Renal Allograft Dysfunction Research Articles

Underlying Causes and Risk Factors of Chronic Renal Allograft Dysfunction Among Renal Transplant Recipients

Objective: Dialysis or renal transplantation are the two treatment options for end-stage renal disease patients. Renal transplantation from an appropriate donor increases survival and quality of life compared to treatment with dialysis. Recent advances in immunosuppressive therapy have significantly improved the success in 1-year graft survival. However, the long-term graft survival remains the same. Therefore, we aimed to determine the underlying causes and risk factors of chronic allograft dysfunction in renal transplant recipients.
 Materials and Methods: From 2000 to 2012, all consecutive renal transplant recipients followed in our tertiary referral center who underwent renal biopsy due to an increase in serum creatinine level were enrolled. Etiologies of chronic allograft dysfunction were assessed according to pathologic results of renal biopsy specimens and laboratory findings. The immunological and non-immunological risk factors of chronic allograft dysfunction were screened and recorded retrospectively.
 Results: Eighty (80) renal transplant recipients with a mean age of 38±10 years were included in the study. Delayed graft function (p=0.007), history of acute rejection (p<0.001), positive panel reactive antibody (p=0.033) (Class I (p=0.013), Class II (p=0.006)), positive donor specific antibodies (p=0.001), number of recurrent acute rejections (p<0.001), number of human leukocyte antigens mismatches (p=0.051), cold ischemia time (p=0.001) were found to be risk factors for chronic allograft dysfunction. The donor specific antibodies positivity (p<0.001) and the panel reactive antibody positivity (Class I (p=0.003), Class II (p=0.001)) were significantly higher in patients with antibody mediated rejection than patients without antibody mediated rejection (p=0.002).
 Conclusion: Delayed graft function, presence and the number of acute rejections, increased cold ischemia time, panel reactive antibody positivity, donor specific antibodies positivity, and the number of human leukocyte antigens mismatches were risk factors for chronic allograft dysfunction.

An Integrated Transcriptomic Approach to Identify Molecular Markers of Calcineurin Inhibitor Nephrotoxicity in Pediatric Kidney Transplant Recipients.

Calcineurin inhibitors are highly efficacious immunosuppressive agents used in pediatric kidney transplantation. However, calcineurin inhibitor nephrotoxicity (CNIT) has been associated with the development of chronic renal allograft dysfunction and decreased graft survival. This study evaluated 37 formalin-fixed paraffin-embedded biopsies from pediatric kidney transplant recipients using gene expression profiling. Normal allograft samples (n = 12) served as negative controls and were compared to biopsies exhibiting CNIT (n = 11). The remaining samples served as positive controls to validate CNIT marker specificity and were characterized by other common causes of graft failure such as acute rejection (n = 7) and interstitial fibrosis/tubular atrophy (n = 7). MiRNA profiles served as the platform for data integration. Oxidative phosphorylation and mitochondrial dysfunction were the top molecular pathways associated with overexpressed genes in CNIT samples. Decreased ATP synthesis was identified as a significant biological function in CNIT, while key toxicology pathways included NRF2-mediated oxidative stress response and increased permeability transition of mitochondria. An integrative analysis demonstrated a panel of 13 significant miRNAs and their 33 CNIT-specific gene targets involved with mitochondrial activity and function. We also identified a candidate panel of miRNAs/genes, which may serve as future molecular markers for CNIT diagnosis as well as potential therapeutic targets.

Evaluation of Early Renal Allograft Dysfunction from Living Donors among Egyptian Patients (Histopathological and Immunohistochemical Study)

BACKGROUND: Early renal graft dysfunction is a major problem in the early post-transplantation period and is considered a major cause of graft loss. Clinical diagnosis based on the clinical criteria alone is unreliable; therefore, biopsy remains the gold standard to differentiate between rejection and non-rejection causes. AIM: This study was designed to identify and differentiate between causes of early graft dysfunction during the first post-transplantation month and to correlate between histological lesions and immunohistochemistry (IHC) for accurate diagnosis and a better outcome. MATERIALS AND METHODS: A total of 163 renal allograft biopsies, performed in the first post-transplantation month over 6 years, were included in the study. New sections were prepared from the paraffin blocks and stained with conventional stains. Additional sections were prepared and treated by complement fragment 4d (C4d) and cluster differentiation 3 (CD3) antibodies for IHC evaluation. RESULTS: All the studied cases were from living donors. The mean patient age was 39 years with predominant males. The clinical indication for most biopsies (94.5%) was impaired graft function. Acute rejection (AR) was the main diagnostic category observed in (98/163, 60.1%); out of which, T cell-mediated rejection (TCMR) was observed in (62/98, 63.2%). Drug toxicity was suspected in (53/163, 32.5%), acute tubular injury (ATI) not otherwise specified (nos) in (21/163, 12.9%), and other lesions including thrombotic microangiopathy were observed in the remaining biopsies. The most common cause of graft dysfunction in the 1st and 2nd weeks was AR representing. A significant correlation was seen between mild glomerulitis (g1) and mild peritubular capillaritis (PTC) 1, on the one side, and negative C4d staining, on the other side. No significant correlation was seen between moderate glomerulitis (g2) and moderate ptc2 at one side and positive C4d staining at the other side reflecting the poor association between the microvascular inflammation (“g” and “ptc” scores) and C4d positivity (r = 0.2). Missed mild tubulitis (t1) was found in a single case and missed moderate tubulitis (t2) was found in a single case detected by CD3 IHC. CONCLUSION: AR and drug toxicity account for the majority of early graft dysfunction, however, other pathological lesions, per se or coincide with them may be the cause. The significance of g2 per se as a marker for diagnosis of antibody-mediated rejection requires further study. Considering C4d score 1 (by IHC) positive; also requires further study with follow-up.

Early Transplant Arteriopathy in Kidney Transplantation

Early dysfunction of renal allografts may be associated with vascular injury, which raises the specter of active rejection processes that require medical intervention. In our practice, we have encountered patients who present with delayed graft function and demonstrate a unique pattern of endothelial cell injury that raises concern for rejection in their biopsy. Therefore, we sought to systematically determine the biopsy characteristics and outcome of these patients. During a 17-year period at the University of Washington in Seattle, United States, we identified 24 cases of a distinct arterial vasculopathy presenting in the first year posttransplantation. This early transplant arteriopathy (ETA) is characterized by endothelial cell swelling and intimal edema but without the intimal arteritis that defines vascular rejection. Approximately 1% of transplant biopsies during the study period showed ETA, almost all of which were in deceased donor organs (96%), and most presented with delayed graft function (54%) or increased serum creatinine (38%) soon after transplantation (median 13 days; range, 5-139). In this study, 77% of patients were managed expectantly, with only 2 patients (7.6%) subsequently developing acute vascular rejection. Except for 1 patient who died, all patients had functioning allografts at 1 year follow-up. Recognizing ETA and distinguishing it from vascular rejection is important to prevent over-treatment because most patients appear to recover allograft function rapidly with expectant management.

POS-773 THE PATTERN OF INFECTION FOLLOWING ANTI-REJECTION THERAPY IN RENAL ALLOGRAFT RECIPIENTS: EXPERIENCE FROM A LOW RESOURCE COUNTRY

Graft rejection is an important cause of renal allograft dysfunction and requires antirejection therapy (ART) for its reversal. However, it is associated with risk of over-immunosuppression, which is often underestimated against improved graft outcome. In this study we aim to assess the complications attributed to ART in a cohort of renal allograft recipients (RAR) out of hospital based renal transplant registry (RTR).

Preservation of epoxyeicosatrienoic acid bioavailability prevents renal allograft dysfunction and cardiovascular alterations in kidney transplant recipients

This study addressed the hypothesis that epoxyeicosatrienoic acids (EETs) synthesized by CYP450 and catabolized by soluble epoxide hydrolase (sEH) are involved in the maintenance of renal allograft function, either directly or through modulation of cardiovascular function. The impact of single nucleotide polymorphisms (SNPs) in the sEH gene EPHX2 and CYP450 on renal and vascular function, plasma levels of EETs and peripheral blood monuclear cell sEH activity was assessed in 79 kidney transplant recipients explored at least one year after transplantation. Additional experiments in a mouse model mimicking the ischemia–reperfusion (I/R) injury suffered by the transplanted kidney evaluated the cardiovascular and renal effects of the sEH inhibitor t-AUCB administered in drinking water (10 mg/l) during 28 days after surgery. There was a long-term protective effect of the sEH SNP rs6558004, which increased EET plasma levels, on renal allograft function and a deleterious effect of K55R, which increased sEH activity. Surprisingly, the loss-of-function CYP2C9*3 was associated with a better renal function without affecting EET levels. R287Q SNP, which decreased sEH activity, was protective against vascular dysfunction while CYP2C8*3 and 2C9*2 loss-of-function SNP, altered endothelial function by reducing flow-induced EET release. In I/R mice, sEH inhibition reduced kidney lesions, prevented cardiac fibrosis and dysfunction as well as preserved endothelial function. The preservation of EET bioavailability may prevent allograft dysfunction and improve cardiovascular disease in kidney transplant recipients. Inhibition of sEH appears thus as a novel therapeutic option but its impact on other epoxyfatty acids should be carefully evaluated.

Elastography: a surrogate marker of renal allograft fibrosis - quantification by shear-wave technique.

PurposeRenal fibrosis is the most common cause of allograft failure in kidney transplantations. Evaluation of renal abnormalities has progressed considerably over the past years. Currently, the diagnosis of intrarenal fibrosis and quantification of its development with non-invasive assessment tools is possible. This may help in early detection of renal allograft dysfunction. This study sought to assess the efficacy of 2D real-time shear-wave elastography (SWE) in the quantitative measurement of renal allograft dysfunction.MethodsA total of 172 patients were included in our study. SWE was performed in all these patients just before renal allograft biopsy. The cortical elasticity was assessed and described in terms of Young’s modulus (kPa). Banff histopathological grading obtained from transplant kidney tissue biopsy was taken as the reference standard. The potential correlation between SWE scores and Banff classification was performed.ResultsThere was a significant correlation between the Banff grade and mean SWE score, with a correlation coefficient of 0.665 (p < 0.001). The individual correlation coefficients of interstitial fibrosis and tubular atrophy with mean SWE score stood at 0.667 and 0.649 respectively (p < 0.001). The correlation of resistive indices was insignificant when compared to mean polar SWE score in respective poles and the Banff grading of fibrosis.ConclusionsRenal stiffness quantified by 2D SWE showed significant correlation with histopathological renal fibrosis. Thus, the study suggests that shear-wave elastography could be used as a surrogate marker for early detection of renal fibrosis.

COVID-19 Manifesting as Renal Allograft Dysfunction, Acute Pancreatitis, and Thrombotic Microangiopathy: A Case Report

Coronavirus disease 2019 (COVID-19) is associated with high morbidity and mortality worldwide in both the general population and kidney transplant recipients. Acute kidney injury is a known complication of COVID-19 and appears to most commonly manifest as acute tubular injury on renal biopsy. Coagulopathy associated with COVID-19 is a known but poorly understood complication that has been reported to cause thrombotic microangiopathy on rare occasions in native kidneys of patients with COVID-19. Here, we report the first case of biopsy-proven thrombotic microangiopathy in a kidney transplant recipient with COVID-19 who developed acute pancreatitis and clinical features of microangiopathic hemolytic anemia. The patient recovered with supportive care alone.

A novel biomarker of chronic allograft dysfunction in renal transplant recipients (serum calreticulin and CD47)

BackgroundChronic allograft dysfunction (CAD) is considered the leading cause of late allograft loss. The cluster of differentiation 47 (CD47) and calreticulin (CRT) are involved in many and diverse cellular processes. The present study was designed to study the role of the pro-phagocytic CRT and anti-phagocytic CD47 signals in patients with renal transplantation in relation to graft function.Thirty renal transplantation recipients (RTR) for more than 6 months [15 with stable renal function and 15 with chronic allograft dysfunction (CAD)] and 15 healthy controls were enrolled in the study. Quantification of CRT, CD47, and high-sensitivity C-reactive protein (hsCRP) levels in serum was done using standardized enzyme-linked immunosorbent assay (ELISA) kits. Measurement of renal function and urinary alkaline phosphatase (U.ALP) was done. Renal interstitial fibrosis (IF) was graded in renal biopsies of CAD.ResultsSerum CRT and urinary ALP levels were statistically significant higher (P < 0.001) while serum CD47 level was statistically significant lower (P < 0.001) in patients with CAD than patients with stable graft function and controls. There was statistically insignificant difference between controls and patients with stable graft function. Serum CRT and serum CD47 levels were positively correlated with each other and with worsening renal and tubular function, serum hsCRP in RTR and with degree of renal IF in patients with CAD (P < 0.05).ConclusionsThe activation and dysregulation of CRT and CD47 could play a role in the development of CAD and could be a potential biomarker for renal allograft dysfunction.

Increased macrophage activation marker soluble CD163 is associated with graft dysfunction and metabolic derangements in renal transplant recipients

BackgroundRenal allograft is vulnerable to numerous insults and is associated with metabolic derangements. Macrophages are regulators of inflammation and play a role in obesity, lipid metabolism and insulin resistance (IR). The present study was designed to assess macrophage activation, reflected by serum soluble CD163 (sCD163), in renal transplant recipients (RTR) and its relation to chronic allograft dysfunction (CAD) and metabolic derangements. MethodsFifty recipients of renal transplantation (RT) [22 with stable renal function and 28 with CAD] and 20 age- and sex-matched healthy controls were enrolled in the study. Serum sCD163 and high sensitivity C-reactive protein (hsCRP) were measured using enzyme-linked immunosorbent assay. Anthropometric measurements, renal function, lipid profile and homeostatic model assessment of IR (HOMA-IR) were estimated. Renal interstitial fibrosis (IF) was graded in renal biopsies of CAD. ResultsRTR mean age was 38.84 ± 9.28 years and 83% of them were males. Post-transplant dyslipidemia, diabetes and IR (HOMA-IR >2) were present in 42%, 24% and 86% of RTR respectively. Serum sCD163 levels were significantly higher in RTR with stable renal function and CAD than in healthy controls (814.41 ± 59.62 ng/ml and 1021.21 ± 120.82 ng/ml vs. 602.90 ± 114.98 ng/ml respectively) and in RTR with CAD than in patients with stable renal function (p < 0.001). Serum sCD163 levels were positively correlated with body mass index, waist-to-hip ratio, worsening renal function, dyslipidemia, HOMA-IR and serum hsCRP in RTR and with the degree of renal IF in RTR with CAD (p < 0.05). ROC curve showed that serum sCD163 was superior to serum hsCRP in detecting CAD after RT (AUC = 0.972 vs. 0.753 respectively, p = 0.001). ConclusionMacrophage activation, reflected by increased circulating sCD163, may play a role in the development of CAD and metabolic derangements after RT. Serum sCD163 could be a potential biomarker for renal allograft dysfunction.

4D flow MRI for the assessment of renal transplant dysfunction: initial results.

(1) Determine inter-observer reproducibility and test-retest repeatability of 4D flow parameters in renal allograft vessels; (2) determine if 4D flow measurements in the renal artery (RA) and renal vein (RV) can distinguish between functional and dysfunctional allografts; (3) correlate haemodynamic parameters with estimated glomerular filtration rate (eGFR), perfusion measured with dynamic contrast-enhanced MRI (DCE-MRI) and histopathology. Twenty-five prospectively recruited renal transplant patients (stable function/chronic renal allograft dysfunction, 12/13) underwent 4D flow MRI at 1.5T. 4D flow coronal oblique acquisitions were performed in the transplant renal artery (RA) (velocity encoding parameter, VENC = 120cm/s) and renal vein (RV) (VENC = 45cm/s). Test-retest repeatability (n = 3) and inter-observer reproducibility (n = 10) were assessed by Cohen's kappa, coefficient of variation (CoV) and Bland-Altman statistics. Haemodynamic parameters were compared between patients and correlated to the estimated glomerular filtration rate, DCE-MRI parameters (n = 10) and histopathology from allograft biopsies (n = 15). For inter-observer reproducibility, kappa was > 0.99 and 0.62 and CoV of flow was 12.6% and 7.8% for RA and RV, respectively. For test-retest repeatability, kappa was > 0.99 and 0.5 and CoV of flow was 27.3% and 59.4%, for RA and RV, respectively. RA (p = 0.039) and RV (p = 0.019) flow were both significantly reduced in dysfunctional allografts. Both identified chronic allograft dysfunction with good diagnostic performance (RA: AUC = 0.76, p = 0.036; RV: AUC = 0.8, p = 0.018). RA flow correlated negatively with histopathologic interstitial fibrosis score ci (ρ = - 0.6, p = 0.03). 4D flow parameters had better repeatability in the RA than in the RV. RA and RV flow can identify chronic renal allograft dysfunction, with RA flow correlating with histopathologic interstitial fibrosis score. • Inter-observer reproducibility of 4D flow measurements was acceptable in both the transplant renal artery and vein, but test-retest repeatability was better in the renal artery than in the renal vein. • Blood flow measurements obtained with 4D flow MRI in the renal artery and renal vein are significantly reduced in dysfunctional renal transplants. • Renal transplant artery flow correlated negatively with histopathologic interstitial fibrosis score.

Inhibition of Glycogen Synthase Kinase 3β Alleviates Chronic Renal Allograft Dysfunction in Rats.

Chronic renal allograft dysfunction (CRAD) is a major condition that impedes the long-term survival of renal allografts. However, the mechanism of CRAD is obscure, and the effective strategies for controlling the progression of CRAD are lacking. The present study used a CRAD rat model to assess the effect of glycogen synthase kinase 3β (GSK-3β) inhibition on the development of CRAD. A classical F334-to-LEW orthotopic renal transplantation was performed on the CRAD group. The treatment group was treated with the GSK-3β inhibitor 4-benzyl-2-methyl-1,2,4-thiadiazolidine-3,5-dione for 12 consecutive weeks following renal transplantation. The study included uninephrectomized F344 and Lewis rats as control subjects. Twelve weeks post surgery, the rats were retrieved for analysis of renal function, urine protein levels, histological, immunohistochemical, and molecular biological parameters. Administration of 4-benzyl-2-methyl-1,2,4-thiadiazolidine-3,5-dione inactivated GSK-3β and thereby improved renal function, attenuated proteinuria, and reduced renal tissue damage in CRAD rats. Besides, inactivation of GSK-3β inhibited nuclear factor-κB activation, macrophage infiltration, and expression of multiple proinflammatory cytokines/chemokines. Inhibition of GSK-3β also decreased the levels of malondialdehyde, increased superoxide dismutase levels, upregulated the expression of heme oxygenase-1 and NAD(P)H quinone oxidoreductase-1, and enhanced nuclear translocation of nuclear factor erythroid 2-related factor 2 in the kidneys of CRAD rats. Inhibition of GSK-3β attenuates the development of CRAD by inhibiting inflammation and oxidant stress. Thus, GSK-3β inhibition may represent a potential therapeutic strategy for the prevention and treatment of CRAD.

SRC INDUCES ENDOTHELIAL-TO-MESENCHYMAL TRANSITION AND RENAL ALLOGRAFT FIBROSIS VIA PROMOTING WNT/β-CATENIN PATHWAY

Endothelial-to-mesenchymal (EndMT) is recognized as an important source of myofibroblasts contributing to the pathogenesis of allograft interstitial fibrosis in our previous studies. Increased proto-oncogene tyrosine-protein kinase Src (Src) activity has been associated with several organs fibrosis including some renal diseases, but its role in allograft fibrosis of kidney transplant remains elusive. In the present study, we used immunohistochemistry (IHC) and immunofluorescence (IF) staining to detect the active form of Src (phopsho-Src Tyr416) of chronic renal allograft dysfunction (CAD) and healthy patients. Moreover, we cultured human umbilical vein endothelial cells (HUVEC) and human arterial endothelial cell (HAEC) which were treated with transforming growth factor-β1 (TGF-β1). Biomarkers of EndMT, as well as total Src and Src Tyr416, were examined in various doses or at various time points with or without PP1, a selective inhibitor of Src, using Western Blotting or qRT- PCR. Furthermore, knockdown or overexpressed Src plasmids in HUVEC and HAEC were constructed to confirm the exclusive effect of Src on the EndMT. Finally, rat renal transplant model was established and injected by PP1. Allograft tissues from human and rats were also collected and prepared for HE, Masson’s trichrome, IHC staining and western blotting assays. As a result, we demonstrate Src activity has been upregulated in glomerulus and vascular endothelium of rat renal transplant model and CAD patients. We found also TGF-β1 significant promoted development of EndMT and Src Tyr416 in a time-dependent and dose-dependent manner through raising β-catenin nuclear translocation. More importantly, PP1 alleviated the progression of EndMT and allograft interstitial fibrosis in vivo and in vitro by inhibiting WNT/β-catenin pathway. Thus, Src is an important mediator of allograft interstitial fibrosis, and suggest that Src will be a potential therapeutic target for prevention and treatment of renal allograft interstitial fibrosis.

Establishment of Rat Model of Insulin Resistance Exposed to Chronic Renal Allograft Dysfunction

BackgroundThe main cause of chronic renal allograft dysfunction (CRAD) still remains unclear. Insulin resistance (IR) may be a potential inducement, but there is insufficient evidence about this association. We aimed to establish a rat model of CRAD complicated with IR and to explore the function and pathologic changes of the renal allograft induced by IR. MethodsF344-to-Lewis rats of CRAD were fed a high-fat diet to induce IR. They were divided into 3 groups: IR (CRAD+IR), CRAD, and control (CTL). Serum levels of blood urea nitrogen (BUN) and serum creatinine (Scr) were measured to evaluate the renal function. The Homeostasis Model Assessment (HOMA)-IR index was detected by comparing the values of fasting serum insulin levels (FINS) with fasting blood glucose levels (FBG). The pathologic analysis was conducted by the degree of renal lesions including glomerular lesions, renal tubular lesions, hemorrhage, inflammatory cell infiltration, fibrillation, and hyperplasia of the renal interstitium. ResultsIn the second, third, and fourth month after surgery, serum levels of Scr and BUN in the IR group were reduced more than those in the CRAD group, while they were both higher compared to the CTL group, suggesting that renal function in the CRAD group was declined. The HOMA-IR in the IR group was greater than that in the CRAD and CTL groups, showing that simple high-fat diet feeding significantly and steadily increased FINS and FBG in CRAD complicated with IR rats. Pathologic changes indicated that the CRAD rat model was successfully constructed and was still in the early-middle stages of renal lesions 4 months after surgery, yet IR presented a significant effect on CRAD. ConclusionThese results indicate that the stable CRAD complicated with IR rat model can be established through a high-fat diet in CRAD rats in 4 months, and IR could be an influencing factor.

Approach and Management of Hypertension After Kidney Transplantation.

Hypertension is one of the most common cardiovascular co-morbidities after successful kidney transplantation. It commonly occurs in patients with other metabolic diseases, such as diabetes mellitus, hyperlipidemia, and obesity. The pathogenesis of post-transplant hypertension is complex and is a result of the interplay between immunological and non-immunological factors. Post-transplant hypertension can be divided into immediate, early, and late post-transplant periods. This classification can help clinicians determine the etiology and provide the appropriate management for these complex patients. Volume overload from intravenous fluid administration is common during the immediate post-transplant period and commonly contributes to hypertension seen early after transplantation. Immunosuppressive medications and donor kidneys are associated with post-transplant hypertension occurring at any time point after transplantation. Transplant renal artery stenosis (TRAS) and obstructive sleep apnea (OSA) are recognized but common and treatable causes of resistant hypertension post-transplantation. During late post-transplant period, chronic renal allograft dysfunction becomes an additional cause of hypertension. As these patients develop more substantial chronic kidney disease affecting their allografts, fibroblast growth factor 23 (FGF23) increases and is associated with increased cardiovascular and all-cause mortality in kidney transplant recipients. The exact relationship between increased FGF23 and post-transplant hypertension remains poorly understood. Blood pressure (BP) targets and management involve both non-pharmacologic and pharmacologic treatment and should be individualized. Until strong evidence in the kidney transplant population exists, a BP of <130/80 mmHg is a reasonable target. Similar to complete renal denervation in non-transplant patients, bilateral native nephrectomy is another treatment option for resistant post-transplant hypertension. Native renal denervation offers promising outcomes for controlling resistant hypertension with no significant procedure-related complications. This review addresses the epidemiology, pathogenesis, and specific etiologies of post-transplant hypertension including TRAS, calcineurin inhibitor effects, OSA, and failed native kidney. The cardiovascular and survival outcomes related to post-transplant hypertension and the utility of 24-h blood pressure monitoring will be briefly discussed. Antihypertensive medications and their mechanism of actions relevant to kidney transplantation will be highlighted. A summary of guidelines from different professional societies for BP targets and antihypertensive medications as well as non-pharmacological interventions, including bilateral native nephrectomy and native renal denervation, will be reviewed.

Criteria for assessing renal allograft dysfunction

The significance of the glomerular filtration rate calculated by the Cockcroft - Gault formula as one of the highly sensitive criteria for assessing renal allograft dysfunction is substantiated. The study demonstrated that in the group of patients with an increased level of daily proteinuria there is a significantly lower level of serum creatine in comparison with the group of patients with a normal level of daily proteinuria. Moreover, in patients with a normal level of daily proteinuria, there are significantly higher values of glomerular filtration rate calculated by the Cockcroft - Gault formula, compared with patients with an increased level of daily proteinuria. Thus, it is shown that the level of serum creatinine currently used in clinical practice, as a laboratory marker of renal allograft dysfunction, does not allow to detect impaired renal allograft function at the earliest possible date. It has been demonstrated that the glomerular filtration rate calculated by the Cockcroft - Gault formula is a highly sensitive and specific laboratory marker of renal transplant dysfunction. Determining the glomerular filtration rate calculated by the Cockcroft - Gault formula makes it possible to diagnose renal allograft dysfunction at the earliest stages, which will significantly improve the survival of the transplanted kidney due to timely changes in patient management tactics and correction of immunosuppressive therapy.

P1687ASSOCIATION OF URINARY MICRORNA-21-5P WITH INTERSTITIAL FIBROSIS AND TUBULAR ATROPHY (IFTA) IN RENAL TRANSPLANT RECIPIENTS

Abstract Background and Aims One of the most limiting factors of long-term graft survival is chronic renal allograft dysfunction (CAD). The major hallmarks of CAD are interstitial fibrosis and tubular atrophy (IFTA). MicroRNAs (miRNAs) are 19-25 nucleotides, small, noncoding molecules involved in the regulation of gene expression. MiRNAs have a role in various immunological processes, including inflammation and fibrosis. Particularly, microRNA-21-5p (miR-21) is reported to be strongly associated with pathogenesis regarding tubulointerstitium. The aim of this study was to analyse expression levels of urinary miR-21 in the renal transplant recipients and evaluate their application in the assessment of IFTA and kidney allograft function. Method The expression levels of urinary miR-21 were measured in 31 renal transplant recipients with biopsy-evaluated IFTA (IFTA 0+I: n=17; IFTA II+III: n=14) by quantitative PCR. Protocolar biopsies were performed 1 or 2 years after renal transplantation. Urine samples were collected at the time of biopsy procedure. MicroRNA-191-5p was used as reference gene. Correlations between the clinicopathological parameters and the level of expression of miR-21 were assessed. Results Relative expression level of miR-21 was significantly increased in IFTA II+III group compared to IFTA 0+I group. MiR-21 correlated positively with serum concentration of creatinine and negatively with eGFR. ROC analysis showed diagnostic value of miR-21 with an area under curve (AUC) of 0.80, high sensitivity and specificity. Conclusion MiR-21 is associated with IFTA and dysfunction of kidney allograft. It may be considered as potential non-invasive biomarker of renal allograft function.

No evidence for the need of a routine renal transplant ultrasound after elective transplant ureteric stent removal-A retrospective cohort study.

Transplant ureteric stent insertion reduces the incidence of MUCs, but it is not known whether routine PSRGU is needed to detect unmasked MUCs. This study evaluated whether routine PSRGU in the pRTR is a useful tool to identify MUCs before they become clinically apparent. A retrospective analysis was undertaken of the clinical outcomes following elective stent removal from pediatric kidney-only transplant recipients at two London centers between 2012 and 2016. Our policy was to perform PSRGU either routinely or urgently if there were concerning symptoms or biochemical evidence of renal allograft dysfunction. Elective stent removal was performed in 86% (97 of 113 pRTR), and 75 (77%) of whom had routine PSRGU at a median (IQR) of 6 (2-8) days after stent removal. There were changes to management in 3 (4%) of pRTR with PSRGU identifying no MUC. Nineteen patients (25%) had urgent PSRGU, most commonly due to renal allograft dysfunction, at a median (IQR) of 5.5 (2.7-12.3) days after stent removal. Of these, two pRTR required ureteric intervention. For our current practice of removing transplant stents at 4-6weeks post-transplantation, our study has found no evidence to support routine PSRGU after elective stent removal.

Combined Heart-Kidney Transplantation: Vasoplegia is Associated with Poorer Post-Kidney Transplant Outcomes

Candidate selection for multi-organ transplants should consider the chances of good function and benefit of all transplanted organs. Risk factors for early renal graft dysfunction after combined heart-kidney transplant (CHKTx) may include vasoplegia and vasopressor need in spite of good cardiac graft function. We aimed to identify risk factors for vasoplegia after CHKTx and its impact on postoperative and renal allograft outcomes. A retrospective review was conducted on 58 consecutive patients who underwent CHKTx at a single center between 1996 and 2019. Baseline characteristics, perioperative complications including post-transplant vasoplegia, graft function, and survival were assessed. Vasoplegia was defined as needing vasopressors to maintain a MAP >70 mmHg with either an ejection fraction >55% or a cardiac index ≥2.0 L/min/m2 within 48 hours of transplantation. The mean transplant age was 53.6 years (± 11.3 SD). Pre-transplant, 17 (29.3%) patients had a left ventricular assist device (VAD) and 1 (1.7%) had a right VAD. The operative mortality rate was 5.2% (3 patients). Seventeen (32.1%) patients experienced vasoplegia; of these, 10 (58.8%) had a VAD pre-transplant, 9 (52.9%) had delayed renal graft function (DGF), and 3 (17.6%) had permanent renal graft failure (PGF). All 3 patients with PGF had vasoplegia and 9 (50.0%) with DGF had vasoplegia. Eight (66.7%) of the patients with either DGF or PGF and vasoplegia had a VAD. Further survival analyses shown in table 1. Vasoplegia is associated with a higher risk of renal allograft dysfunction following CHKTx, and is frequently associated with LVAD as a bridge to transplant. Identifying further risk factors associated with poor post-CHKTx renal graft function could help define patients for whom CHKTx is appropriate. A review of the CHKTx allocation process in high risk patient groups is warranted.

Magnetic resonance elastography vs. point shear wave ultrasound elastography for the assessment of renal allograft dysfunction

PurposeTo investigate the utility of magnetic resonance elastography (MRE) vs. ultrasound (US) point shear wave elastography (pSWE) for the assessment of chronic renal allograft dysfunction, prediction of outcome and determine the correlation with Banff pathology scores. MethodsIn this IRB approved prospective study, 27 enrolled patients with functional (n = 15) and chronic dysfunctional (n = 12) renal allografts underwent same day 2D MRE and pSWE. Histogram parameters [including mean, median, standard deviation, kurtosis and skewness] of the magnitude of the complex shear modulus (MRE) and median Young’s modulus (pSWE) were measured in the cortex (MRE and pSWE) and combined corticomedullary regions (MRE). Histopathology was available for 16 patients (4 functional, 12 dysfunctional). ResultsMRE and pSWE stiffness were not significantly different between functional and dysfunctional groups (p range 0.139-0.347). The skewness of MRE corticomedullary stiffness was significantly lower (p = 0.04) in patients with chronic dysfunction and correlated significantly with Banff histopathologic scores (range r=-0.518–0.567, p = 0.035–0.040). MRE cortical and corticomedullary mean stiffness showed strong performance in predicting graft loss/relist (AUC 0.958, p = 0.011 for both). Reliable pSWE measurements were obtained in 13 patients (48 %). pSWE stiffness did not correlate with Banff scores and did not predict outcome. ConclusionsThe skewness of MRE corticomedullary stiffness is sensitive to changes in chronic allograft dysfunction, while mean/median MRE renal stiffness and median US stiffness did not differentiate patients with stable function vs those with chronic renal allograft dysfunction. MRE corticomedullary mean stiffness appears to be a predictor of graft loss/relist. pSWE was not found to be a useful method for assessing renal allografts.