Combining Clinical Parameters and Acute Tubular Injury Grading Is Superior in Predicting the Prognosis of Deceased-Donor Kidney Transplantation: A 7-Year Observational Study.

Background: We developed a pragmatic dichotomous grading criterion to stratify the acute tubular injury (ATI) of deceased-donor kidneys. We intended to verify the predictive value of this criterion for the prognosis of deceased-donor kidney transplantation. Methods: The allografts with ATI were classified into severe and mild groups. Severe ATI was defined as the presence of extreme and diffuse flattening of the tubular epithelial cells, or denudement of the tubular basement membrane. The clinical delayed graft function (DGF) risk index was calculated based on a regression model for posttransplant DGF using 17 clinical parameters related to donor-recipient characteristics. Results: A total of 140 recipients were enrolled: 18 severe and 122 mild ATI. Compared with the mild ATI group, the severe ATI group had more donors after cardiac death, higher median donor terminal serum creatinine level (dScr), and longer median cold ischemia time. Severe ATI had a higher DGF rate (55.6% vs 14.6%, p < 0.001), longer DGF recovery time (49.6 vs 26.3 days, p < 0.001), and a lower estimated glomerular filtration rate (eGFR) at 1 month (23.5 vs 54.0 ml/min/1.73 m2, p < 0.001), 3 months (40.4 vs 59.0, p = 0.001), and 6 months after transplant (46.8 vs 60.3, p = 0.033). However, there was no significant difference in eGFR at 1 year or beyond, graft, and patient survival. The predictive value of combined dScr with ATI severity for DGF rate and DGF recovery time was superior to that of dScr alone. The predictive value of the combined DGF risk index with ATI severity for DGF was also better than that of the DGF risk index alone; however, the association of the DGF risk index with DGF recovery time was not identified. Chronic lesions including glomerulosclerosis, interstitial fibrosis, arterial intimal fibrosis, and arteriolar hyalinosis were associated with declined posttransplant 1-year eGFR. Conclusion: Based on our pragmatic dichotomous grading criterion for ATI in a preimplantation biopsy, donor kidneys with severe ATI increased DGF risk, prolonged DGF recovery, and decreased short-term graft function but demonstrated favorable long-term graft function. Our grading method can offer additive valuable information for assessing donor kidneys with acute kidney injury and may act as an effective supplementary index of the Banff criteria.

Histological evaluation of ischemic alterations in donors after cardiac death: A useful tool to predict post-transplant renal function.

Kidneys retrieved from donors after cardiac death (DCD) pose significant challenges from a clinical and technical point of view, undergoing a variable degree of ischemia-reperfusion injury. At present, the utilization of kidneys is assessed according to the Karpinski score, which does not take into account the ischemic insult and does not predict the functional recovery of the organ once transplanted. Therefore, the correlation between biopsy results and post-transplant graft function is still debated. In this study we examined kidney biopsies from DCD donors; we calculated the Karpinski score and subsequently identified and quantified the ischemic lesions in the glomerular, interstitial, and tubular compartments. These same lesions were quantified in kidney biopsies from donors after brain death (DBD) in a case-control analysis. The collected data were correlated with the clinical data of the donors and the post-transplant follow-up. Proximal tubule alterations are crucial in ischemia-reperfusion damage, showing precise histological alterations, which are more frequent in DCD than in DBD donors and are statistically correlated with functional recovery of the organ. Quantification of ischemic tubular lesions in biopsies of kidneys from DCD donors is a useful tool for predicting post-transplant renal function and a valid parameter for assessing the quality of the graft.

Hyperspectral Imaging (HSI) of Human Kidney Allografts.

OBJECTIVE: Aim of our study was to test a noninvasive HSI technique as an intraoperative real time assessment tool for deceased donor kidney quality and function in human kidney allotransplantation. SUMMARY OF BACKGROUND DATA: HSI is capable to deliver quantitative diagnostic information about tissue pathology, morphology, and composition, based on the spectral characteristics of the investigated tissue. Because tools for objective intraoperative graft viability and performance assessment are lacking, we applied this novel technique to human kidney transplantation. METHODS: Hyperspectral images of distinct components of kidney allografts (parenchyma, ureter) were acquired 15 and 45 minutes after reperfusion and subsequently analyzed using specialized HSI acquisition software capable to compute oxygen saturation levels (StO2), near infrared perfusion indices (NIR), organ hemoglobin indices, and tissue water indices of explored tissues. RESULTS: Seventeen kidney transplants were analyzed. Median recipient and donor age were 55 years. Cold ischemia time was 10.8 ±â€Š4.1 hours and anastomosis time was 35 ±â€Š7 minutes (mean ±â€Šstandard deviation). Two patients (11.8%) developed delayed graft function (DGF). cold ischemia time was significantly longer (18.6 ±â€Š1.6) in patients with DGF (P < 0.01). Kidneys with DGF furthermore displayed significant lower StO2 (P = 0.02) and NIR perfusion indices, 15 minutes after reperfusion (P < 0.01). Transplant ureters displayed a significant decrease of NIR perfusion with increased distance to the renal pelvis, identifying well and poor perfused segments. CONCLUSION: Intraoperative HSI is feasible and meaningful to predict DGF in renal allografts. Furthermore, it can be utilized for image guided surgery, providing information about tissue oxygenation, perfusion, hemoglobin concentration, and water concentration, hence allowing intraoperative viability assessment of the kidney parenchyma and the ureter.

Recipient pre-existing chronic hypotension is associated with delayed graft function and inferior graft survival in kidney transplantation from elderly donors.

BACKGROUND: Pre-existing chronic hypotension affects a percentage of kidney transplanted patients (KTs). Although a relationship with delayed graft function (DGF) has been hypothesized, available data are still scarce and inconclusive. METHODS: A monocentric retrospective observational study was performed on 1127 consecutive KTs from brain death donors over 11 years (2003-2013), classified according to their pre-transplant Mean Blood Pressure (MBP) as hypotensive (MBP < 80 mmHg) or normal-hypertensive (MBP ≥ 80 mmHg, with or without effective antihypertensive therapy). RESULTS: Univariate analysis showed that a pre-existing hypotension is associated to DGF occurrence (p<0.01; OR for KTs with MBP < 80 mmHg, 4.5; 95% confidence interval [CI], 2.7 to 7.5). Chronic hypotension remained a major predictive factor for DGF development in the logistic regression model adjusted for all DGF determinants. Adjunctive evaluations on paired grafts performed in two different recipients (one hypotensive and the other one normal-hypertensive) confirmed this assumption. Although graft survival was only associated with DGF but not with chronic hypotension in the overall population, stratification according to donor age revealed that death-censored graft survival was significantly lower in hypotensive patients who received a KT from >50 years old donor. CONCLUSIONS: Our findings suggest that pre-existing recipient hypotension, and the subsequent hypotension-related DGF, could be considered a significant detrimental factor, especially when elderly donors are involved in the transplant procedure.

Mitochondrial Consequences of Organ Preservation Techniques during Liver Transplantation.

Allograft ischemia during liver transplantation (LT) adversely affects the function of mitochondria, resulting in impairment of oxidative phosphorylation and compromised post-transplant recovery of the affected organ. Several preservation methods have been developed to improve donor organ quality; however, their effects on mitochondrial functions have not yet been compared. This study aimed to summarize the available data on mitochondrial effects of graft preservation methods in preclinical models of LT. Furthermore, a network meta-analysis was conducted to determine if any of these treatments provide a superior benefit, suggesting that they might be used on humans. A systematic search was conducted using electronic databases (EMBASE, MEDLINE (via PubMed), the Cochrane Central Register of Controlled Trials (CENTRAL) and Web of Science) for controlled animal studies using preservation methods for LT. The ATP content of the graft was the primary outcome, as this is an indicator overall mitochondrial function. Secondary outcomes were the respiratory activity of mitochondrial complexes, cytochrome c and aspartate aminotransferase (ALT) release. Both a random-effects model and the SYRCLE risk of bias analysis for animal studies were used. After a comprehensive search of the databases, 25 studies were enrolled in the analysis. Treatments that had the most significant protective effect on ATP content included hypothermic and subnormothermic machine perfusion (HMP and SNMP) (MD = -1.0, 95% CI: (-2.3, 0.3) and MD = -1.1, 95% CI: (-3.2, 1.02)), while the effects of warm ischemia (WI) without cold storage (WI) and normothermic machine perfusion (NMP) were less pronounced (MD = -1.8, 95% CI: (-2.9, -0.7) and MD = -2.1 MD; CI: (-4.6; 0.4)). The subgroup of static cold storage (SCS) with shorter preservation time (< 12 h) yielded better results than SCS ≥ 12 h, NMP and WI, in terms of ATP preservation and the respiratory capacity of complexes. HMP and SNMP stand out in terms of mitochondrial protection when compared to other treatments for LT in animals. The shorter storage time at lower temperatures, together with the dynamic preservation, provided superior protection for the grafts in terms of mitochondrial function. Additional clinical studies on human patients including marginal donors and longer ischemia times are needed to confirm any superiority of preservation methods with respect to mitochondrial function.

Outcomes of Delayed Graft Function in Kidney Transplant Recipients Stratified by Histologic Biopsy Findings.

Delayed graft function (DGF) after kidney transplantation is associated with an increased risk of graft failure. We studied the histologic findings among adult kidney transplant recipients transplanted between January 2000 and June 2015 who had DGF and had a kidney biopsy within 14 days of transplant. Death censored graft failure (DCGF) and death at 1 and 3 years after transplant were examined. A total of 269 transplant recipients fulfilled our selection criteria, of which 152 (56.51%) had acute tubular necrosis (ATN), 44 (16.4%) had acute rejection (AR), mainly T-cell mediated rejection (n = 31), 35 (13%) had ATN with AR (mainly T-cell mediated rejection, n = 26), and 38 (14.1%) had other pathology. Compared with those with ATN alone, kidney transplant recipients with AR alone had a significantly higher risk of DCGF at 1 year post transplant (adjusted hazard ratio = 3.70; 95% confidence interval 1.5-9.5; P = .006). Those with AR alone had an increased risk of DCGF at 3 years post transplant (hazard ratio = 3.10; 95% confidence interval 1.3-8.5; P = .01) in crude analyses. There was no association between DGF etiology and mortality. Early renal biopsy can be used to distinguish AR, which has protocolized treatments, from other etiologies. This could potentially alter allograft survival within 1 year of transplant complicated by DGF.

The Histological Picture of Indication Biopsies in the First 2 Weeks after Kidney Transplantation.

BACKGROUND AND OBJECTIVES: In preclinical studies, ischemia-reperfusion injury and older donor age are associated with graft inflammation in the early phase after transplantation. In human kidney transplantation, impaired allograft function in the first days after transplantation is often adjudicated to donor- and procedure-related characteristics, such as donor age, donor type, and ischemia times. DESIGN: , setting, participants, & measurementsIn a cohort of 984 kidney recipients, 329 indication biopsies were performed within the first 14 days after transplantation. The histologic picture of these biopsies and its relationship with alloimmune risk factors and donor- and procedure-related characteristics were studied, as well as the association with graft failure. Multivariable Cox models were applied to quantify the cause-specific hazard ratios for early rejection and early inflammatory scores, adjusted for potential confounders. For quantification of hazard ratios of early events for death-censored graft failure, landmark analyses starting from day 15 were used. RESULTS: Early indication biopsy specimens displayed microvascular inflammation score ≥2 in 30% and tubulointerstitial inflammation score ≥2 in 49%. Rejection was diagnosed in 186 of 329 (57%) biopsies and associated with the presence of pretransplant donor-specific HLA antibodies and the number of HLA mismatches, but not nonimmune risk factors in multivariable Cox proportional hazards analysis. In multivariable Cox proportional hazards analysis, delayed graft function, the graft dysfunction that prompted an early indication biopsy, HLA mismatches, and pretransplant donor-specific HLA antibodies were significantly associated with a higher risk for death-censored graft failure, whereas early acute rejection was not. CONCLUSIONS: Indication biopsies performed early after kidney transplantation display inflammatory changes related to alloimmune risk factors. Nonimmune risk factors for ischemia-reperfusion injury, such as cold and warm ischemia time, older donor age, and donor type, were not identified as strong risk factors for early inflammation after human kidney transplantation.

Outcomes of kidney transplantation from elderly deceased donors of a Korean registry.

To overcome organ shortage, expanded criteria donors, including elderly deceased donors (DDs), should be considered. We analyzed outcomes of kidney transplantation (KT) from elderly DDs in a nationwide study. In total, data of 1049 KTs from DDs using the database of Korean Organ Transplantation Registry (KOTRY) were retrospectively analyzed based on the age of DDs: age ≥60 years vs. <60 years. Clinical information, graft status, and adverse events were reviewed in DDs and recipients. The mean age of the 1006 DDs was 51.04±10.54 years, and 21.5% of donors were aged ≥60 years. Elderly DDs had a significantly higher prevalence of diabetes and hypertension and higher Kidney Donor Risk Index (KDRI) and Kidney Donor Profile Index (KDPI). The mean age of the recipients was 47.45±14.87 years. Patients who received KT from elderly DDs were significantly older (53.12±15.14 vs. 45.88±14.41, P<0.001) and had a higher rate of diabetes (41.9 vs. 24.4%, P<0.001). Graft outcomes were not significantly different. Renal function was similar between the groups at the time of discharge and at 6 months, 1 year, and 2 years after KT. The rate of delayed graft function (DGF) was not significantly different. Risk factors of DGF were significantly different in DDs aged ≥60 years and <60 years. In the multivariable model, male sex (odds ratio: 3.99, 95% confidence interval: 1.42-11.22; P = 0.009) and KDRI (12.17, 2.23-66.34; P = 0.004) were significant risk factors for DGF in DDs aged ≥60 years. In DDs aged <60 years, thymoglobulin induction (2.62, 1.53-4.48; P<0.001) and continuous renal replacement therapy (3.47, 1.52-7.96; P = 0.003) were significant factors. Our data indicated that graft outcomes, including renal function and DGF, were similar for elderly DDs and DDs aged <60 years. Elderly DDs might be considered tolerable donors for KT, with active preoperative surveillance.

FGF15 improves outcomes after brain dead donor liver transplantation with steatotic and non-steatotic grafts in rats.

BACKGROUND & AIMS: Donation after brain death (DBD) grafts are associated with reduced graft quality and function post liver transplantation (LT). We aimed to elucidate i) the impact of FGF15 levels on DBD grafts; ii) whether this impact resulted from altered intestinal FXR-FGF15; iii) whether administration of FGF15 to donors after brain death could confer a benefit on graft function post LT; and iv) whether FGF15 affects bile acid (BA) accumulation. METHODS: Steatotic and non-steatotic grafts from DBD donors and donors without brain death were transplanted in rats. FGF15 was administered alone or combined with either a BA (cholic acid) or a YAP inhibitor. RESULTS: Brain death induced intestinal damage and downregulation of FXR. The resulting reduced intestinal FGF15 was associated with low hepatic FGF15 levels, liver damage and regenerative failure. Hepatic FGFR4-Klb - the receptor for FGF15 - was downregulated whereas CYP7A1 was overexpressed, resulting in BA accumulation. FGF15 administration to DBD donors increased hepatic FGFR4-Klb, reduced CYP7A1 and normalized BA levels. The benefit of FGF15 on liver damage was reversed by cholic acid, whereas its positive effect on regeneration was maintained. YAP signaling in DBD donors was activated after FGF15 treatment. When a YAP inhibitor was administered, the benefits of FGF15 on regeneration were abolished, whereas its positive effect on hepatic damage remained. Neither the Hippo-YAP-BA nor the BA-IQGAP1-YAP axis was involved in the benefits of FGF15. CONCLUSION: Alterations in the gut-liver axis contribute to the reduced quality of DBD grafts and the associated pathophysiology of LT. FGF15 pre-treatment in DBD donors protected against damage and promoted cell proliferation. LAY SUMMARY: After brain death, potential liver donors have reduced intestinal FXR, which is associated with reduced intestinal, circulatory and hepatic levels of FGF15. A similar reduction in the cell-surface receptor complex Fgfr4/Klb is observed, whereas CYP7A1 is overexpressed; together, these molecular events result in the dangerous accumulation of bile acids, leading to damage and regenerative failure in brain dead donor grafts. Herein, we demonstrate that when such donors receive appropriate doses of FGF15, CYP7A1 levels and hepatic bile acid toxicity are reduced, and liver regeneration is promoted.

Effect of Glomerulopathy Recurrence in the Outcome and Graft Survival of Kidney Transplanted Patients.

BACKGROUND: Recurrent glomerulopathy (GP) after kidney transplantation is a complication of kidney transplantation that could negatively affect kidney function and graft survival. This study aimed to evaluate the outcome, graft survival, and GP recurrence and its predictive factors in kidney-transplanted patients. METHODS: Patients were divided into 2 groups: G1 (with GP; n = 95) and G2 (with other causes of end-stage renal disease; n = 373). Graft survival analyses were performed using the Kaplan-Meier for living donor (LD) and deceased donor (DD). Cox proportional hazards regression were used to investigate the predictors for graft loss and for GP recurrence. RESULTS: Disease recurrence was observed in 9 patients who received a kidney from an LD, of which 4 lost their grafts. In patients who received a kidney from a DD, recurrence was also observed in 9 patients, of which 3 lost their grafts. No statistically significant differences in graft survival between G1 and G2 in relation to LD and DD were noted (P = .299 and .434, respectively). However, differences in graft survival were found when GP subtypes and GP recurrence were analyzed. The predictors of graft loss were delayed graft function (hazard ratio [HR] = 2.226, P = .002), rejection episodes (HR = 1.904, P = .017), and recurrence or transplant GP (HR = 3.243, P = .006). The predictors of disease recurrence or transplant GP were age (HR = 0.945, P = .028) and cold ischemia time (HR = 1.117, P = .003). CONCLUSION: Kidney transplantation could be a reasonable treatment for GP with end-stage renal disease. Despite the disease recurrence, which is a significant cause of graft loss in transplant recipients, graft survival remains satisfactory.

The "oldest and coldest" shipped living donor kidneys transplanted through kidney paired donation.

To date, thousands of living donor kidneys have been shipped through kidney paired donation (KPD). To expand on this growing segment of living donor transplantation, we evaluated the effect of advanced age donation ("oldest kidneys") and prolonged cold ischemia time ("coldest kidneys") on graft function and survival using the National Kidney Registry database from February 2008 to May 2018. Donors were stratified by age at time of donation (<65 or ≥65 years) and kidneys were stratified by cold ischemia time (<16 or ≥16 hours). We evaluated delayed graft function and death-censored graft failure (DCGF) for up to seven posttransplant years. Of the 2363 shipped living donor kidney transplants, 4.1% of donors were ≥65 years and 6.0% of transplanted kidneys had cold ischemia times ≥16 hours. Delayed graft function and DCGF occurred in 5.2% and 4.7% of cases. There were no significant associations between delayed graft function and donor age (P = .947) or cold ischemia (P = .532). Donor age and cold ischemia time were not predictive of delayed graft function (OR = 0.86,1.20; P = .8, .6) or DCGF (HR = 1.38,0.35, P = .5, .1). These findings may alleviate concerns surrounding the utilization of kidneys from older donors or those originating from distant transplant centers.

Utility and safety of early allograft biopsy in adult deceased donor kidney transplant recipients.

INTRODUCTION: Delayed graft function (DGF) is considered a risk factor for rejection after kidney transplantation (KTx). Clinical guidelines recommend weekly allograft biopsy until DGF resolves. However, who may benefit the most from such an aggressive policy and when histology should be evaluated remain debated. METHODS: We analyzed 223 biopsies in 145 deceased donor KTx treated with basiliximab or anti-thymocyte globulin (rATG) and calcineurin inhibitor-based maintenance. The aim of the study was to assess the utility and safety of biopsies performed within 28 days of transplant. Relationships between transplant characteristics, indication, timing, and biopsy-related outcomes were evaluated. RESULTS: Main indication for biopsy was DGF (87.8%) followed by lack of improvement in graft function (9.2%), and worsening graft function (3.1%). Acute tubular necrosis was the leading diagnosis (89.8%) whereas rejection was detected in 8.2% specimens. Rejection was more frequent in patients biopsied due to worsening graft function or lack of improvement in graft function than DGF (66.7% vs. 3.5%; P = 0.0075 and 33.3% vs. 3.5%; P = 0.0104, respectively) and in biopsies performed between day 15 and 28 than from day 0 to 14 (31.2% vs. 3.7%; P = 0.0002). Complication rate was 4.1%. Management was affected by the information gained with histology in 12.2% cases (7% considering DGF). CONCLUSIONS: In low-immunological risk recipients treated with induction and calcineurin inhibitors maintenance, protocol biopsies obtained within 2 weeks of surgery to rule out rejection during DGF do not necessarily offer a favourable balance between risks and benefits. In these patients, a tailored approach may minimize complications thus optimizing results.

Endothelial Cell-Derived Interleukin-18 Released During Ischemia Reperfusion Injury Selectively Expands T Peripheral Helper Cells to Promote Alloantibody Production.

BACKGROUND: Ischemia reperfusion injury (IRI) predisposes to the formation of donor-specific antibodies, a factor contributing to chronic rejection and late allograft loss. METHODS: We describe a mechanism underlying the correlative association between IRI and donor-specific antibodies by using humanized models and patient specimens. RESULTS: IRI induces immunoglobulin M-dependent complement activation on endothelial cells that assembles an NLRP3 (NOD-like receptor pyrin domain-containing protein 3) inflammasome via a Rab5-ZFYVE21-NIK axis and upregulates ICOS-L (inducible costimulator ligand) and PD-L2 (programmed death ligand 2). Endothelial cell-derived interleukin-18 (IL-18) selectively expands a T-cell population (CD4+CD45RO+PD-1hiICOS+CCR2+CXCR5-) displaying features of recently described T peripheral helper cells. This population highly expressed IL-18R1 and promoted donor-specific antibodies in response to IL-18 in vivo. In patients with delayed graft function, a clinical manifestation of IRI, these cells were Ki-67+IL-18R1+ and could be expanded ex vivo in response to IL-18. CONCLUSIONS: IRI promotes elaboration of IL-18 from endothelial cells to selectively expand alloreactive IL-18R1+ T peripheral helper cells in allograft tissues to promote donor-specific antibody formation.

Live Confocal Tissue Assessment With SYTO16/PI and WGA Staining Visualizes Acute Organ Damage and Predicts Delayed Graft Function in Kidney Transplantation.

OBJECTIVE: The aim of our prospective clinical trial was to test a tissue staining technique (real-time confocal analysis [RTCA]) as a rapid assessment tool for donor kidney quality and function in human kidney transplantation. SUMMARY BACKGROUND DATA: Tools for objective graft tissue viability assessment before kidney transplantation are lacking. RTCA has recently been established and tested in a pilot study using rodent kidneys. METHODS: RTCA was performed in kidney biopsies stained with SYTO16/PI and WGA. A score between -3 (100% nonviable) and +3 (100% viable) describes the sum of viable cells divided by the number of nonviable cells per examined area (glomerulus, proximal, and distal tubules). The primary study endpoint was the delayed graft function (DGF). RESULTS: Seventy-one kidney transplant recipients were transplanted. The median recipient and donor age were 58.5 and 57 years, respectively. Cold ischemia time was 13.6 ±â€Š4.7 hours; anastomosis time was 30.8 ±â€Š8.7 minutes (mean ±â€ŠSD). Overall, 23 (33.8%) patients developed DGF. The RTCA score was significantly lower in kidneys developing DGF -0.43 ±â€Š1.78 versus no DGF 0.91 ±â€Š2.17, P = 0.01. The Remuzzi score did not differ between DGF and no DGF, P = 0.13. Remuzzi score and RTCA score correlate inversely significantly; P = 0.004. In the multivariate analysis, solely RTCA score was revealed as a significant independent factor predicting DGF; P = 0.015, Wald = 5.95, odds ratio = 0.72, 95% confidence interval = 0.55 to 0.94. CONCLUSIONS: Our data demonstrate that RTCA is feasible and clinically meaningful. The RTCA score predicts DGF and is a valid option to be applied in renal transplantation.

Endogenous intronic antisense long non-coding RNA, MGAT3-AS1, and kidney transplantation.

ß-1,4-mannosylglycoprotein 4-ß-N-acetylglucosaminyltransferase (MGAT3) is a key molecule for the innate immune system. We tested the hypothesis that intronic antisense long non-coding RNA, MGAT3-AS1, can predict delayed allograft function after kidney transplantation. We prospectively assessed kidney function and MGAT3-AS1 in 129 incident deceased donor kidney transplant recipients before and after transplantation. MGAT3-AS1 levels were measured in mononuclear cells using qRT-PCR. Delayed graft function was defined by at least one dialysis session within 7 days of transplantation. Delayed graft function occurred in 22 out of 129 transplant recipients (17%). Median MGAT3-AS1 after transplantation was significantly lower in patients with delayed graft function compared to patients with immediate graft function (6.5 × 10-6, IQR 3.0 × 10-6 to 8.4 × 10-6; vs. 8.3 × 10-6, IQR 5.0 × 10-6 to 12.8 × 10-6; p < 0.05). The median preoperative MGAT3-AS1 was significantly lower in kidney recipients with delayed graft function (5.1 × 10-6, IQR, 2.4 × 10-6 to 6.8 × 10-6) compared to recipients with immediate graft function (8.9 × 10-6, IQR, 6.8 × 10-6 to 13.4 × 10-6; p < 0.05). Receiver-operator characteristics showed that preoperative MGAT3-AS1 predicted delayed graft function (area under curve, 0.83; 95% CI, 0.65 to 1.00; p < 0.01). We observed a positive predictive value of 0.57, and a negative predictive value of 0.95. Long non-coding RNA, MGAT3-AS1, indicates short-term outcome in patients with deceased donor kidney transplantation.

Micro RNA 146a-5p expression in Kidney transplant recipients with delayed graft function / Expressão do Micro RNA 146a-5p em pacientes transplantados renais com disfunção inicial do enxerto

ABSTRACT Introduction: The development of novel non-invasive biomarkers of kidney graft dysfunction, especially in the course of the delayed graft function period would be an important step forward in the clinical practice of kidney transplantation. Methods: We evaluated by RT-PCR the expression of miRNA-146 to -5p ribonucleic micro-acids (miRNAs) in the peripheral blood and renal tissue obtained from kidney transplant recipients who underwent a surveillance graft biopsy during the period of delayed graft function. Results: In biopsy samples, the expression of miR-146a-5p was significantly increased in the group of patients with delayed graft function (DGF) (n = 33) versus stables patients (STA) (n = 13) and patients with acute rejection (AR) (n = 9) (p = 0.008). In peripheral blood samples, a non-significant increase of miR-146a-5p expression was found in the DGF group versus STA and AR groups (p = 0.083). No significant correlation was found between levels of expression in biopsy and plasma. ROC curve analysis revealed an AUC of 0.75 (95% CI: 0.62-0.88) for the renal tissue expression and 0.67 (95% CI 0.52-0.81) for the peripheral blood expression. Conclusion: We conclude that miR-146a-5p expression has a distinct pattern in the renal tissue and perhaps in the peripheral blood in the setting of DGF. Further refinements and strategies for studies should be developed in the field of non-invasive molecular diagnosis of kidney graft dysfunction.

RESUMO Introdução: O desenvolvimento de novos biomarcadores não invasivos para disfunção do enxerto renal, especialmente no decurso da disfunção inicial do enxerto, seria de enorme valia para a prática clínica do transplante renal. Métodos: A técnica de RT-PCR foi utilizada para avaliar a expressão de microRNA 146a-5p no sangue periférico e no tecido renal de receptores de transplante submetidos a biópsia renal de controle no decurso de disfunção inicial do enxerto. Resultados: A expressão de miR-146a-5p estava significativamente aumentada nas amostras de biópsia do grupo de pacientes com disfunção inicial do enxerto (DIE) (n = 33) em relação aos pacientes estáveis (n = 13) e aos com rejeição aguda (RA) (n = 9) (p = 0,008). Foi detectado aumento não significativo da expressão de miR-146a-5p nas amostras de sangue periférico do grupo com DIE em comparação aos pacientes estáveis e com RA (p = 0,083). Não foi identificada correlação significativa entre os níveis de expressão no plasma e na biópsia. A análise da curva COR revelou uma ASC de 0,75 (IC 95%: 0,62-0,88) para a expressão no tecido renal e de 0,67 (IC 95% 0,52-0,81) no sangue periférico. Conclusão: A expressão de miR-146a-5p tem um padrão distinto no tecido renal e talvez no sangue periférico em cenários de DIE. Maiores refinamentos e estratégias adicionais de estudo devem ser desenvolvidos na área do diagnóstico molecular não invasivo da disfunção do enxerto renal.

Pediatric deceased donor kidney transplant outcomes under the Kidney Allocation System.

The Kidney Allocation System (KAS) has resulted in fewer pediatric kidneys being allocated to pediatric deceased donor kidney transplant (pDDKT) recipients. This had prompted concerns that post-pDDKT outcomes may worsen. To study this, we used SRTR data to compare the outcomes of 953 pre-KAS pDDKT (age <18 years) recipients (December 4, 2012-December 3, 2014) with the outcomes of 934 post-KAS pDDKT recipients (December 4, 2014-December 3, 2016). We analyzed mortality and graft loss by using Cox regression, delayed graft function (DGF) by using logistic regression, and length of stay (LOS) by using negative binomial regression. Post-KAS recipients had longer pretransplant dialysis times (median 1.26 vs 1.07 years, P = .02) and were more often cPRA 100% (2.0% vs 0.1%, P = .001). Post-KAS recipients had less graft loss than pre-KAS recipients (hazard ratio [HR]: 0.35 0.540.83 , P = .005) but no statistically significant differences in mortality (HR: 0.29 0.721.83 , P = .5), DGF (odds ratio: 0.93 1.321.93 , P = .2), and LOS (LOS ratio: 0.96 1.061.19 , P = .4). After adjusting for donor-recipient characteristics, there were no statistically significant post-KAS differences in mortality (adjusted HR: 0.37 1.042.92 , P = .9), DGF (adjusted odds ratio: 0.94 1.412.13 , P = .1), or LOS (adjusted LOS ratio: 0.93 1.041.16 , P = .5). However, post-KAS pDDKT recipients still had less graft loss (adjusted HR: 0.38 0.590.91 , P = .02). KAS has had a mixed effect on short-term posttransplant outcomes for pDDKT recipients, although our results are limited by only 2 years of posttransplant follow-up.

Histopathologic Findings on Implantation Renal Allograft Biopsies Correlate With Kidney Donor Profile Index and 30-Day Serum Creatinine.

BACKGROUND: The Kidney Donor Profile Index (KDPI) provides a numerical estimate of deceased donor kidney quality. The KDPI uses 10 donor factors but it does not consider histopathologic findings. We examined whether the KDPI and its component donor factors correlate with the degree of histopathologic changes seen in implantation renal allograft biopsies. METHODS: All deceased donor kidney transplants at our institution from July 1, 2016 to March 15, 2017 that had an implantation biopsy were included. The biopsies were graded based on the Banff criteria for interstitial fibrosis, tubular atrophy, arterial intimal fibrosis, and arteriolar hyalinosis, as well as percent glomerulosclerosis. Linear and logistic regression were used to assess the correlation between histopathologic findings and KDPI and the ability of these variables to predict 30-day serum creatinine (SCr) and delayed graft function (DGF). RESULTS: One hundred thirty-four recipients from 107 donors were included. All histopathologic features examined correlated significantly with KDPI, with arteriolar hyalinosis correlating most strongly. Arteriolar hyalinosis was also associated with the most component donor factors of the KDPI. Histopathologic findings alone or in combination with KDPI predicted 30-day SCr but not DGF. Using the KDPI in combination with degree of interstitial fibrosis and tubular atrophy was the best predictor of 30-day SCr. CONCLUSION: Histopathologic changes seen in implantation renal allograft biopsies correlate with KDPI and predict 30-day SCr. Using a combination of donor histopathologic findings and KDPI may be the best predictor of short-term graft function.

Oxalate deposition in renal allograft biopsies within 3 months after transplantation is associated with allograft dysfunction.

BACKGROUND: Calcium oxalate (CaOx) deposition in the kidney may lead to loss of native renal function but little is known about the prevalence and role of CaOx deposition in transplanted kidneys. METHODS: In patients transplanted in 2014 and 2015, all for-cause renal allograft biopsies obtained within 3 months post-transplantation were retrospectively investigated for CaOx deposition. Additionally, all preimplantation renal biopsies obtained in 2000 and 2001 were studied. RESULTS: In 2014 and 2015, 388 patients were transplanted, of whom 149 had at least one for-cause renal biopsy. Twenty-six (17%) patients had CaOx deposition. In the population with CaOx deposition: Patients had significantly more often been treated with dialysis before transplantation (89 vs. 64%; p = 0.011); delayed graft function occurred more frequently (42 vs. 23%; p = 0.038); and the eGFR at the time of first biopsy was significantly worse (21 vs. 29 ml/min/1.73m2; p = 0.037). In a multivariate logistic regression analysis, eGFR at the time of first biopsy (OR 0.958, 95%-Cl: 0.924-0.993, p = 0.019), dialysis before transplantation (OR 4.868, 95%-Cl: 1.128-21.003, p = 0.034) and the time of first biopsy after transplantation (OR 1.037, 95%-Cl: 1.013-1.062, p = 0.002) were independently associated with CaOx deposition. Graft survival censored for death was significantly worse in patients with CaOx deposition (p = 0.018). In only 1 of 106 preimplantation biopsies CaOx deposition was found (0.94%). CONCLUSION: CaOx deposition appears to be primarily recipient-derived and is frequently observed in for-cause renal allograft biopsies obtained within 3 months post-transplantation. It is associated with inferior renal function at the time of biopsy and worse graft survival.