Clinical performance of the iPREDICTLIVING tool for the prediction of the post-transplant recipient and living donor outcomes in a European cohort.

A living donor kidney transplant (LDKT) is the best treatment for ESRD. A prediction tool based on clinical and demographic data available pre-KT was developed in a Norwegian cohort with three different models to predict graft loss, recipient death, and donor candidate's risk of death, the iPREDICTLIVING tool. No external validations are yet available. We sought to evaluate its predictive performance in our cohort of 352 pairs LKDT submitted to KT from 1998 to 2019. The model for censored graft failure (CGF) showed the worse discriminative performance with Harrell's C of .665 and a time-dependent AUC of .566, with a calibration slope of .998. For recipient death, at 10 years, the model had a Harrell's C of .776, a time-dependent AUC of .773, and a calibration slope of 1.003. The models for donor death were reasonably discriminative, although with a poor calibration, particularly for 20 years of death, with a Harrell's C of .712 and AUC of .694 with a calibration slope of .955. These models have moderate discriminative and calibration performance in our population. The tool was validated in this Northern Portuguese cohort, Caucasian, with a low incidence of diabetes and other comorbidities. It can improve the informed decision-making process at the living donor consultation joining clinical and other relevant information.

Renal Artery Stenosis in Living Donor Kidney Transplantation: A Rare Cause of "Flash Edema".

Transplant renal artery stenosis (TRAS) is a well-recognized vascular complication after kidney transplantation, with an incidence ranging from 1% to 23%. TRAS often presents with clinical features such as refractory hypertension, de novo hypertension, allograft dysfunction, and the presence of a bruit over the graft. A rare manifestation of TRAS is flash pulmonary edema. Here, we present a case of a 37-year-old male who received a living donor kidney. Four years after the transplant, he presented with acute kidney injury, hypertensive crisis, and flash pulmonary edema. Initially, methylprednisolone pulses were administered due to suspicion of acute rejection, which was later ruled out after a kidney graft biopsy. Computed tomography angiography showed findings suggesting stenosis or thrombus in the renal artery. The patient developed sudden acute pulmonary edema, requiring hemodialysis, with notable clinical improvement. Subsequently, stent placement was performed without complications, resulting in the complete recovery of renal function and effective blood pressure control. The incidence of renal artery stenosis is higher in living donor kidney transplantation, mainly due to technical complexities during surgery. Acute presentations, such as flash edema, are exceptionally rare but can occur years after transplantation. Prompt intervention can lead to favorable outcomes.

Living Donors' Age Modifies the Impact of Pre-Donation Estimated Glomerular Filtration Rate on Graft Survival.

BACKGROUND: The global scarcity of organs for kidney transplants (KTs) has led to the increased acceptance of living donors (LDs) with minor abnormalities to increase the donor pool.. We sought to evaluate the effects of some of these LDs' clinical characteristics (older age, borderline renal function, hypertension, dyslipidemia, smoking, and obesity) on graft outcomes. METHODS: We studied 352 recipients of LDKTs (1998-2020). Firstly, considering the recipients and KT variables, we identified relevant predictors of overall and censored graft failure (GF). Then, adjusting for these predictors, we explored LD variables as predictors of overall and censored GF in a multivariable Cox model. RESULTS: The recipients from LD with higher eGFR (≥90 mL/min/1.73 m2) had significantly better overall and censored graft survival GS) at 15 y after KT (respectively, 67 and 75% vs. 46 and 46%, p < 0.001). Importantly, none of the remaining LD factors which were evaluated (hypertension, dyslipidemia, smoking, proteinuria, and obesity) were independent predictors of GF. In recipients from LDs < 50 y, having an eGFR < 90 was an independent predictor of overall GF [adjusted HR (95%CI) of 2.578 (1.120-5.795)] and censored GF [adjusted HR (95%CI) of 3.216 (1.300-7.959)], compared to recipients from LDs with eGFR ≥ 90. Contrarily, when donors were older, no difference in the risk of GF was observed between eGFR categories. CONCLUSION: In our cohort, lower pre-donation eGFR had an impact on GS only in younger LDs. An age-adjusted eGFR cutoff may be pursued for improved donor admissibility.

Excess Mortality in Kidney and Kidney-Pancreas Transplant Recipients in the COVID-19 Pandemic in Portugal-A Cohort Study.

The COVID-19 pandemic increased morbidity and mortality worldwide, particularly in the Kidney and Kidney-Pancreas Transplant Recipient (KTR/KPTR) population. Aiming at assessing the absolute and relative excess mortality (EM) in a Portuguese KTR/KPTR cohort, we conducted a retrospective observational study of two KTR/KPTRs cohorts: cohort 1 (P1; n = 2,179) between September/2012 and March/2020; cohort 2 (P2; n = 2067) between March/2020, and August/2022. A correlation between relative and absolute EM and age, sex, time from transplantation and cause of death was explored. A total of 145 and 84 deaths by all causes were observed in P1 and P2, respectively. The absolute EM in P2 versus P1 was 19.2 deaths (observed/expected mortality ratio 1.30, p = 0.006), and the relative EM was 1.47/1,000 person-months (95% CI 1.11-1.93, p = 0.006). Compared to the same period in the general population, the standardized mortality rate by age in P2 was 3.86 (95% CI 2.40-5.31), with a peak at 9.00 (95% CI 4.84-13.16) in P2C. The higher EM identified in this population was associated, mainly, with COVID-19 infection, with much higher values during the second seasonal COVID-19 peak when compared to the general population, despite generalized vaccination. These highlight the need for further preventive measures and improved therapies in these patients.

An Unexpected Catastrophe-Renal Artery Thrombosis in a Living Donor: A Case Report.

BACKGROUND: Renal artery thrombosis is a devastating complication if not detected early. Cardioembolic disease or surgical and technical complications are frequent causes of renal artery thrombosis. There are some reports of renal artery thrombosis in a renal allograft, but to our knowledge, this is the first case of renal artery thrombosis reported in a kidney donor.

Pregnancy After Kidney Donation: The Experience in a Cohort of Portuguese Living Donors.

BACKGROUND: Living kidney donation (LKD) is a preferred treatment option for end-stage chronic kidney disease, but it can also pose potential risks for the donor, including hypertension and end-stage renal disease. Many donors are women of reproductive age who may have concerns about the effects of donation on future pregnancies. The aim of this study was to determine fetal and maternal outcomes in a cohort of pregnancies after LKD and to compare them with pregnancies before LKD. METHODS: We conducted a retrospective analysis of living kidney donors of childbearing age (<46 years old) at the time of donation who got pregnant after LKD in our center between 1987 and 2020 (N = 13). Clinical data were collected, including demographic characteristics and maternal and fetal outcomes. RESULTS: We observed 16 pregnancies after LKD and 12 pregnancies before LKD in the same group of patients. The rate of gestational hypertension was 12.5% in pregnancies after LKD and 8.3% before LKD (P = .999). There were 13 successful pregnancies after LKD with a mean gestational age of 38.6 ± 1.7 weeks. There were no episodes of acute kidney injury or other complications. CONCLUSION: The present study suggests that LKD does not have a negative effect on maternal and fetal outcomes. However, caution should be taken due to the small sample size. We agree with the guidelines recommending close monitoring of post-donation pregnancies.

Is Erythrocytosis More Common After Simultaneous Pancreas Kidney Transplantation? A Single-Center Experience.

Post-transplant erythrocytosis (PTE) is reported in 8% to 22% of kidney transplant recipients. Few studies have evaluated the prevalence of PTE in simultaneous kidney-pancreas transplantation (SPKT). This study aimed to evaluate the prevalence of PTE in a cohort of SPKT and same-donor single kidney transplant patients and find predictive factors for erythrocytosis development. A single-center retrospective cohort study was performed with 65 SPKT recipients and 65 same-donor single kidney transplant patients. Post-transplant erythrocytosis was defined as a hematocrit persistently >51% without a known cause of erythrocytosis. The PTE prevalence was 23.1% and was more frequent in SPKT patients than in single donor patients (38.5% vs 7.7%; P < .001). The mean time for PTE development was 11.2 ± 13.3 months. In the multivariate model, SPKT was the only predictor for PTE development. De novo hypertension was more frequent in the PTE group (P = .002), but there was no difference in stroke and pancreatic or kidney thrombosis occurrence. Post-transplant erythrocytosis is more common after SPKT than after single kidney transplantation. De novo hypertension was more frequent in the erythrocytosis group, but allograft thrombosis rates.

Association of the Calcification Score of the Abdominal Aorta, Common Iliac, and Renal Arteries with Outcomes in Living Kidney Donors.

BACKGROUND: Vascular calcification is an ever-more-common finding in protocoled pre-transplant imaging in living kidney donors. We intended to explore whether a connection could be found between the Agatston calcification score, prior to kidney donation, and post-donation renal function. METHODS: This is a retrospective analysis of 156 living kidney donors who underwent living donor nephrectomy between January 2010 and December 2016. We quantified the total calcification score (TCaScore) by calculating the Agatston score for each vessel, abdominal aorta, common iliac, and renal arteries. Donors were placed into two different groups based on their TCaScore: <100 TCaScore group and ≥100 TCaScore group. The relationship between TCaScore, 1-year eGFR, proteinuria, and risk of 1 measurement of decreased renal function (eGFR < 60 mL/min/1.73 m2) over 5 years of follow-up was investigated. RESULTS: The ≥100 TCaScore group consisted of 29 (19%) donors, with a median (interquartile range) calcification score of 164 (117-358). This group was significantly older, 56.7 ± 6.9 vs. 45.5 ± 10.6 (p < 0.001), had a higher average BMI (p < 0.019), and had a lower preoperative eGFR (p < 0.014). The 1-year eGFR was similarly diminished, 69.9 ± 15.7 vs. 76.3 ± 15.5 (p < 0.048), while also having an increased risk of decreased renal function during the follow-up, 22% vs. 48% (p < 0.007). CONCLUSIONS: Our study, through univariate analyses, found a relationship between a TCaScore > 100, lower 1-year eGFR, and decreased renal function in 5 years. However, a higher-than-expected vascular calcification should not be an excluding factor in donors, although they may require closer monitoring during follow-up.

Impact of Donor Age on Long-Term Outcomes in Simultaneous Pancreas-Kidney Transplantation.

BACKGROUND: Simultaneous pancreas-kidney transplantation (SPKT) is the treatment of choice for type 1 diabetes patients with end-stage renal disease. Donor characteristics are determinants of graft and patient survival. We aimed to study the impact of donor age on outcomes in SPKT. METHODS: We retrospectively studied 254 patients submitted to SPKT between 2000 and 2021. Patients were classified as "younger donor" (donor age <40 years) and "older donor" (donor age ≥40 years). RESULTS: Fifty-three patients received grafts from older donors. Pancreas graft survival rates at 1, 5, 10, and 15 years were 89%, 83%, 77%, and 73% in the younger donor group, respectively, and 77%, 73%, 67%, and 62% in the older donor group, respectively (P = .052). Older donors and previous major adverse cardiovascular events (MACEs) were associated with pancreas graft failure at 15 years. Kidney transplant survival (1, 5, 10, and 15 years) was lower in the older donor cohort (94%, 92%, 69%, 60% vs 97%, 94%, 89%, and 84%, respectively; P = .004). Older donor, recipient age, and previous MACE predicted kidney graft failure at 15 years. Patient survival rates at 1, 5, 10, and 15 years were 98%, 95%, 91%, and 81% in the younger donor group, respectively, versus 92%, 90%, 84%, and 72% in the older donor group, respectively (P = .127). CONCLUSIONS: The kidney graft survival rate was lower in the older donor group, whereas pancreas graft survival and patient survival did not differ significantly. Multivariate analysis showed that a donor age of ≥40 years was an independent predictor of pancreas and kidney graft failure at 15 years in SPKT patients.

External Validation of the Toulouse-Rangueil Predictive Model to Estimate Donor Renal Function After Living Donor Nephrectomy.

A predictive model to estimate post-donation glomerular filtration rate (eGFR) and risk of CKD at 1-year was developed from a Toulouse-Rangueil cohort in 2017 and showed an excellent correlation to the observed 1-year post-donation eGFR. We retrospectively analyzed all living donor kidney transplants performed at a single center from 1998 to 2020. Observed eGFR using CKD-EPI formula at 1-year post-donation was compared to the predicted eGFR using the formula eGFR (CKD-EPI, mL/min/1.73 m2) = 31.71+ (0.521 × preoperative eGFR) - (0.314 × age). 333 donors were evaluated. A good correlation (Pearson r = 0.67; p < 0.001) and concordance (Bland-Altman plot with 95% limits of agreement -21.41-26.47 mL/min/1.73 m2; p < 0.001) between predicted and observed 1-year post-donation eGFR were observed. The area under the ROC curve showed a good discriminative ability of the formula in predicting observed CKD at 1-year post-donation (AUC = 0.83; 95% CI: 0.78-0.88; p < 0.001) with optimal cutoff corresponding to a predicted eGFR of 65.25 mL/min/1.73 m2 in which the sensibility and specificity to predict CKD were respectively 77% and 75%. The model was successfully validated in our cohort, a different European population. It represents a simple and accurate tool to assist in evaluating potential donors.

CT volumetry performs better than nuclear renography in predicting estimated renal function one year after living donation.

The evaluation of split renal function (SRF) is a critical issue in living kidney donations and can be evaluated using nuclear renography (NR) or computerized tomography (CT), with unclear comparative advantages. We conducted this retrospective study in 193 donors to examine the correlation of SRF assessed by NR and CT volumetry and compared their ability to predict remaining donor renal function at 1 year, through multiple approaches. A weak correlation between imaging techniques for evaluating the percentage of the remaining kidney volume was found in the global cohort, with an R2 = 0.15. However, the Bland-Altman plot showed an acceptable agreement (95% of the difference between techniques falling within - 8.51 to 6.11%). The predicted and observed eGFR one year after donation were calculated using the CKD-EPI, and CG/BSA equations. CT volume showed a better correlation than NR for both formulas (adjusted R2 of 0.42. and 0.61 vs 0.37 and 0.61 for CKD-EPI and CG/ BSA equations, respectively). In non-nested modeling tests, CT volumetry was significantly superior to NR for both equations. CT volumetry performed better than NR in predicting the estimated renal function of living donors at 1-year, independently from the eGFR equation.

Antibody-Mediated Rejection in Kidney Transplantation: A Retrospective Study on the Impact of Donor-Specific Antibodies and on the Timing of Diagnosis.

Introduction Limited information exists concerning the clinical significance of histologically confirmed antibody-mediated rejection (h-AMR) without detectable circulating donor-specific antibodies (DSA). In this study, we compared the outcomes of patients with h-AMR according to DSA status. Methods A total of 80 kidney transplant (KT) recipients who met the 2018 Banff criteria for h-AMR were included. Clinical and immunological characteristics were evaluated, and outcomes were compared according to DSA status after kidney biopsy (KB). Results There were 57 patients who had DSA-positive (+) h-AMR and 23 patients who had DSA-negative (-) h-AMR. Groups had similar baseline characteristics and time between KT and KB. Concerning histopathological diagnoses/Banff scores, DSA+ patients had higher interstitial fibrosis (ci) and tubular atrophy (ct) (ci+ct) scores and lower arterial hyalinosis (ah) scores compared to DSA- patients. Graft survival (GS) was similar for both groups (64% versus 44% at five years and 44% versus 34% at 10 years). Multivariate analysis revealed the time of KB (less than six months after KT or more than six months after KT) to be associated with GS. A stratified analysis was conducted, targeting DSA status according to the time of biopsy. For KB performed less than six months after KT, GS was higher for DSA+ patients at 10 years (66% versus 23%). For KB performed more than six months after KT, DSA- patients had higher GS at 10 years (58% versus 9%). Conclusion Both the timing of AMR diagnosis and DSA status had an impact on AMR outcomes. For patients diagnosed with AMR more than six months after transplantation, GS was worst for those in which circulating DSA were identified. Biopsy specimens from DSA- specimens had higher ct-ci and ah scores.

Biologically Unrelated Living Donor for Kidney Transplantation Associated With Higher Acute Rejection Rate but With Similar Graft Survival of a Related Living Donor.

INTRODUCTION: Kidney transplantation (KT) from living donors has been shown to have multiple benefits compared to those from deceased donors. We sought to compare significant graft outcomes, namely acute rejection (AR), graft function, and survival between transplant recipients who received a kidney from living related donor (LRD) and living unrelated donor (LURD). METHODS: Our cohort comprised 198 donor and recipient pairs undergoing living-donor KT at our center over 10 years. The LRD recipients were compared with LURD recipients according to demographic and clinical characteristics, transplant variables (including immunosuppression), graft function, survival, and AR rate. RESULTS: The estimated glomerular filtration rate (eGFR) was similar in both groups over the follow-up time i.e., 60-65 mL/min (p>0.05 over 10 years). Censored graft survival was similar between LRD and LURD recipients (96.9% vs. 98.0% at five years and 87.8% vs. 79.4% at 10 years, respectively; p=0.837). The LURD recipients had a higher incidence of AR, although LURD recipient status was not an independent risk factor for AR. Multivariate analysis showed that human leukocyte antigen (HLA)-DR mismatch (MM) was an independent predictor of AR (hazard ratio (HR) 2.256, p<0.05). Both HLA-A and HLA-B MM did not affect the AR HR between the groups. CONCLUSION:  Graft function and censored graft survival rates were similar between LURD and LRD KT recipients in our study. The AR was higher in LURD recipients, although the LURD recipient status was not an independent risk factor for AR. The HLA-DR MM was an independent predictor of AR, while HLA-A and HLA-B MM did not affect AR HR between groups of patients.

Why Donors Do Not Donate: A Living Donation Program Experience.

BACKGROUND: A living donor (LD) kidney transplant is the best therapeutic option for end-stage kidney disease. Potential donors must undergo multiple analyses and the rates of live donation can be as low as 8% to 18%. Here, we report on the live kidney donor program in our unit with emphasis on the reasons why potential donors do not proceed to donation. METHODS: We performed a single-center retrospective study of all potential kidney donors with a first LD appointment at Centro Hospitalar Universitário do Porto between January 2016 and December 2020. RESULTS: In our cohort there were 395 potential donors. From the potential donors who finished assessment, 131 were approved for donation and 239 dropped out. After assessment, 104 (28.1%) recipients received a living kidney transplant, 24 of which received a living kidney transplant through the kidney paired exchange program. The individuals who did not proceed to the surgery (n = 239) had a median age of 46.5 years, 64.4% were female, and 34 pairs were ABO-incompatible. The most frequent donor-recipient relationships were spouses, siblings and parents. The 2 most important causes of dropout were due to medical, surgical or psychological contraindications and the donor's voluntary withdrawal. When we evaluated the variables most related to dropout, they were not because of being a spouse and ABO incompatibility. CONCLUSIONS: When compared to other studies, we showed a relatively higher rate of successful live donations, possibly aided by the presence of cross-over transplantation. Targeted education and support at an earlier stage of the donor assessment process may lead to a better engagement and lower probability of early dropout.

Eplet-based virtual PRA increases transplant probability in highly-sensitized patients.

BACKGROUND: The reduced access of highly-sensitized (HS) patients to kidney transplantation (KTx) is one of the major challenges for transplant community. Therefore, the aim of our study was to estimate the impact of three different vPRA calculations, assessed traditionally and using eplet-based analysis, in donor offers. METHODS: At 01-01-2020, 157 HS patients are waitlisted for deceased donor KTx and were included in this study. Total vPRA (vPRAt) was calculated considering all patient allosensitization history, using 1 k MFI cut-off. Current vPRA (vPRAc) refers only to the last year SAB assays, using 1 k MFI cut-off. For eplet vPRA (vPRAe) every SAB assay was analyzed by HLAMatchmaker and HLAfusion software. Matching runs have been performed taking vPRA calculation as unacceptable antigens (UAs). RESULTS: All patients had at least one previous sensitizing event and patients with 100% vPRA were predominantly candidates for retransplantation (P < 0.001), had higher PRA-CDC (P < 0.001), and longer dialysis vintage waiting time (P < 0.001). Inter-group movement analysis between vPRA measures showed that 70 (45%), 124 (79%) and 80 (51%) patients were reclassified to a lower group when considering vPRAt to vPRAc, vPRAt to vPRAe and vPRAc to vPRAe, respectively. The median percentage of change in estimated number of match runs needed for 95% probability of finding an acceptable donor was significantly more pronounced by increasing vPRAt intervals, when considering the reclassification from vPRAt to vPRAe (P < 0.001) or vPRAc to vPRAe (P = 0.045), while from vPRAt to vPRAc it was not (P = 0.899). CONCLUSIONS: Our study demonstrated that the use of total or current vPRA calculations are impairing HS patients, by decreasing transplant probability, leading to dramatically longer waiting times, when compared to eplet based vPRA.

SARS-CoV-2 infection in kidney transplant recipients: Early report of five cases.

From December 2019 to March 2020, China was the epicenter of the SARS-CoV-2 infection pandemic, but from that moment on, Europe surpassed China in the number of new cases and deaths related to this novel viral respiratory infection. The emergence of this world pandemic is particularly important for solid organ transplant recipients, who might have an increased risk of mortality, not only due to their chronic immunosuppression status, but also to the cardiovascular risk that correlates with several years of chronic kidney disease. To the extent that there is still a lack of knowledge about the clinical characteristics, evolution, and prognosis of SARS-CoV-2 infection in kidney transplant recipients, we will report the first 5 cases diagnosed and followed in our transplant unit, as well as share the therapeutic strategies adopted.

HLA class II eplet mismatch load improves prediction of dnDSA development after living donor kidney transplantation.

HLA donor-specific antibodies developed de novo after transplant remain a major cause of chronic allograft dysfunction. Our study main purpose was to determine whether HLA MM, assessed traditionally and by HLA total and AbVer eplet mismatch load (EptMM and EpvMM) assessed with HLAMatchMaker, had impact on dnDSA development after living donor kidney transplantation (LDKT). We retrospectively analysed a cohort of 96 LDKT between 2008 and 2017 performed in Hospital Santo António. Seven patients developed dnDSA-II and EpvMM and EptMM were greater in dnDSA-II group compared to the no dnDSA-II (18.0 ± 8.7 versus 9.9 ± 7.9, p = .041 and 41.3 ± 18.9 versus 23.1 ± 16.7, p = .018), which is not observed for AgMM (2.29 versus 1.56; p = .09). In a multivariate analysis, we found that preformed DSA (HR = 7.983; p = .023), living unrelated donors (HR = 8.052; p = .024) and retransplantation (HR = 14.393; p = .009) were predictors for dnDSA-II (AUC = 0.801; 0.622-0.981). HLA-II EpvMM (HR = 1.105; p = .028; AUC = 0.856) showed to be a superior predictor of dnDSA-II, when compared to AgMM (HR = 1.740; p = .113; AUC = 0.783), when adjusted for these clinical variables. Graft survival was significantly lower within dnDSA-II patient group (36% versus 88%, p < .001). HLA molecular mismatch analysis is extremely important to minimize risk for HLA-II dnDSA development improving outcome and increasing chance of retransplant lowering allosensitization.

Lower donated kidney volume is associated with increased risk of lower graft function and acute rejection at 1 year after living donor kidney-a retrospective study.

Kidney volume has been proven to be a surrogate marker of nephron mass and renal function. We studied 190 donor and recipient pairs undergoing living donor kidney transplantation at our institution during 9 years. Different metrics of donor kidney volume (DKV) were explored: alone or indexed to recipient's anthropometry, as body surface area (BSA). DKV/BSA (min. 49.7; P33rd 77.7; P67th 95.3; max. 176 cm3 /m2 ) was chosen given its higher correlation with eGFR at 1 year, and recipients were divided according to its tertiles (T). The eGFR at 1 year was lower in T1, when compared with T2 (P = 0.015) and T3 (P < 0.001). In a multivariable model, a regression spline revealed that a DKV/BSA lower than 80 was significantly associated with an eGFR at 1 year <60. In the first 6 years, the overall annual eGFR slope was -0.90 ml/min/year. Acute rejection occurred in 19%, 11%, and 0% of patients in T1, T2, and T3, respectively (P < 0.001). DKV/BSA increased stepwise from cellular- (n = 12) to antibody-mediated (n = 7) AR cases and to those without AR (n = 171; P = 0.002; no AR versus cellular AR). Lower DKV/BSA ratio was associated with significantly worse graft function and higher incidence of AR. Hence, it can be a tool for better selection of donors in order to improve graft outcomes, particularly in the setting of multiple potential living donors or kidney paired exchange programs.

4-Nitro-benzyl 3,4-bis-(acet-yloxy)-2-(4-meth-oxy-phen-yl)pyrrolidine-1-carboxyl-ate: crystal structure, Hirshfeld surface analysis and computational chemistry.

The title compound, C23H24N2O9, is a tetra-substituted pyrrolidine derivative with a twisted conformation, with the twist evident in the C-C bond bearing the adjacent acet-yloxy substituents. These are flanked on one side by a C-bound 4-meth-oxy-phen-yl group and on the other by a methyl-ene group. The almost sp 2-N atom [sum of angles = 357°] bears a 4-nitro-benzyl-oxycarbonyl substituent. In the crystal, ring-methyl-ene-C-H⋯O(acet-yloxy-carbon-yl) and methyl-ene-C-H⋯O(carbon-yl) inter-actions lead to supra-molecular layers lying parallel to (01); the layers stack without directional inter-actions between them. The analysis of the calculated Hirshfeld surfaces indicates the combined importance of H⋯H (42.3%), H⋯O/O⋯H (37.3%) and H⋯C/C⋯H (14.9%) surface contacts. Further, the inter-action energies, largely dominated by the dispersive term, point to the stabilizing influence of H⋯H and O⋯O contacts in the inter-layer region.

1-Ethyl 2-methyl 3,4-bis-(acet-yloxy)pyrrolidine-1,2-di-carboxyl-ate: crystal structure, Hirshfeld surface analysis and computational chemistry.

The title compound, C13H19NO8, is based on a tetra-substituted pyrrolidine ring, which has a twisted conformation about the central C-C bond; the Cm-Ca-Ca-Cme torsion angle is 38.26 (15)° [m = methyl-carboxyl-ate, a = acet-yloxy and me = methyl-ene]. While the N-bound ethyl-carboxyl-ate group occupies an equatorial position, the remaining substituents occupy axial positions. In the crystal, supra-molecular double-layers are formed by weak methyl- and methyl-ene-C-H⋯O(carbon-yl) inter-actions involving all four carbonyl-O atoms. The two-dimensional arrays stack along the c axis without directional inter-actions between them. The Hirshfeld surface is dominated by H⋯H (55.7%) and H⋯C/C⋯H (37.0%) contacts; H⋯H contacts are noted in the inter-double-layer region. The inter-action energy calculations point to the importance of the dispersion energy term in the stabilization of the crystal.