–79% of liver transplant patients (2,14–16). The incidence of end-stage renal failure ranges between 2 and 9.5%, increasing with the time elapsed since transplantation (3,15,16). Calcineurin inhibitor-related CRD occurs later in the course after transplantation, in the presence of much lower drug levels and is it thought not to be reversible even after CNI dose reduction because of underlying morphological changes (17).
Previous reports support the use of MMF in the management of patients (14–17,19) with CNI-related CRD. In our study of 50 patients with CNI-related CRD, renal function, assessed by serum creatinine, blood urea nitrogen and creatinine clearance levels improved during the entire follow-up period after CNI dose reduction or withdrawal and MMF introduction. These results are similar to those published in previous series. In our experience, improvement of renal function was greater during the first 3 months of MMF therapy and CNI dose reduction, possibly as a result of the suppression of acute nephrotoxicity caused by calcineurin inhibitors. Moreover, in one third of the patients with renal dysfunction, serum creatinine levels were normal on the last follow-up evaluation. Most of these patients had mild CRD at the beginning of the study.
Hypertension is a risk factor for ischemic heart disease, peripheral vascular disease, renal failure, and early death. Its onset is rapid, usually within the first weeks of initiation of immunosuppressive therapy. The mechanism of hypertension after liver transplantation is multifactorial, but vasoconstriction caused by CNI is the main factor. Studies in long-term survivors after liver transplantation have shown an incidence of arterial hypertension between 46–64% in patients treated with tacrolimus (10,20), and 75–82% in patients treated with cyclosporine (7,10). The development of hyperuricemia and gout following liver transplantation has received little attention. In the study by Neal et al. (11) the prevalence of hyperuricemia was 47%, and 6% of the patients developed gout. In our study there was a decrease of blood pressure in 60% of the hypertensive patients, with a significant decrease in the number of antihypertensive drugs used, and also a statistically significant decrease in the mean uric acid value, results similar to those reported in other series (14,16). As in renal function, the largest improvement in hypertension and hyperuricemia occurred during the first 3 months after CNI dose reduction and the start of MMF therapy. As in renal toxicity, this early improvement in hypertension could be related to cessation of CNI acute toxicity.
Complete CNI withdrawal was achieved in most patients, with only a 12% rate of rejection episodes and no cases of late rejection after a mean follow -up time of 1 year on MMF monotherapy. All the graft rejection episodes appeared during CNI dose reduction or in the first 3 months after CNI withdrawal. Our results report an incidence of acute rejection less than the incidence reported by Herrero (14), Schlitt (16) and Stewart (18) and higher than the incidence reported by Raimondo (19). The longer time elapsed from transplantation to CNI suppression in our study compared with others, and the fact that most of our patients were on monotherapy before switching to mycophenolate, could explain the relatively low rates of rejection found. Of note, in our series, patients younger than 50 years and with a history of previous rejection episodes who started MMF monotherapy earlier than 6 years after transplantation were a high-risk group for developing rejection with the withdrawal of CNI.
Half the patients had adverse events. This is similar to the data reported by Schlitt (16). It should be pointed out, however, that there was a high number of patients who developed HHV1 stomatitis (17.6%) compared with other series (16). We do not have an explanation for this fact. Only 15% of our patients required MMF dose reduction owing to side-effects, a slightly higher incidence than that reported by Schlitt (16).
In summary, MMF monotherapy in liver transplant patients with chronic CNI-related toxicity allows CNI withdrawal in most patients. This approach was effective, as renal function, blood pressure control and hyperuricemia were significantly improved; well tolerated, as no major adverse events occurred; and safe, as only a few patients had graft rejection and there were no episodes of late rejection during MMF monotherapy. However, our data suggest that this approach is not advisable during the first 5 years after transplantation in patients younger than 50 years with a history of previous rejection episodes.