A Multi-Institutional Report of Intermediate-Term Kidney Outcomes in Uterus Transplant Recipients

Uterus transplant (UTx) is a treatment for uterine factor infertility (UFI). Globally, the number of UTx recipients is increasing (1Brannstrom M, Tulius SG, Brucker S et al. Registry of the International Society of Uterus Transplantation: First Report. Transplantation 2022; online ahead of print.Google Scholar, 2Johannesson L. Testa G. Putman J.M. et al.Twelve Live Births After Uterus Transplantation in the Dallas UtErus Transplant Study.Obstet Gynecol. 2021 1; 137: 241-249Crossref PubMed Scopus (33) Google Scholar, 3Vali S. Jones B.P. Saso S. Yazbek J. Quiroga I. Smith J.R. Uterus Transplantation: A 50-Year Journey.Clin Obstet Gynecol. 2022; 65: 92-100Crossref PubMed Scopus (1) Google Scholar). Many recipients have Mayer-Rokitansky-Kuster-Hauser syndrome (MRKH); MRKH may include unilateral kidney agenesis in addition to a congenitally absent uterus and vaginal aplasia (4Chen N. Pan H. Luo G. et al.Clinical characteristics of 1,055 Chinese patients with Mayer-Rokitansky-Kuster-Hauser syndrome: a nationwide multicentric study.Fertil Steril. 2021; 116: 558-565Abstract Full Text Full Text PDF PubMed Scopus (15) Google Scholar). Thus, kidney dysfunction is a potential complication of UTx. We have previously demonstrated that UTx recipients experience a decrease in estimated GFR (eGFR) early posttransplant (5Sawinski D. Johannesson L. Kristek J. et al.A multi-institutional study of renal outcomes and renal-related pregnancy outcomes in uterus transplant recipients.Am J Transplant. 2022 Jul 13; (online ahead of print)https://doi.org/10.1111/ajt.17149Abstract Full Text Full Text PDF Scopus (0) Google Scholar), that persists into the early postpartum period. We have also demonstrated that the incidence of acute kidney injury (AKI) and pre-eclampsia (28%) are increased (5Sawinski D. Johannesson L. Kristek J. et al.A multi-institutional study of renal outcomes and renal-related pregnancy outcomes in uterus transplant recipients.Am J Transplant. 2022 Jul 13; (online ahead of print)https://doi.org/10.1111/ajt.17149Abstract Full Text Full Text PDF Scopus (0) Google Scholar). However, UTx is a unique transplant paradigm - after childbearing is complete, a graft hysterectomy is performed and immunosuppression is discontinued. The cumulative effect of pregnancy, AKI episodes, pre-eclampsia, and temporary calcineurin inhibitor (CNI) exposure on longer-term kidney function remains undefined.We undertook this study in a cohort representing most of the United States UTx population and selected participants from Europe to elucidate intermediate-term kidney outcomes among UTx recipients. Twenty-two women who received UTx from 9/2016-2/2020 across four institutions were included (Table 1; Supplementary Methods/References; Supplemental Table 1). All have had at least one successful pregnancy; five have delivered two children. At last follow-up, 20 have had a hysterectomy and discontinued immunosuppression; two recipients have retained their uteri for an additional pregnancy. Most had MRKH as etiology of UFI (95.5%) and only one had radiological evidence of a solitary kidney. Mean pretransplant serum creatinine in the cohort overall was 0.76mg/dL (±0.08mg/dL) and the mean pretransplant eGFR was 106.5ml/min/1.73m2 (±11.4ml/min/1.73m2). Median follow up since UTx was 3.01 years (IQR 2.23-3.43 years) and the median exposure to immunosuppression was 2 years (IQR 1.2-3.1 years). Mean eGFR at last follow up (92.1ml/min/1.73m2± 18.4 ml/min/1.73m2) was significantly lower than the pretransplant eGFR (pre eGFR 106.4 ml/min/1.73m2 ±11.8ml/min/1.73m2, p= 0.001) (Supplemental Figure 1).Table 1Demographics of the uterus transplant recipients included in this cohort.UTx recipientsN=22Mean age at transplant in years (±SD)31 (±4.9)RaceBlackMiddle EasternWhite1 (4.5%)1 (4.5%)20 (90.9%)Etiology of Uterine factor infertilityMRKHHysterectomy21 (95.5%)1 (4.5%)Solitary kidney1 (4.5%)Transplant typeLivingDeceased14 (63.6%)8 (36.4%)Mean pretransplant creatinine, mg/dL (±SD)0.76 (±0.08)Mean pretransplant eGFR, ml/min/1.73m2 (±SD)106.5 (±11.4)On immunosuppression at last follow up2 (9.1%)AKI at any time during pregnancy10 (45.5%)Pre-eclampsia5 (22.7%)SD: standard deviation; MRKH: Mayer-Rokitansky-Kuster-Hauser syndrome; eGFR: estimated glomerular filtration rate; AKI: acute kidney injury Open table in a new tab SD: standard deviation; MRKH: Mayer-Rokitansky-Kuster-Hauser syndrome; eGFR: estimated glomerular filtration rate; AKI: acute kidney injury Figure 1a-c depicts eGFR slope. Using linear mixed effect models, we estimated the postpartum eGFR while on immunosuppression was 25.7 ml/min/1.73m2 lower (95%CI 18.7-32.7 ml/min/1.73m2) than pretransplant values. eGFR rebounds after immunosuppression discontinuation by an average 11.6 ml/min/1.73m2 (95%CI 6.1 – 17.1 ml/min/1.73m2); however, eGFR off immunosuppression was still 14.1 ml/min/1.73m2 lower (95%CI 8.5-19.8 ml/min/1.73m2) than pretransplant. Rebound in eGFR was smallest early after immunosuppression discontinuation (rebound of 8.0 ml/min/1.73m2, 95%CI: 1.9-14.1 and 9.9 ml/min/1.73m2, 95%CI 3.7-16.0 at 1 and 3 months after stopping) but increased at later timepoints (15.0 ml/min/1.73m2, 95%CI: 8.8-21.2 at 6 months). The eGFR slope at 12 months postpartum was -10.2 ml/min/1.73m2 lower than the pretransplant eGFR (Figure 1a). We examined factors hypothesized to moderate eGFR change. Participants experiencing AKI during pregnancy (6.3 ml/min/1.73m2 greater decline, 95%CI: -4.8 to 17.3 ml/min/1.73m2) and pre-eclampsia (7.3 ml/min/1.73m2 greater decline, 95% CI: -5.4-20.0 ml/min/1.73m2) had greater declines in eGFR from baseline but differences were not statistically significant. The effect of immunosuppression duration was small (0.1 ml/min/1.73m2 difference in eGFR per 100 days of additional immunosuppression, 95%CI: -1.1-1.4 ml/min/1.73m2). For every 10ml/min/m2 decline in eGFR from pre-UTx to embryo transfer, we observed an estimated 5.2ml/min/m2 (95% CI 3.4-7.0 ml/min/m2) greater decline in postpartum eGFR slope. We demonstrate that during a median of 3-years follow up, UTx recipients are at risk for ongoing kidney dysfunction, manifested as a persistent reduction in eGFR of 10.2ml/min/1.73m2, despite hysterectomy and immunosuppression withdrawal. We observed a trend towards lower eGFR among UTx recipients who experienced AKI or pre-eclampsia during pregnancy. This study, with more participants and longer follow up, extends our previous observations (5Sawinski D. Johannesson L. Kristek J. et al.A multi-institutional study of renal outcomes and renal-related pregnancy outcomes in uterus transplant recipients.Am J Transplant. 2022 Jul 13; (online ahead of print)https://doi.org/10.1111/ajt.17149Abstract Full Text Full Text PDF Scopus (0) Google Scholar) of a numerically lower eGFR in the postpartum period. We demonstrate a significant difference in both pretransplant versus 12 months postpartum eGFR and in estimates of eGFR slope. This has important implications for the long-term health of UTx recipients. An annual decline in eGFR of -3ml/min/1.73m2/year confers a 31% increase in all-cause mortality (6Turin T.C. Coresh J. Tonelli M. et al.Change in the estimated glomerular filtration rate over time and risk of all-cause mortality.Kidney Int. 2013; 83: 684-691Abstract Full Text Full Text PDF PubMed Scopus (98) Google Scholar,7Rifkin D.E. Shlipak M.G. Katz R. Fried L.F. Siscovick D. Chonchol M. et al.Rapid kidney function decline and mortality risk in older adults.Arch Intern Med. 2008; 168: 2212-2218Crossref PubMed Scopus (289) Google Scholar). The rate of eGFR decline we observed exceeds typical eGFR loss rates of -0.3-1ml/min/1.73m2/1.73m2/year expected in individuals without significant comorbidities or proteinuria (8Kidney Disease: Improving Global Outcomes CKD Work GroupKDIGO 2012 clinical practice guideline for the evaluation and management of chronic kidney disease.Kidney Int. Suppl. 2003; 3: 1-150Google Scholar). Immunosuppression discontinuation did not completely restore kidney function, despite UTx recipients being healthy, rigorously pre-screened for systemic illnesses and having normal pretransplant kidney function (in contrast to other solid organ transplant recipients who often have comorbidities including pre-existing kidney disease). UTx recipients are young women with normal life expectancies; therefore, an early loss of kidney function is particularly concerning. Chronic kidney disease (CKD), where stage I is defined as an eGFR ≤90ml/min/1.73m2, has negative implications for overall health, increasing the risk of mortality, cardiovascular disease, AKI, and end-stage kidney disease (8Kidney Disease: Improving Global Outcomes CKD Work GroupKDIGO 2012 clinical practice guideline for the evaluation and management of chronic kidney disease.Kidney Int. Suppl. 2003; 3: 1-150Google Scholar). UTx is not a life-saving procedure and the risks must be weighed against the benefits. Longer follow up of UTx recipients is needed to determine if their eGFR slope stabilizes over several years or if GFR decline continues. In the general population, pre-eclampsia and AKI episodes have been associated with an increased risk of future CKD (9, S8). We also observed a trend towards lower eGFR slope among UTx recipients who experienced AKI or pre-eclampsia in our cohort. This observation is useful when counseling UTx recipients considering a second pregnancy, as AKI or pre-eclampsia during a first pregnancy could increase their future CKD risk. Our findings highlight the need for mitigation strategies. Effective options to prevent pre-eclampsia are limited. All UTx recipients are maintained on low-dose aspirin, the standard intervention in the general population (S9). AKI episodes during pregnancy are infrequent but more common among those with pre-existing CKD or transplants (S10); fluctuations and inaccuracies in whole blood CNI measurements during pregnancy may contribute to this risk among transplant recipients (S11). While the effect of immunosuppression duration on eGFR among UTx recipients was minimal, efforts to reduce CNI exposure, such as reducing the time interval between transplant and embryo transfer and withdrawing immunosuppression immediately after hysterectomy, are warranted. Dedicated studies to determine the ideal CNI trough levels among UTx recipients and optimize CNI dosing during pregnancy would be beneficial. CNIs have well-described nephrotoxicity. Alternatives, such as belatacept, exist but have not been extensively studied in pregnancy (S12) and there are theoretical concerns regarding fetal toxicity (S13). Our study highlights the need for prospective study of targeted interventions, such as CNI-free immunosuppressive regimens, that could mitigate some of the deleterious effects of UTx on kidney function. Our study has notable strengths. Our cohort represents a large, multi-center and international group of UTx recipients with serial kidney function measurements. We used linear mixed effects models to examine trends in eGFR. Linear mixed effects models naturally handle missing data and are enhanced by multiple observations across different timepoints. We were able to account for the impact of AKI and pre-eclampsia. There are limitations to our work: a lack of consistent proteinuria assessments, variation in candidate evaluation and follow up, and center-level variation in immunosuppression protocols. Compared to typical studies of eGFR slope trajectory, the overall size of our cohort is small; however, this should bias our findings towards the null. UTx is an established treatment for UFI and moving into general clinical care; however, kidney risks persist beyond the period in which recipients are on immunosuppression. Reduction in eGFR has negative implications for long-term health outcomes. It will be important to clarify the contribution of MRKH versus aspects of the transplant procedure or immunosuppression. Further study is required to delineate these risks and provided optimal informed consent to UTx candidates. The authors have no relevant financial conflicts of interest to disclose. 9Kristensen J.H. Basit S. Wohlfahrt J. Damholt M.B. Boyd H.A. Pre-eclampsia and risk of later kidney disease: nationwide cohort study.BMJ. 2019; 365: I1516Crossref PubMed Scopus (0) Google Scholar. Download .pdf (.17 MB) Help with pdf files