Diagnostic and Prognostic Potential of Multiparametric Renal MRI in Kidney Transplant Patients.

BACKGROUND: Multiparametric MRI provides assessment of functional and structural parameters in kidney allografts. It offers a non-invasive alternative to the current reference standard of kidney biopsy. PURPOSE: To evaluate the diagnostic and prognostic utility of MRI parameters in the assessment of allograft function in the first 3-months post-transplantation. STUDY TYPE: Prospective. SUBJECTS: 32 transplant recipients (54 ± 17 years, 20 females), divided into two groups according to estimated glomerular filtration rate (eGFR) at 3-months post-transplantation: inferior graft function (IGF; eGFR<45 mL/min/1.73 m2 , n = 10) and superior graft function (SGF; eGFR ≥ 45 mL/min/1.73 m2 , n = 22). Further categorization was based on the need for hemodialysis (C1) and decrease in s-creatinine (C2) at 1-week post-transplantation: delayed-graft-function (DGF: n = 4 C1, n = 10 C2) and early graft-function (EGF: n = 28 C1, n = 22 C2). FIELD STRENGTH/SEQUENCE: 3-T, pseudo-continuous arterial spin labeling, T1-mapping, and diffusion-weighted imaging. ASSESSMENT: Multiparametric MRI was evaluated at 1-week in all patients and 3-months after transplantation in 28 patients. Renal blood flow (RBF), diffusion coefficients (ADC, ΔADC, D, ∆ $$ \Delta $$ D, D*, flowing fraction f), T1 and ∆ $$ \Delta $$ T1 were calculated in cortex and medulla. The diagnostic and prognostic value of these parameters, obtained at 3-months and 1-week post-transplantation, respectively, was evaluated in the cortex to discriminate between DGF and EGF, and between SGF and IGF. STATISTICAL TESTS: Logistic regression, receiver-operating-characteristics, area-under-the-curve (AUC), confidence intervals (CIs), analysis-of-variance, t-test, Wilcoxon-Mann-Whitney test, Fisher's exact test, Pearson's correlation. P-value<0.05 was considered significant. RESULTS: DGF patients exhibited significantly lower cortical RBF and f and higher D*. The diagnostic value of MRI for detecting DGF was excellent (AUC = 100%). Significant differences between patients with IGF and SGF were found in RBF, ∆T1 , and ∆D. Multiparametric MRI showed higher diagnostic (AUC = 95.32%; CI: 88%-100%) and prognostic (AUC = 97.47%, CI: 92%-100%) values for detecting IGF than eGFR (AUC = 89.50%, CI: 79%-100%). DATA CONCLUSION: Multiparametric MRI may show high diagnostic and prognostic value in transplanted patients, yielding better results compared to eGFR measurements. LEVEL OF EVIDENCE: 2 TECHNICAL EFFICACY: Stage 1.

Multiparametric renal magnetic resonance imaging: A reproducibility study in renal allografts with stable function.

Monitoring renal allograft function after transplantation is key for the early detection of allograft impairment, which in turn can contribute to preventing the loss of the allograft. Multiparametric renal MRI (mpMRI) is a promising noninvasive technique to assess and characterize renal physiopathology; however, few studies have employed mpMRI in renal allografts with stable function (maintained function over a long time period). The purposes of the current study were to evaluate the reproducibility of mpMRI in transplant patients and to characterize normal values of the measured parameters, and to estimate the labeling efficiency of Pseudo-Continuous Arterial Spin Labeling (PCASL) in the infrarenal aorta using numerical simulations considering experimental measurements of aortic blood flow profiles. The subjects were 20 transplant patients with stable kidney function, maintained over 1 year. The MRI protocol consisted of PCASL, intravoxel incoherent motion, and T1 inversion recovery. Phase contrast was used to measure aortic blood flow. Renal blood flow (RBF), diffusion coefficient (D), pseudo-diffusion coefficient (D*), flowing fraction ( f ), and T1 maps were calculated and mean values were measured in the cortex and medulla. The labeling efficiency of PCASL was estimated from simulation of Bloch equations. Reproducibility was assessed with the within-subject coefficient of variation, intraclass correlation coefficient, and Bland-Altman analysis. Correlations were evaluated using the Pearson correlation coefficient. The significance level was p less than 0.05. Cortical reproducibility was very good for T1, D, and RBF, moderate for f , and low for D*, while medullary reproducibility was good for T1 and D. Significant correlations in the cortex between RBF and f (r = 0.66), RBF and eGFR (r = 0.64), and D* and eGFR (r = -0.57) were found. Normal values of the measured parameters employing the mpMRI protocol in kidney transplant patients with stable function were characterized and the results showed good reproducibility of the techniques.

Pregnancy in cystinosis patients with chronic kidney disease: A European case series.

Cystinosis is a rare autosomal recessive disease leading to end-stage renal disease within the second or third decade of life. Since the era of specific treatment with cysteamine, prognosis has substantially improved and pregnancy becomes an increasing concern. Pregnancy data in patients with cystinosis were collected through an anonymized survey. We collected data for 19 pregnancies in 12 women. Seventeen patients were transplanted, 1 was on hemodialysis and 1 had chronic kidney disease (CKD) stage 4. These 19 pregnancies resulted in 13 live births (68.4%): 3 spontaneous early miscarriages, 1 ectopic pregnancy, 1 early pre-eclampsia (at 21 weeks), and 1 preterm birth with neonatal death at 24 weeks were reported. After exclusion of early miscarriage or termination, pregnancy success rate was 86.7%. In successful pregnancies, median gestational age at delivery was 34 weeks (24-37). Preeclampsia occurred in seven pregnancies (7/15, 46.7%). A cesarean section was performed in all pregnancies. Median baby weight at delivery was 2175 g (620-3374 g). After pregnancy, one patient reached end-stage renal disease, but she already had advanced CKD before pregnancy (creatinine 239 µmol/L, eGFR 23 ml/min/1.73 m2 ). In three other patients, there was a decrease of eGFR of 8, 20, and 53 ml/min/1.73 m2 , respectively. The majority of pregnancies were successful, but severe antenatal and post-natal complications may occur, in particular preeclampsia that was noticed in nearly half of patients and fetal loss in one-third of them. These results may help pre-pregnancy counseling and pregnancy management.

Paternal safety of the use of mycophenolic acid in kidney transplant recipients. Results of the EMVARON study.

BACKGROUND: The use of mycophenolic acid (MPA) in women during pregnancy causes an increase in miscarriages and birth defects with a typical embryopathy profile. Although epidemiological data does not suggest a greater risk among the offspring of male kidney transplant recipients, the European Medicines Agency and The Spanish Agency of Medicines and Medical Devices introduced the recommendation of using contraceptive methods. METHODS: We conducted a national retrospective study in 15 Spanish Kidney Transplant Centers to evaluate the frequency of miscarriages and birth defects between the offspring from male kidney transplants recipients. We included 151 males who had fathered 239 offspring, 225 under MPA and 14 without MPA. RESULTS: The results of our study showed an incidence of miscarriages in the MPA group of 9.8%, and of birth defects of 4%. CONCLUSIONS: We observed an incidence of miscarriages between the offspring fathered by kidney transplant males under MPA lower than the general population. The incidence of birth defects was similar to the incidence described in other studies and the fact that we did not find the typical embryopathy profile makes it difficult to associate them to the use of MPA. Because of that, we urge the European and Spanish Agencies to reconsider their recommendations for males.

Use of tocilizumab in kidney transplant recipients with COVID-19.

Acute respiratory distress syndrome associated with coronavirus infection is related to a cytokine storm with large interleukin-6 (IL-6) release. The IL-6-receptor blocker tocilizumab may control the aberrant host immune response in patients with coronavirus disease 2019 (COVID-19) . In this pandemic, kidney transplant (KT) recipients are a high-risk population for severe infection and showed poor outcomes. We present a multicenter cohort study of 80 KT patients with severe COVID-19 treated with tocilizumab during hospital admission. High mortality rate was identified (32.5%), related with older age (hazard ratio [HR] 3.12 for those older than 60 years, P = .039). IL-6 and other inflammatory markers, including lactic acid dehydrogenase, ferritin, and D-dimer increased early after tocilizumab administration and their values were higher in nonsurvivors. Instead, C-reactive protein (CRP) levels decreased after tocilizumab, and this decrease positively correlated with survival (mean 12.3 mg/L in survivors vs. 33 mg/L in nonsurvivors). Each mg/L of CRP soon after tocilizumab increased the risk of death by 1% (HR 1.01 [confidence interval 1.004-1.024], P = .003). Although patients who died presented with worse respiratory situation at admission, this was not significantly different at tocilizumab administration and did not have an impact on outcome in the multivariate analysis. Tocilizumab may be effective in controlling cytokine storm in COVID-19 but randomized trials are needed.

Update on posttransplant lymphoproliferative disease.

PURPOSE OF REVIEW: Posttransplant lymphoproliferative disorder (PTLD), frequently associated with Epstein-Barr virus (EBV), is one of the most serious complications leading to worse patient and graft outcomes. Hence, we summarize in this review relevant studies published about PTLD in the last 18 months. RECENT FINDINGS: Recent studies have improved the knowledge about epidemiology, prophylaxis, diagnosis and PTLD treatment. Special interest has developed in improving the last PTLD classification of the World Health Organization, increasing the accuracy of diagnostic tests for EBV viral load quantification and discriminating the genetic differences between PTLD types. There seems to be no real advantage in the use of antiviral drugs for prophylaxis, but better results in therapeutic approaches are being obtained mainly with the use of rituximab with or without chemotherapy, but also with the possibility of using adoptive T-cell therapy or new drugs. SUMMARY: PTLD continues being a complication that requires continued effort of the scientific community to reduce its incidence and to develop better diagnostic tests and new strategies that improve results in prophylaxis and treatment.

Efficacy of the Combination of Immunoadsorption and Rituximab for Treatment in a Case of Severe Focal and Segmental Glomerulosclerosis Recurrence after Renal Transplantation.

BACKGROUND/AIMS: We present a case of a male patient with severe recurrence of focal and segmental glomerulosclerosis (FSGS) after transplant. METHODS: Before the transplant he was treated with plasma exchange. Massive proteinuria was detected post-transplantation and plasma exchanges were performed without response. We administered 5 doses of Rituximab (375 mg/m2) and partial remission was achieved. Proteinuria relapse occurred 1 year post-transplant, so Immunoadsorption (IA) was started instead of plasma exchange with reduction of proteinuria. Later, 2 new episodes of proteinuria relapse were detected and treated by increasing the number of IA sessions and administering new cycles of Rituximab. After achieving partial remission, IA was reduced to one session every 7-10 days as maintenance therapy. RESULTS: Despite the fact of the severe recurrence, renal function and proteinuria remain stable over 8 years after the transplantation was performed. CONCLUSION: Combination of maintenance IA and cycles of Rituximab is an effective treatment for aggressive forms of FSGS recurrence after renal transplantation.

[Biomarkers of oxidative stress and inflammation in contrast-associated acute kidney injury].

BACKGROUND: Iodinated contrast-induced acute kidney injury (CI-AKI) is a common cause of renal failure, especially in patients with risk factors. This study analyses different renal biomarkers in patients undergoing computed tomography scans with iodinated contrast to identify the molecular and cellular mechanisms involved in the pathogenesis of CI-AKI. METHODOLOGY: Prospective study that included patients with high risk of renal disease who received iodinated contrast (iohexol) for the computed tomography scans. Functional biomarkers (creatinine and cystatin C), inflammatory and oxidative stress markers (neutrophil gelatinase-associated lipocalin [NGAL], interleukin-8 [IL-8], superoxide dismutase [SOD], F2-isoprostanes, and cardiotrophin-1), and cell cycle biomarkers (Nephrocheck®) were analysed before the iodinated contrast and 4, 12, 24, and 48 hours post-contrast, in relation to the incidence of IC-AKI. RESULTS: IC-AKI was observed in 30.6% of the 62 study participants and in 57.1% of the patients with diabetes and renal dysfunction. Factors associated with IC-AKI were a higher mean age (74.4 vs 64.9 years), pre-existing renal dysfunction (60 vs 16.7%), and higher adjusted mean volume of iohexol (42.9 vs 32.1%). As for non-functional biomarkers. No differences were found between patients with and without CI-AKI. The use of iodinated contrast was associated with a decrease in SOD antioxidant activity at 4 hours and an increase in IL-8 at 12 hours post-administration of the iodinated contrast. CONCLUSIONS: Administration of iohexol in computed tomography scans in patients with high risk of renal disease results in an elevated percentage of CI-AKI, attributable to ischemia/reperfusion injury and/or direct toxicity of the iodinated contrast.

A deep learning image analysis method for renal perfusion estimation in pseudo-continuous arterial spin labelling MRI.

Accurate segmentation of renal tissues is an essential step for renal perfusion estimation and postoperative assessment of the allograft. Images are usually manually labeled, which is tedious and prone to human error. We present an image analysis method for the automatic estimation of renal perfusion based on perfusion magnetic resonance imaging. Specifically, non-contrasted pseudo-continuous arterial spin labeling (PCASL) images are used for kidney transplant evaluation and perfusion estimation, as a biomarker of the status of the allograft. The proposed method uses machine/deep learning tools for the segmentation and classification of renal cortical and medullary tissues and automates the estimation of perfusion values. Data from 16 transplant patients has been used for the experiments. The automatic analysis of differentiated tissues within the kidney, such as cortex and medulla, is performed by employing the time-intensity-curves of non-contrasted T1-weighted MRI series. Specifically, using the Dice similarity coefficient as a figure of merit, results above 93%, 92% and 82% are obtained for whole kidney, cortex, and medulla, respectively. Besides, estimated cortical and medullary perfusion values are considered to be within the acceptable ranges within clinical practice.

Adenosinergic Pathway and Linked Suppression: Two Critical Suppressive Mechanisms of Human Donor Antigen Specific Regulatory T Cell Lines Expanded Post Transplant.

Regulatory T cells are an important component of an immune response shaping the overall behavior to potential antigens including alloantigens. Multiple mechanisms have been shown to contribute towards developing and sustaining a immunological regulatory response. One of the described contact dependent suppressive mechanisms regulatory cells have been shown to utilize is through the production of adenosine from extracellular ATP mediated by CD39 and CD73. In this study we demonstrate that the adenosinergic pathway plays a major role in the suppressive/regulatory effects antigen specific regulatory T cell enriched lines (ASTRLs) that have been of expanded ex vivo from stable kidney transplant patients. We have previously shown that these ASTRL cells are capable of suppressing alloimmune responses in vitro and significantly prolonging allograft survival in an animal model of kidney transplantation. For this study nineteen ASTRLs were expanded from 17 kidney transplant patients by repeated stimulation of recipient peripheral blood mononuclear cells with donor specific HLA-DR peptides. All 19 ASTRLs showed upregulation of numerous markers associated with regulatory cells and were able to inhibit donor antigen specific T cell proliferation in a dose dependent fashion. ASTRLs suppressed indirect and direct alloimmune responses compatible with our previous animal study findings. Upregulation of both CD39 and CD73 was observed post expansion and ASTRLs demonstrated extracellular hydrolysis of ATP, indicating functionality of the upregulated proteins. We also showed that inhibition of the adenosinergic pathway using inhibitors of CD39 resulted in abrogation of suppression and increased antigen specific T cell proliferation. This demonstrates that the main mechanism of action of the suppressive activity donor peptide driven ASTRLs generated from kidney transplant patients is the adenosinergic pathway. Furthermore this suggests the possibility that combining infusion of Tregs with other treatments, such as adenosine receptor agonists or increasing CD39 expression in the grafts may further enhance a regulatory response to the allograft and possibly achieve transplantation tolerance.

Breakthrough Infections Following mRNA SARS-CoV-2 Vaccination in Kidney Transplant Recipients.

BACKGROUND: The clinical effectiveness of coronavirus disease 2019 (COVID-19) vaccination in kidney transplant (KT) recipients is lower than in the general population. METHODS: From April to October 2021, 481 KT recipients with COVID-19, included in the Spanish Society of Nephrology COVID-19 Registry, were analyzed. Data regarding vaccination status and vaccine type were collected, and outcomes of unvaccinated or partially vaccinated patients (n = 130) were compared with fully vaccinated patients (n = 351). RESULTS: Clinical picture was similar and survival analysis showed no differences between groups: 21.7% of fully vaccinated patients and 20.8% of unvaccinated or partially vaccinated died (P = 0.776). In multivariable analysis, age and pneumonia were independent risk factors for death, whereas vaccination status was not related to mortality. These results remained similar when we excluded patients with partial vaccination, as well as when we analyzed exclusively hospitalized patients. Patients vaccinated with mRNA-1273 (n = 213) showed a significantly lower mortality than those who received the BNT162b2 vaccine (n = 121) (hazard ratio: 0.52; 95% confidence interval, 0.31-0.85; P = 0.010). CONCLUSIONS: COVID-19 severity in KT patients has remained high and has not improved despite receiving 2 doses of the mRNA vaccine. The mRNA-1273 vaccine shows higher clinical effectiveness than BNT162b2 in KT recipients with breakthrough infections. Confirmation of these data will require further research taking into account the new variants and the administration of successive vaccine doses.

Live donor kidney transplantation. Situation analysis and roadmap.

Living donor kidney transplantation (LDKT) is the best treatment option for end stage renal disease in terms of both patient and graft survival. However, figures on LDKT in Spain that had been continuously growing from 2005 to 2014, have experienced a continuous decrease in the last five years. One possible explanation for this decrease is that the significant increase in the number of deceased donors in Spain during the last years, both brain death and controlled circulatory death donors, might have generated the false idea that we have coped with the transplant needs. Moreover, a greater number of deceased donor kidney transplants have caused a heavy workload for the transplant teams. Furthermore, the transplant teams could have moved on to a more conservative approach to the information and assessment of patients and families considering the potential long-term risks for donors in recent papers. However, there is a significant variability in the LDKT rate among transplant centers and regions in Spain independent of their deceased donor rates. This fact and the fact that LDKT is usually a preemptive option for patients with advanced chronic renal failure, as time on dialysis is a negative independent factor for transplant outcomes, lead us to conclude that the decrease in LDKT depends on other factors. Thus, in the kidney transplant annual meeting held at ONT site in 2018, a working group was created to identify other causes for the decrease of LDKT in Spain and its relationship with the different steps of the process. The group was formed by transplant teams, a representative of the transplant group of the Spanish Society of Nephrology (SENTRA), a representative of the Spanish Society of Transplants (SET) and representatives of the Spanish National Transplant Organization (ONT). A self-evaluation survey that contains requests about the phases of the LDKT processes (information, donor work out, informed consent, surgeries, follow-up and human resources) were developed and sent to 33 LDKT teams. All the centers answered the questionnaire. The analysis of the answers has resulted in the creation of a national analysis of strengths, weaknesses, opportunities, threats (SWOT) of the LDKT program in Spain and the development of recommendations targeted to improve every step of the donation process. The work performed, the conclusions and recommendations provided, have been reflected in the following report: Spanish living donor kidney transplant program assessment: recommendations for optimization. This document has also been reviewed by a panel of experts, representatives of the scientific societies (Spanish Society of Urology (AEU), Spanish Society of Nephrology Nursery (SEDEN), Spanish Society of Immunology (SEI/GETH)) and the patient association ALCER. Finally, the report has been submitted to public consultation, reaching ample consensus. In addition, the transplant competent authorities of the different regions in Spainhave adopted the report at institutional level. The work done and the recommendations to optimize LDKT are summarized in the present manuscript, organized by the different phases of the donation process.

Live donor kidney transplantation. Situation analysis and roadmap. / Trasplante renal de donante vivo. Análisis de situación y hoja de ruta.

Living donor kidney transplantation (LDKT) is the best treatment option for end stage renal disease in terms of both patient and graft survival. However, figures on LDKT in Spain that had been continuously growing from 2005 to 2014, have experienced a continuous decrease in the last five years. One possible explanation for this decrease is that the significant increase in the number of deceased donors in Spain during the last years, both brain death and controlled circulatory death donors, might have generated the false idea that we have coped with the transplant needs. Moreover, a greater number of deceased donor kidney transplants have caused a heavy workload for the transplant teams. Furthermore, the transplant teams could have moved on to a more conservative approach to the information and assessment of patients and families considering the potential long-term risks for donors in recent papers. However, there is a significant variability in the LDKT rate among transplant centers and regions in Spain independent of their deceased donor rates. This fact and the fact that LDKT is usually a preemptive option for patients with advanced chronic renal failure, as time on dialysis is a negative independent factor for transplant outcomes, lead us to conclude that the decrease in LDKT depends on other factors. Thus, in the kidney transplant annual meeting held at ONT site in 2018, a working group was created to identify other causes for the decrease of LDKT in Spain and its relationship with the different steps of the process. The group was formed by transplant teams, a representative of the transplant group of the Spanish Society of Nephrology (SENTRA), a representative of the Spanish Society of Transplants (SET) and representatives of the Spanish National Transplant Organization (ONT). A self-evaluation survey that contains requests about the phases of the LDKT processes (information, donor work out, informed consent, surgeries, follow-up and human resources) were developed and sent to 33 LDKT teams. All the centers answered the questionnaire. The analysis of the answers has resulted in the creation of a national analysis of strengths, weaknesses, opportunities, threats (SWOT) of the LDKT program in Spain and the development of recommendations targeted to improve every step of the donation process. The work performed, the conclusions and recommendations provided, have been reflected in the following report: Spanish living donor kidney transplant program assessment: recommendations for optimization. This document has also been reviewed by a panel of experts, representatives of the scientific societies (Spanish Society of Urology (AEU), Spanish Society of Nephrology Nursery (SEDEN), Spanish Society of Immunology (SEI/GETH)) and the patient association ALCER. Finally, the report has been submitted to public consultation, reaching ample consensus. In addition, the transplant competent authorities of the different regions in Spain have adopted the report at institutional level. The work done and the recommendations to optimize LDKT are summarized in the present manuscript, organized by the different phases of the donation process.

Comparison of Intravenous and Oral Hydration in the Prevention of Contrast-Induced Acute Kidney Injury in Low-Risk Patients: A Randomized Trial.

AIMS: Contrast-induced acute kidney injury (CI-AKI) is a common cause of renal failure. We evaluated the effectiveness of oral sodium citrate versus intravenous (IV) sodium bicarbonate for CI-AKI prophylaxis as well as their influence on kidney injury biomarkers. MATERIAL AND METHODS: A randomized, controlled, single-center study including 130 hospitalized patients (62.3% men), who were randomized to receive sodium bicarbonate (1/6 men, 3 ml/kg/h for 1 h; n = 43), oral sodium citrate (75 ml/10 kg divided into 4 doses; n = 43) or nonspecific hydration (n = 44) before contrast administration, was conducted. Serum creatinine and kidney injury biomarkers (cystatin C, neutrophil gelatinase-associated lipocalin, interleukin-8, F2-isoprostanes and cardiotrophin-1 [CT-1]) were assessed. RESULTS: Incidence of CI-AKI was 9.2% with no differences found between hydration groups: 7.0% in sodium bicarbonate group, 11.6% in oral sodium citrate group and 9.1% in the nonspecific hydration group. Urinary creatinine and urinary CT-1/creatinine ratio decreased 4 h after contrast infusion (p < 0.001), but none of the biomarkers assessed were affected by the treatments. CONCLUSIONS: There were no differences in hydration with oral sodium citrate and IV sodium bicarbonate for the prophylaxis of CI-AKI. Therefore, oral hydration represents a safe, inexpensive and practical method for preventing CI-AKI in low-risk patients. No effect on biomarkers for kidney injury could be demonstrated.