To avoid graft rejection during pregnancy, frequent monitoring of serum drug levels is recommended. Pregnancy induces hyperfiltration in transplanted kidneys, as in native kidneys; therefore, detection of rejection can be difficult when monitoring by serum creatinine. If rejection is suspected, ultrasonograph-guided graft biopsy can be done; once proven, it can be treated with pulse steroids, but data are scarce regarding other agents. Here, we present a 28-year-old pregnant female patient with resistant acute rejection but with successful pregnancy outcome. Our patient had end-stage kidney disease secondary to lupus nephropathy and underwent living-donor renal transplant in May 2013 after hemodialysis support for 1 year. She received thymoglobulin as induction therapy and was maintained on prednisolone, mycophenolate mofetil, and tacrolimus. She had normal renal graft function without proteinuria. After she received counseling, she became pregnant in February 2015. In June 2015, she presented with acute graft dysfunction with serum creatinine level of 365 µmol/L. Her abdominal ultrasonography showed mild hydronephrosis and viable fetus. She received empirical pulse steroids with partial response, and her graft biopsy showed acute T-cell-mediated rejection and negative C4d. Intravenous immunoglobulins and minipulse steroids were administered but without response. After gynecologic counseling and informed consent, she received 5 doses of thymoglobulin. She was dialysis dependent until premature vaginal labor, which resulted in birth of a viable 2-kg boy. We suggest that successful pregnancy outcomes could occur with close monitoring and daily dialysis in female kidney transplant patients with resistant rejection.
Key words : Dialysis, Female, Gestation, Outcome, Renal transplant
The renal allograft is able to adapt to physiologic changes of pregnancy with an increase in creatinine clearance of nearly 30% in the first trimester, which is sustained with a small decrease in the second trimester and a return to prepregnancy levels during the third trimester.1
Risk factors associated with poor pregnancy outcomes are hypertension, elevated prepregnancy creatinine levels of ≥ 1.4 mg/dL, proteinuria, and history of ≥ 2 renal transplants. The likelihood of poor fetal outcomes (still birth, miscarriage, neonatal death, birth < 32 weeks, and congenital anomalies) is about 6-fold higher in women with high prep-regnancy creatinine levels and high diastolic pressure during the second and third trimesters.2 The risk of allograft loss at 5 years has been shown to be 3.3-fold higher if prepregnancy creatinine is > 1.3 mg/dL and 7.4-fold higher if prepregnancy creatinine is > 1.6 mg/dL.3
Acute rejection may be higher in the postpartum period due to return to normal immunosurveillance status.4 The rate of allograft rejection is not increased during pregnancy or 3 months postpartum and varies between 1% and 14.5%, which is comparable to nonpregnant transplant recipients.3 Risk factors include high serum creatinine, rejection before pregnancy, and changing levels of immunosup-pressive agents but not the different immunosup-pression regimens.5
The diagnosis of rejection is difficult, since rejection is frequently associated with a small rise in creatinine and could be confounded due to hyperfiltration-related decreases in creatinine levels during pregnancy. It is safe to do ultrasonograph-guided allograft biopsy during pregnancy to diagnose rejection.6 Moreover, the use of high-dose steroids has been successful in treating allograft rejection during pregnancy, and these remain a first-line treatment. Data regarding the use of other agents like antithymocyte globulin and rituximab for treatment of acute rejection in pregnancy are limited, and there are no specific recommendations.7
The timing of dialysis remains the most important approach and the aim of treatment of pregnant patients in chronic hemodialysis. Direct consequences of hemodialysis in pregnant women may be a severe reduction of amniotic fluid due to impairment of liquid removal and hypertension or hypotension during dialysis, which may cause ischemic fetal-maternal damage.3
Pregnancy in renal transplant recipients is high risk and should be managed by a multidisciplinary team of high-risk obstetricians, neonatologists, and transplant nephrologists.4 Vaginal delivery is the preferred route of delivery, and cesarean section is indicated only for obstetric indications.6 Here, we present a pregnant kidney transplant patient who had developed resistant T-cell-mediated acute rejection and who had a successful outcome of her pregnancy. She was given daily hemodialysis despite treatment with pulse steroids, intravenous immu-noglobulin (IVIG), and thymoglobulin.
A 28-year-old woman from Kuwait with end-stage kidney disease secondary to lupus nephropathy underwent living unrelated renal transplant in May 2013 after hemodialysis support for 1 year. The procedure proceeded without complication. She received thymoglobulin as induction therapy, and she was maintained on prednisolone, mycophenolate mofetil (MMF), and tacrolimus. In addition, methylprednisolone (1000 mg) was administered intraoperatively before reperfusion of the allograft, with a taper to prednisone 20 mg/day at discharge. Both tacrolimus and MMF (1000 mg twice daily) were started on the day of transplant. Pregnancy risks associated with MMF were discussed with the patient before beginning therapy. She had normal renal graft function (serum creatinine of about 74 μmol/L) without proteinuria.
Despite counseling efforts on the importance of having a planned pregnancy after kidney transplant so that medications could be optimized, the patient became pregnant 2 years after transplant (February 2015). Therefore, she was switched from MMF to azathioprine 150 mg/day immediately on discovery of pregnancy to reduce the risk of fetal deformities or death. Both prednisone and tacrolimus were continued. In July 2015, the patient presented with elevated serum creatinine levels (365 mmol/L) and a subtherapeutic tacrolimus trough level of 4 ng/mL. Her abdominal ultrasonography showed mild hydronephrosis of the graft and a viable fetus.
The patient received empirical pulse steroids for possible rejection with partial response, and she was admitted to the hospital for graft biopsy. The next day, graft pathology revealed acute T-cell-mediated rejection 1B and negative C4d. The patient met with the gynecologist who discussed the risks and possible complications of receiving potent antire-jection medications and the possible alternative of return to hemodialysis if treatment was either unsuccessful or denied. Topics discussed with the patient included the increased risk of severe preeclampsia, preterm delivery, potential infectious complications, worsening of kidney function, fetal abnormalities, and miscarriage. She was informed that the necessary treatment for rejection had limited safety and efficacy data regarding use during pregnancy. Specifically, due to the lack of infor-mation, unknown risks of rabbit antithymocyte globulin (rATG) therapy were discussed, including the potential for abnormal development of the fetus’s thymus, prolonged or permanent impairment of T-cell immunity, and long-term consequences of bone marrow suppression for both the patient and her child.
The patient decided to pursue resolution of her rejection episode and continue the pregnancy despite the potential risks to the fetus. The patient received IVIG and also minipulse steroids (250 mg methylprednisolone); however, she did not respond to either. After gynecologic counseling and informed consent (from her and the husband), she received 5 doses of thymoglobulin (1 mg/kg/d) without any report of intolerance to either rATG or IVIG over the course of her admission. Before antirejection therapy, the patient’s white blood cell count and platelet count were 7.3 × 103/mm3 (normal range, 4.0-11.0 × 103/mm3) and 140 × 103/mm3 (normal range, 150-450 × 103/mm3), respectively. After com-pletion of the antirejection course and before discharge, her white blood cell count and platelet count were 9.2 × 103/mm3 and 88 × 103/mm3, respectively. After she finished the antirejection therapy, her fetal ultrasonography scan showedno fetal defects and a normal fetal heart rate of 155 beats/min. On discharge, the patient was maintained on azathioprine 150 mg/day, tacrolimus 7 mg twice/day (trough level of 10.2 ng/mL), and pred-nisone 30 mg/day.
Her graft did not improve, and she received daily hemodialysis support for 2 months until the date of labor. The patient was induced into labor at 32 weeks of gestation due to intrauterine growth restriction. She had a vaginal delivery that occurred without complications and gave birth to a healthy baby boy. His Apgar score was 8/9 at 1/5 minutes, respectively, indicating good health. The baby weighed 2.1 kg, had spontaneous respiration, and had no notable abnormalities.
After birth, her home immunosuppression regimen consisted of prednisone 5 mg/day, azathioprine 150 mg/day, and tacrolimus 8 mg twice/day (trough level of 10 ng/mL). More than 6 months after delivery, both mother and child have not demonstrated any infectious complications.
Due to advancements in transplant surgery and immunosuppressive regimens over the past 50 years, pregnancy in solid-organ transplant recipients has become safer and more feasible despite numerous risks to the mother. These potential risks include rejection, gestational diabetes mellitus, and pre-eclampsia. Risk to the fetus include birth defects, preterm delivery, and low birth weight.8
Risks that occur with pregnancy in solid-organ transplant recipients can be managed through intensive, multidisciplinary prenatal care and a proper immunosuppressive regimen. Little data are available to suggest safe and effective treatments for acute rejection episodes in pregnant solid-organ transplant recipients. The preferred maintenance immunosuppressive regimen in pregnancy consists of corticosteroids, azathioprine, and cyclosporine or tacrolimus, as they are categorized as category C by the US Food and Drug Administration. Azathioprine results in less fetal abnormalities because the developing embryo may lack the enzyme required to metabolize azathioprine to its active metabolite, 6-mercaptopurine.9
Despite early transplant counseling about preg-nancy, our patient had unplanned pregnancy while she was on MMF, which was switched to azathioprine at the time of verification of pregnancy. Mycophenolate mofetil is known to carry a higher risk of first-trimester pregnancy loss, anomalies of distal limbs, and congenital malformations. Therefore, health care providers are strongly encouraged to ensure that females of childbearing potential are not pregnant throughout their course of therapy with MMF.10 Fortunately, her baby did not show any anomalies at birth.
Optimization of the maintenance immunosup-pression regimen in pregnant transplant recipients is vital to prevent allograft rejection. Despite optimized maintenance immunosuppression in our patient, she developed acute rejection during the second trimester. The risk of rejection is 2% to 4% among pregnant renal transplant recipients receiving calcineurin inhibitor-based immunosuppression.12 In addition, patients with suboptimal renal function, defined as serum creatinine of > 1.5 mg/dL, are at an increased risk of experiencing rejection.11 Fortunately, our patient had stable graft function.
Although data are available to help guide maintenance immunosuppression regimens in preg-nant solid-organ transplant recipients, data on management of acute episodes of rejection in this population are still lacking.9
In our patient, high-dose corticosteroids, IVIG, and rATG were used to treat T-cell-mediated rejection 1b with no satisfactory response. Therefore, she was maintained on daily hemodialysis for 2 months until delivery. Corticosteroids, IVIG, and rATG are designated by the US Food and Drug Administration as category C. Despite no animal studies on the use of IVIG, multiple reports have shown it to be successful in pregnant women for indications other than solid-organ transplant without maternal or fetal adverse effects.12
There have been some reports of orofacial malformations linked to corticosteroid use in preg-nancy, but the use of corticosteroids is generally considered acceptable.13 We did not observe such complications in our patient, possibly because of its late use during pregnancy.
The patient and her husband were counseled, all risks were explained, and consent was obtained before the patient was given thymoglobulin. We did not observe any hematologic adverse effects or infection related to its use. Aitchison and associates reported the only case series regarding the use of antilymphocytic globulin (ALG) during patient pregnancy, with ALG administered in 3 cases.14 In 2 of these 3 cases, ALG was given after termination of pregnancy. In the third case, a 21-year-old patient presented with aplastic anemia at 15 weeks of gestation and received ALG at 23 weeks of gestation. A baby boy was vaginally delivered at 36 weeks, weighing 1.7 kg. Three months after ALG therapy and 1 week after the patient gave birth, the patient died of pneumonia without evidence of recovery of her aplasia. At this time, no reports have been found describing the use of rATG in human pregnancy. In one study, anti-CD8 and anti-CD4 therapy demonstrated reduced placental proliferation in murine pregnancy.15
Although the pathophysiology of polyhydramnios has not yet been clarified, it is the most common complication of hemodialysis during pregnancy, leading to a bigger risk of premature delivery. Daily dialysis is recommended for its control and to maintain the ideal value of serum urea nitrogen under 50 mg/dL.16 Direct consequences of hemo-dialysis in pregnant women may be a severe reduction of amniotic fluid due to impairment of liquid removal and hypertension or hypotension during dialysis, which could result in ischemic fetal-maternal damage.3 Our patient did not respond to antirejection therapy, and she was dialysis dependent for nearly 2 months. We were obliged to support her with daily dialysis during such a period without significant ultrafiltration that compromised her hemodynamics. Thus, duration and frequency of hemodialysis treatment are the primary targets and the challenge for having a better outcome. An influence of the fetal osmotic diuresis, caused by the increased concentrations of urea and related sub-stances in the maternal blood, has been proposed.16
Some reports have shown polyhydramnios at week 19 of gestation before start of daily hemodialysis, probably because of insufficient hemodialysis and impaired fetal osmotic diuresis.16 In our case, daily hemodialysis had optimized amniotic fluid with a prolonged gestational period until a higher fetal weight and fetal lung maturity were reached. Most studies have suggested that increasing dialysis time during pregnancy results in a longer gestational period, in a higher number of viable pregnancies, and in a higher birth weight because of the reduction of plasmatic urea, which favors a better maternal diet, better blood pressure levels, and good control of intravascular and extravascular fluid mass.16
Although maternal prognosis is good with multi-disciplinary management, fetal outcomes remain poor; therefore, the aim is to check and correct blood pressure, anemia, and blood coagulation and to check and establish better fetal growth, amniotic fluid levels, and fetal-maternal Doppler velocimetry.17
For solid-organ transplant recipients presenting with acute rejection, empiric high-dose corticosteroids should be considered as the first-line therapy. If the rejection is unresponsive to corticosteroids alone, rATG may be considered. However, a meeting with the patient and her relatives to determine the patient’s wishes and to ensure that the patient understands the potential risks and benefits of treatment is needed. Close monitoring of the patient and the fetus is warranted during therapy until birth. Until further information or safety studies are made available regarding the use of rATG in this population, we hope that our case described here can offer insight to a potential treatment option and outcome for pregnant solid-organ transplant recipients who experience severe rejection episodes.
A successful outcome of pregnancy was shown with close monitoring and daily dialysis in a kidney transplant patient with thymoglobulin-resistant T-cell-mediated rejection. The risks and uncertainties of treating rejection episodes should always be discussed with and understood by the patient before an informed decision is made.
Volume : 17
Issue : 1
Pages : 159 - 163
DOI : 10.6002/ect.MESOT2018.P38
From the 1Hamed Al-Essa Organ Transplant Center, Kuwait; the 2Urology and
Nephrology Center, Mansoura University, Mansoura, Egypt; and the 3Department of
Internal Medicine and Nephrology, Ain Shams University
Acknowledgements: The authors have no sources of funding for this study and have no conflicts of interest to declare.
Corresponding author: Osama A. Gheith, Hamed Al-Essa Organ Transplant Center, Ministry of Health, Ibn Sina Hospital, Kuwait
Phone: +96 566641967