Successful Maternal and Fetal Outcome in a Kidney Transplant Patient with Everolimus Exposure Throughout Pregnancy: A Case Report

Pregnancy after kidney transplantation is becoming more common as more patients of childbearing age are undergoing successful transplantation. There is limited evidence on the safety and efficacy of mammalian target of rapamycin inhibitors during pregnancy, which are considered Category C. We will review the use of this class of medications in pregnancy, which is currently contraindicated due to risk of fetal complications. We will also present the case of a successful pregnancy and renal outcome in a 33-year-old kidney transplant recipient who was administered everolimus throughout pregnancy.     

Renal function preservation with the mTOR inhibitor,Everolimus, after lung transplant

Chronic kidney disease (CKD) is a common complication of calcineurin inhibitors (CNIs) in solid organ transplantation. Previous data suggest that the use of everolimus as an immunosuppressant drug leads to improvement in renal function. The aim of our study was to establish the effect of everolimus in combination with lower doses of CNIs on renal function among lung transplant recipients. Data regarding renal function and pulmonary function were collected from 41 lung transplanted patients in whom treatment was converted to a combination of everolimus with lower doses of CNIs. Patients transferred to everolimus and low dose CNIs showed an improvement in renal function. Patients who continued treatment with everolimus showed improvement in renal function, as opposed to patients who discontinued the treatment. Subjects without proteinuria at baseline showed a better improvement compared with subjects with proteinuria. The incidence of graft rejection did not increase. We concluded that a protocol that includes everolimus and lower doses of CNIs is effective for preserving renal function in lung transplant recipients with CKD. We also believe that an early implementation of everolimus, before proteinuria occurs or creatinine clearance is reduced, could lead to better outcomes.     

Conversion to Everolimus in Kidney Transplant Recipients With Calcineurin Inhibitor-Induced Nephropathy: 3 Case Reports

BackgroundCalcineurin inhibitors (CNIs), which remain the most important immunosuppressants in kidney transplant recipients, are a major cause of renal dysfunction due to CNI-induced nephropathy. However, a safe and effective CNI-sparing protocol is yet to be established. Herein, we report a case series of kidney transplant recipients experiencing CNI nephropathy, whose renal function is improved after conversion from CNIs to everolimus.CasesThe 3 kidney transplant recipients included in this study were diagnosed with CNI arteriolopathy by episode biopsy between 9 months and 11 years after transplantation. All patients received triple immunosuppressive therapy consisting of CNI (tacrolimus or cyclosporine), mycophenolate mofetil, and methylprednisolone. All allografts were transplanted from elderly living donors to ABO-compatible and donor-specific antibody-negative recipients. All allograft biopsy specimens exhibited CNI arteriolopathy with alternative quantitative criteria for hyaline arteriolar thickening (aah score: 2 or 3), according to the Banff classification; however, histopathologic assessment did not show any evidence of allograft rejection. Conversely, total dose and blood concentrations of CNIs were within appropriate ranges. After conversion from CNIs to everolimus (1.5 mg/day, twice daily; trough level, 3–5 ng/mL), serum creatinine levels returned to baseline levels measured before the diagnosis of CNI arteriolopathy. In all patients, renal allograft function remained stable, with no evidence of donor-specific antibodies, 1 year after conversion from CNIs to everolimus.ConclusionConversion from CNIs to everolimus can safely and effectively improve renal function in kidney transplant recipients experiencing CNI-induced nephropathy.     

Pregnancy in women receiving renal dialysis or transplantation in Japan: a nationwide survey.

BACKGROUND: Since a report on the first successful pregnancy of a woman on long-term haemodialysis in Japan in 1977, there has been a growing number of case reports on successful pregnancy in patients on dialysis. We undertook a nationwide survey on pregnancy in women on renal replacement therapy in 1996. METHODS: A preliminary questionaire was sent to 2504 dialysis units and 143 renal transplant units in Japan. For each reported pregnancy, a more detailed questionaire was sent to collect nephrological, obstetric and neonatal information. RESULTS: There were 172 pregnancies (0.44%) reported in 38889 women on dialysis, with 90 successful pregnancies (0.23%), and 194 pregnancies reported in 852 female renal transplant recipients. Detailed pregnancy information was collected from 74 women on dialysis and 194 renal transplant recipients. Of the 74 pregnancies in the women on dialysis, 36 (48.6%) resulted in surviving infants, nine (12.2%) in neonatal death, nine (12.2%) spontaneous abortions and 14 (18.9% elective abortions were reported. The outcome of six pregnancies (8.1%) was unknown. Of 194 pregnancies in renal transplant recipients, 159 (82.0%) resulted in surviving infants, two (1.4%) in neonatal death and 28 (14.4%) in spontaneous or elective abortion. In five cases the pregnancy outcome was not reported. No congenital anomalies were reported, except two infants with mental retardation and one with epilepsy. CONCLUSION: The current survey revealed that the rate of successful pregnancy in women on dialysis has improved. More than half of the pregnancies resulted in infant survival. But, premature birth is a major problem for the children of women on dialysis and there is a higher rate of neonatal death. There are significant differences in gestational age, birth weight, frequency and severity of prematurity and rates of neonatal death between pregnancies of women undergoing dialysis and those who are renal transplant recipients.     

Fertility following solid organ transplantation

Fertility is usually restored in women after solid organ transplantation, and successful pregnancies have been reported in female recipients of kidney, liver, heart, pancreas-liver, and lung transplants. However, women with solid organ allografts have higher incidence of pregnancy complications like hypertension, preeclampsia, preterm delivery. Hypertension appears to be dependent on the type of immunosuppressive agents. The influence of pregnancy on the risk of rejection is poorly known on the basis of available data. Rejection rate appears to be at least similar to the nonpregnant population. In some cases, such as in liver transplant pregnant women, even higher as compared to the nonpregnant population. Maintaining appropriate blood levels of immunosuppressive drugs is currently recommended. Malformation rate in the offsprings of transplanted women appears to not be increased; long-term follow- up of children born to allograft recipients is necessary to investigate possible developmental, immunological, or oncological disorders. We followed 70 pregnancies after kidney transplantation and nine after liver transplantation. All recipients were maintained on immunosuppressive therapy during pregnancy, except one mother who refused immunosuppression and experienced transplant rejection. Hypertension was the most frequent complication during pregnancy: in 23% of kidney transplantated mothers and in one out of nine liver transplant recipients. The only malformation observed in the newborns was the dislocation of the hip in the child of a kidney transplant recipient.     

Everolimus (Certican) in renal transplantation: a review of clinical trial data,current usage,and future directions

The efficacy and tolerability of everolimus have been demonstrated in a number of clinical trials, and there is also an increasing body of clinical experience. The efficacy of everolimus after renal transplantation is at least equivalent to that of mycophenolate mofetil. Studies combining everolimus with full- or reduced-dose cyclosporine (CsA) have shown that CsA exposure can be minimized, without increasing the risk of acute rejection, particularly when combined with therapeutic drug monitoring. A role for everolimus in regimens involving elimination of calcineurin inhibitors is currently being investigated. Everolimus with significantly reduced-dose CsA has not been shown to enhance CsA-related nephrotoxicity. Adverse events seen in trials of everolimus are generally class-specific and include edema, arthralgia, dyslipidemia, impaired wound healing, and proteinuria. A low incidence of malignancy has been observed with everolimus, and studies are ongoing to examine its antitumor effects in the treatment of certain malignancies. It seems likely that everolimus will continue to play a role in the development of reduced-exposure calcineurin inhibitor regimens and has considerable potential to improve outcomes for transplant recipients, focused perhaps on “old-for-old” transplant recipients and patients at high risk of poor graft function or malignancy. This review considers the available data on the clinical application of everolimus and identifies current and future strategies for improving outcomes after renal transplantation.     

Pregnancy and kidney transplantation

Despite decades of experience with child bearing in women with kidney transplants, these pregnancies remain high risk with an increased prevalence of hypertension and pre-eclampsia. Infertility, common in women with end-stage renal disease, is rapidly restored after transplant although pregnancy rates appear lower in transplant recipients than the general public. Many unanswered questions exist, some old questions such as what is the optimal timing of pregnancy after transplant, whether breast feeding is safe, the long-term impact if any on the offspring, and whether pregnancy negatively affects the kidney graft; and some new questions such as whether to modify immunosuppression in a patient taking a mycophenolic acid-containing drug, whether kidney donation has a deleterious impact on future pregnancies, whether to use erythropoietin-stimulating agents, and the role of BK virus. Counseling about contraception and pregnancy after transplant should be initiated during the pretransplant evaluation process. It is important because of the rapid restoration of fertility that occurs after transplant as well as the many risks and unanswered questions that remain.     

Pregnancy After Liver Transplantation

The first known posttransplantation pregnancy was in 1958 in a renal transplant recipient who had received a kidney from her identical twin sister. The first known posttransplantation pregnancy in a liver transplant recipient was in 1978. Information available from female kidney transplant recipients helped in the decision making involved in the management of this case, as well as those that followed. Over the last 20 years, issues specific to liver transplantation and pregnancy have been identified. Similar to the kidney transplant recipient population, when prepregnancy recipient graft function is stable and adequate, pregnancy appears to be well tolerated. Also similar to kidney transplant recipients, there has been no evidence of a specific malformation pattern among the children, and although prematurity and low birth weight occur, overall newborn outcomes have been favorable. Pregnancy in the setting of recurrent liver disease, such as recurrent hepatitis C, poses a potential problem among liver transplant recipients, as well as the possible adverse effects of immunosuppression on maternal kidney function. Also of significance, peripartum graft deterioration has more severe consequences in this transplant recipient population. Therefore, pregnancy must be considered carefully in this transplant recipient group. Since 1991, the National Transplantation Pregnancy Registry (NTPR) has studied the safety of pregnancy outcomes in solid-organ transplant recipients. The purpose of this review is to catalog studies in the literature, as well as to present current data from the registry with management guidelines. (Liver Transpl 2000;6:671-685.)     

Case Report of COVID-19 Infection After Kidney Transplant Treated With Casirivimab-Imdevimab and Mycophenolate Mofetil Changed to Everolimus

BackgroundCasirivimab-imdevimab is a cocktail of 2 monoclonal antibodies designed to prevent infection by SARS-CoV-2, the virus that causes COVID-19. Casirivimab-imdevimab has been approved in Japan for treating mild to moderate COVID-19; however, to our knowledge, there are no reports of its use after kidney transplant from a live donor. Everolimus, an antineoplastic chemotherapy drug, is expected to be effective in inhibiting the spread of SARS-CoV-2 and preventing its replication, which may facilitate treatment. Here, we report a case of COVID-19 infection after kidney transplant that was initially treated with casirivimab-imdevimab and mycophenolate mofetil but was later changed to everolimus.Case ReportA 47-year-old man underwent living donor kidney transplant from his mother in 2017. Immunosuppression therapy was underway through the administration of tacrolimus, mycophenolate mofetil, and methylprednisolone. In early September 2021, he was diagnosed as having COVID-19 and was hospitalized on day 3. On hospitalization, mycophenolate mofetil was discontinued and casirivimab-imdevimab and heparin were started. The patient started an everolimus regimen on day 5. The clinical course was successful without rejection. There was no exacerbation of COVID-19; the patient's serum creatinine levels and renal function had otherwise remained stable.ConclusionsWe could safely treat a patient with casirivimab-imdevimab after kidney transplant. It is suggested that casirivimab-imdevimab can prevent COVID-19 from becoming severe and can be administered without worsening renal function. In addition, everolimus may have inhibited the spread of the virus and prevented it from replicating.     

Pregnancy after organ transplantation: a report from the UK Transplant pregnancy registry

BACKGROUND: Maternal and fetal complications in pregnancies after renal transplantation have been highlighted in several reports, but information on their main predisposing factors is limited. The U.K. Transplant Pregnancy Registry was established in 1997 to obtain detailed information on pregnancies in female organ transplant recipients across the U.K. METHODS: For each female kidney, liver, or cardiothoracic organ transplant recipient who had had a recent pregnancy, data on maternal and fetal factors and pregnancy outcomes were collected using forms completed by their transplant follow-up and obstetric units. For kidney transplant recipients, the factors that influence pregnancy outcome were studied using logistic regression, and the effect of pregnancy on graft function was analyzed. RESULTS: There were live births in 83%, 69%, and 79% of pregnancies in cardiothoracic organ, liver, and kidney recipients, respectively. In 50% of live births from renal patients, delivery was preterm (<37 weeks), with 83% of the preterm infants delivered via caesarean. Preterm delivery was associated with maternal drug-treated hypertension and impaired renal function. A matched case-control study showed no evidence of increased renal allograft loss after pregnancy. A univariate survival analysis, however, suggested an association between drug-treated hypertension during pregnancy and poorer postpregnancy graft survival. In patients with prepregnancy serum creatinine (SCr) >150 micromol/L, a trend toward increased postpregnancy SCr was identified. CONCLUSIONS: Pregnancy is likely to end in a live birth in a majority of organ transplant recipients. In patients with greater prepregnancy SCr and/or drug-treated hypertension during pregnancy, however, subsequent renal function may be adversely affected.     

Treatment of Mixed Dyslipidemia With Alirocumab in a Kidney Transplant Recipient: A Case Report

Dyslipidemia is common in kidney transplant recipients owing to the disturbance of lipid metabolism caused by chronic kidney disease and the effect of immunosuppression on lipid metabolism. Patients receiving treatment with mammalian target of rapamycin inhibitors show more prominent lipid disorders, which are attributed mainly, but not only, to adipocyte lipid uptake disruption, lipolysis promotion and lipogenic gene expression enhancement. Dyslipidemias in kidney transplant recipients predispose these patients to an increased risk of developing cardiovascular disease; thus, current guidelines recommend treatment initiation with a statin, regardless of low-density lipoprotein cholesterol (LDL-C) concentration, with ezetimibe as a secondary option for patients who do not tolerate such therapy or for those with inadequate response. Treatment with pro-protein convertase subtilisin/kexin type 9 inhibitors such as alirocumab, although effectively reducing LDL-C in patients with chronic kidney disease, has not been evaluated in kidney transplant recipients. In this case report, we present a case of a female kidney transplant recipient who developed substantial dyslipidemia after everolimus initiation. This case was resistant to treatment with simvastatin/ezetimibe combination, and the patient subsequently received alirocumab. Our patient showed a mean reduction of 46.6% in LDL-C during an 18-month period after alirocumab initiation, which is comparable to the results of studies on patients with or without renal impairment. Furthermore, treatment with alirocumab proved to be well tolerated without adverse effects or interactions with the immunosuppression regimen.     

Conversion of Stable Kidney Transplant Recipients From a Twice-Daily to Once-Daily Everolimus Regimen

Once-daily everolimus administration is a further option to improve compliance to immunosuppressive therapy. We randomized 23 stable kidney transplant recipients already on everolimus therapy to receive a single daily morning dose or to continue the twice-daily regimen. The everolimus levels evaluated after 2 weeks showed a slight reduction from 5.13 ± 1.61 ng/mL at baseline to 4.76 ± 1.61 ng/mL, which was not statistically significant. After 2 weeks we also evaluated cyclosporine (CsA) levels together with renal function parameters, neither of which showed episodes, any difference between the converted versus twice-daily groups. We did not record any adverse event, such as an infection, an acute rejection episode, or graft loss, over the 6-month study period. Single dosing of everolimus is possible and safe and may achieve better patient compliance to multiple-drug immunosuppressive therapy.     

Successful pregnancy in renal transplant recipient with previous known polyomavirus nephropathy

Pregnancy after renal transplantation has become increasingly common. Studies in non-immunocompromised patients have shown that pregnant women have increased susceptibility to infection or reactivation of latent virus such as BK virus. To what extent a renal transplant recipient is at risk for reactivation of polyoma virus during pregnancy remains unknown. We hereby report successful pregnancy outcome in a renal transplant recipient with a known history of BK virus nephropathy treated with cidofovir i.v. To our knowledge, this is the first published experience with a successful pregnancy in renal transplant recipients with known history of polyomavirus-associated nephropathy.     

What is the impact of immunosuppressive treatment on the post-transplant renal osteopathy?

Although glucocorticoid therapy is considered to be the main pathogenic factor, a consistent body of evidence suggests that other immunosuppressants might also play an important role in the development of the post-transplant renal osteopathy (PRO) through their pleiotropic pharmacological effects. Glucocorticoids seem to induce osteoclasts’ activity suppressing the osteoblasts while data regarding other immunosuppressive drugs are still controversial. Mycophenolate mofetil and azathioprine appear to be neutral regarding the bone metabolism. However, the study analyzing any independent effect of antimetabolites on bone turnover has not been conducted yet. Calcineurin inhibitors (CNIs) induce trabecular bone loss in rodent, with contradictory results in renal transplant recipients. Suppression of vitamin D receptor is probably the underlying mechanism of renal calcium wasting in renal transplant recipients receiving CNI. In spite of an increased 1,25(OH)2 vitamin D level, the kidney is not able to reserve calcium, suggesting a role of vitamin D resistance that may be related to bone loss. More efforts should be invested to determine the role of CNI in PRO. In particular, data regarding the role of mammalian target of rapamycin inhibitors (mTORi), such as sirolimus and everolimus, in the PRO development are still controversial. Rapamycin markedly decreases bone longitudinal growth as well as callus formation in experimental models, but also lowers the rate of bone resorption markers and glomerular filtration in clinical studies. Everolimus potently inhibits primary mouse and human osteoclast activity as well as the osteoclast differentiation. It also prevents the ovariectomy-induced loss of cancellous bone by 60 %, an effect predominantly associated with a decreased osteoclast-mediated bone resorption, resulting in a partial preservation of the cancellous bone. At present, there is no clinical study analyzing the effect of everolimus on bone turnover in renal transplant recipients or comparing sirolimus versus everolimus impact on bone, so only general conclusions could be drawn. Hence, the use of mTORi might be useful in patients with PRO due to their possible potential to inhibit osteoclast activity which might lead to a decreased rate of bone resorption. In addition, it should be also emphasized that they might inhibit osteoblast activity which may lead to a decreased bone formation and adynamic bone disease. Further studies are urgently needed to solve these important clinical dilemmas.     

Everolimus immunosuppression in de novo heart transplant recipients: What does the evidence tell us now?

The efficacy of everolimus with reduced cyclosporine in de novo heart transplant patients has been demonstrated convincingly in randomized studies. Moreover, everolimus-based immunosuppression in de novo heart transplant recipients has been shown in two randomized trials to reduce the increase in maximal intimal thickness based on intravascular ultrasound, indicating attenuation of cardiac allograft vasculopathy (CAV). Randomized trials of everolimus in de novo heart transplantation have also consistently shown reduced cytomegalovirus infection versus antimetabolite therapy. In maintenance heart transplantation, conversion from calcineurin inhibitors to everolimus has demonstrated a sustained improvement in renal function. In de novo patients, a renal benefit may only be achieved if there is an adequate reduction in exposure to calcineurin inhibitor therapy. Delayed introduction of everolimus may be appropriate in patients at high risk of wound healing complications, e.g. diabetic patients or patients with ventricular assist device. The current evidence base suggests that the most convincing reasons for use of everolimus from the time of heart transplantation are to slow the progression of CAV and to lower the risk of cytomegalovirus infection. A regimen of everolimus with reduced-exposure calcineurin inhibitor and steroids in de novo heart transplant patients represents a welcome addition to the therapeutic armamentarium.     

Glomerular filtration rate in normal and abnormal pregnancies

During normal pregnancy, an early, marked, and sustained increase occurs in glomerular filtration rate (GFR) secondary to renal vasodilation. An optimal increase in GFR is a good predictor of pregnancy outcome. The pregnant rat provides an excellent model of the gestational renal hemodynamic response, and invasive studies in this species have extended our understanding of the glomerular hemodynamic mechanisms involved. Of note, the chronic renal vasodilation of pregnancy is not associated with glomerular hypertension, and pregnancy has no long-term injurious effects when kidney function is normal. The renal vasodilatory response to pregnancy is robust and persists in a range of mild renal diseases and in renal transplant recipients. When maternal renal function is moderately or severely compromised, however, the renal responses during pregnancy are often attenuated, and pregnancy may also accelerate the course of the renal disease. Studies in the rat have indicated a wide range of possible renal hemodynamic responses to pregnancy in rats with underlying kidney damage, which seem to be disease specific. Irrespective of the renal vascular response to pregnancy, there is no evidence to date suggesting that pregnancy leads to glomerular hypertension.     

An overview of the efficacy and safety of everolimus in adult solid organ transplant recipients

As the risk of graft loss due to acute rejection has declined, the goal of post-transplant management has switched to long-term preservation of organ function. Minimizing calcineurin inhibitor (CNI)-related nephrotoxicity is a key component of this objective. Everolimus is a mammalian target of rapamycin inhibitor/proliferation-signal inhibitor with potent immunosuppressive and anti-proliferative effects. It has been widely investigated in large randomized clinical studies that have shown it to have similar anti-rejection efficacy compared with standard-of-care regimens across organ transplant indications. With demonstrated potential to facilitate the reduction of CNI therapy and preserve renal function, everolimus is an alternative to the current standard-of-care CNI-based regimens used in de novo and maintenance solid organ transplantation recipients.Here, we provide an overview of the evidence from the everolimus clinical study program across kidney, liver, heart, and lung transplants, as well as other key data associated with its use in CNI reduction strategies in adult transplant recipients.     

Renal Function Outcomes in Kidney Transplant Recipients After Conversion to Everolimus-Based Immunosuppression Regimen with CNI Reduction or Elimination

Background

Chronic allograft nephropathy (CAN) is a major cause of progressive renal failure in kidney transplant recipients. Its etiology is multifactorial and can be due to immunologic or nonimmunologic conditions including calcineurin inhibitor (CNI) toxicity.

Objective

To evaluate the effect of conversion from CNIs to everolimus in kidney transplant recipients with CAN.

Patients and Methods

In this 12-month pilot study in renal transplant recipients with biopsy-proved CAN, therapy was changed to an everolimus-based immunosuppression regimen. Cyclosporine or tacrolimus dosage was reduced by 80% (group 1, n = 10) or discontinued (group 2, n = 10). Mycophenolate mofetil or azathioprine were withdrawn in group 1, whereas both agents were maintained in group 2. All patients received prednisone.

Results

Twenty renal allograft recipients switched to an everolimus-based regimen, and patients were followed up for a mean (SD) of 12 (0.1) months. Baseline and end-of-study data were as follows: serum creatinine concentration, 1.27 (0.35) mg/dL vs 1.24 (0.4) mg/dL in group 1, and 1.27 mg/dL (0.36) vs 1.25 (0.3) mg/dL in group 2 (difference not significant); and estimated glomerular filtration rate, 72.4 (19.86) mL/min vs 76.26 (22.69) mL/min in group 1 (not significant), and 66.2 (12.95) mL/min vs 66.2 (13.73) mL/min in group 2 (not significant). One patient in group 1 experienced an acute rejection episode (Banff grade Ib), and 2 patients in group 1 and 1 patient in group 2 demonstrated borderline changes, all associated with everolimus blood concentration less than 3 ng/mL.

Conclusions

Reduction or withdrawal of CNI and introduction of everolimus may be useful to slow the rate of loss of renal function in patients with CAN.     

Conversion from a calcineurin inhibitor-based immunosuppressive regimen to everolimus in renal transplant recipients: effect on renal function and proteinuria

New immunosuppressive agents are being actively researched to avoid complications of chronic allograft nephropathy (CAN), calcineurin inhibitor (CNI) nephrotoxicity, and posttransplantation cancer. The family of mTOR inhibitors offers a unique immunosuppressive opportunity to avoid CNI toxicity and reduce the incidence of malignancy. Nevertheless, increasing data have demonstrated that sirolimus (SRL), the first mTOR introduced in the treatment of solid organ transplant recipients, induces proteinuria, an adverse event that could produce deterioration of long-term renal function. In this short-term study of patients followed for 1 to 16 months, we examined changes in renal function and proteinuria among renal transplant recipients converted from a CNI-based regimen to an everolimus (EVL)-based one, a recently introduced mTOR inhibitor. Our data showed that renal function can be optimized after conversion to EVL by up to 42% in recipients showing CAN grade 1 or 2, or CNI nephrotoxicity. Importantly, patients who improved their creatinine clearance did not show increased proteinuria measured in a voided specimen as the ratio of urinary protein and creatinine concentration (P/C). These results, if confirmed with long-term follow-up and a larger number of patients, would allow us to consider EVL as a promising agent for maintenance immunosuppressive regimens in kidney transplantation.