Cause Of Delayed Graft Function Research Articles

Evolving Medical Imaging Techniques for the Assessment of Delayed Graft Function: A Narrative Review.

Purpose of review:Delayed graft function (DGF) is a significant complication that contributes to poorer graft function and shortened graft survival. In this review, we sought to evaluate the current and emerging role of medical imaging modalities in the assessment of DGF and how it may guide clinical management.Sources of information:PubMed, Google Scholar, and ClinicalTrial.gov up until February 2021.Methods:This narrative review first examined the pathophysiology of DGF and current clinical management. We then summarized relevant studies that utilized medical imaging to assess posttransplant renal complications, namely, DGF. We focused our attention on noninvasive, evolving imaging modalities with the greatest potential for clinical translation, including contrast-enhanced ultrasound (CEUS) and multiparametric magnetic resonance imaging (MRI).Key findings:A kidney biopsy in the setting of DGF can be used to assess the degree of ischemic renal injury and to rule out acute rejection. Biopsies are accompanied by complications and may be limited by sampling bias. Early studies on CEUS and MRI have shown their potential to distinguish between the 2 most common causes of DGF (acute tubular necrosis and acute rejection), but they have generally included only small numbers of patients and have not kept pace with more recent technical advances of these imaging modalities. There remains unharnessed potential with CEUS and MRI, and more robust clinical studies are needed to better evaluate their role in the current era.Limitations:The adaptation of emerging approaches for imaging DGF will depend on additional clinical trials to study the feasibility and diagnostic test characteristics of a given modality. This is limited by access to devices, technical competence, and the need for interdisciplinary collaborations to ensure that such studies are well designed to appropriately inform clinical decision-making.

Reduced Flow in Delayed Graft Function as Assessed by IVIM Is Associated With Time to Recovery Following Kidney Transplantation.

Delayed graft function (DGF), defined as the need for dialysis in the first week after kidney transplantation, frequently complicates posttransplantation care. The most common cause of DGF is ischemia-reperfusion injury (IRI). To date, no clinical tools can accurately estimate its severity, nor the time required for recovery of kidney function. To investigate if parameters related to directed flow and diffusion of water, as determined by intravoxel incoherent motion diffusion-weighted imaging (IVIM-DWI), could be used to differentiate DGF from normal graft function posttransplantation, predict time to recovery from DGF, and hence serve as a surrogate measure of IRI severity. Prospective, cross-sectional cohort study. Fifty consecutive kidney transplant recipients within 3-10 days posttransplantation at our hospital. 3.0T/IVIM-DWI. The following IVIM-DWI parameters were studied: flow-fraction (f), apparent diffusion coefficient (ADC), and total-ADC (ADCT ). Mean intrarenal resistive index (R.I.) from Doppler ultrasound was also included for a comparison of IVIM-DWI with the clinical standard of care. Welch's t-test, Spearman's correlation, and linear regression. f was significantly reduced in DGF compared to non-DGF patients in the cortex, medulla, and whole renal parenchyma (P < 0.05). Time to recovery with respect to MRI correlated negatively with f (P < 0.05; rho = -0.52 (cortex), and -0.65 [parenchyma]), ADC (P < 0.05; rho = -0.59 [cortex], 0.59 [medulla], and -0.59 [parenchyma]) and ADCT (P < 0.05; rho = -0.54 [cortex], and -0.52 [medulla]). Whole renal parenchymal f predicted time to recovery relative to MRI (P < 0.05, adjusted r-squared = 0.36). R.I. was significantly different between the groups but did not correlate with time to recovery with respect to MRI (rho = 0.43, P = 0.096). Quantification of renal flow using IVIM-DWI has the potential to serve as a surrogate measure of IRI severity to estimate the degree of and recovery from DGF. 2 TECHNICAL EFFICACY STAGE: 3.

Delayed graft function in kidney transplantation.

Delayed graft function (DGF) has several long-term graft implications in the field of kidney transplantation and remains a challenge. The incidence of DGF is on the rise because of an increasing use of marginal kidneys in an era of organ shortage. Risk factors for DGF are numerous and stem from multiple sources in the transplant chain starting from the donor to its final allocation in the recipient. There is no FDA-approved therapy for DGF, and several therapies are being studied to mitigate ischemic injury and prolong graft survival. Published data from studies suggest that ischemia-reperfusion injury (IRI) and immune responses to transplants are the leading cause of DGF, which in turn is associated with an increased incidence in acute renal rejection. Several novel methods are being developed and are undergoing further clinical validation to prove as an effective therapy against DGF. Recent studies have proposed several different mechanisms to mitigate ischemic injury to prevent acute renal injury, both of which are representative of DGF. New therapies must be effectively reviewed to ensure advancement of DGF prevention. A number of immunotherapies targeted towards inhibition of complement activation in addition to other novel therapies might prove promising towards mitigating DGF.

Allogeneic mesenchymal stem cell as induction therapy to prevent both delayed graft function and acute rejection in deceased donor renal transplantation: study protocol for a randomized controlled trial

BackgroundUsing kidneys from deceased donors is an available strategy to meet the growing need of grafts. However, higher incidences of delayed graft function (DGF) and acute rejection exert adverse effects on graft outcomes. Since ischemia-reperfusion injury (IRI) and ongoing process of immune response to grafts are the major causes of DGF and acute rejection, the optimal induction intervention should possess capacities of both repairing renal structure injury and suppressing immune response simultaneously. Mesenchymal stem cells (MSCs) with potent anti-inflammatory, regenerative and immune-modulatory properties are considered as a candidate to prevent both DGF and acute rejection in renal transplantation. Previous studies just focused on the safety of autologous MSCs on living-related donor renal transplants, and lack of concomitant controls and the sufficient sample size and source of MSCs. Here, we propose a prospective multicenter controlled study to assess the clinical value of allogeneic MSCs in preventing both DGF and acute rejection simultaneously as induction therapy in deceased-donor renal transplantation.Methods/designRenal allograft recipients (n = 100) will be recruited and divided into trial and control groups, and 50 patients in the trial group will be administered with a dose of 2 × 106 per kilogram human umbilical-cord-derived MSCs (UC-MSCs) via peripheral vein injection preoperatively, and a dose of 5 × 106 cells via renal arterial injection during surgery, with standard induction therapy. Incidences of postoperative DGF and biopsy-proved acute rejection (BPAR) will be recorded and analyzed. Additionally, other clinical parameters such as baseline demographics, graft and recipient survival and other severe postoperative complications, including complicated urinary tract infection, severe pneumonia, and severe bleeding, will be also assessed.DiscussionThis study will clarify the clinical value of UC-MSCs in preventing DGF and acute rejection simultaneously in deceased-donor renal transplantation, and provide evidence as to whether allogeneic MSCs can be used as clinically feasible and safe induction therapy.Trial registrationClinicalTrials.gov, NCT02490020. Registered on 29 June 2015.

Protective Effects of L-Carnitine Against Delayed Graft Function in Kidney Transplant Recipients: A Pilot, Randomized, Double-Blinded, Placebo-Controlled Clinical Trial

Delayed graft function (DGF) is an early complication after deceased donor kidney transplantation with significant adverse effects on graft outcomes. Ischemia-reperfusion injury during transplantation is a major cause of DGF. Tissue concentrations of carnitine, an antioxidant and regulator of cellular energy supply, decrease in the kidney following ischemia-reperfusion insult. Based on promising animal data, this study evaluated the possible protective effect of L-carnitine against DGF. This study is a pilot, randomized, double-blind, placebo-controlled clinical trial that was conducted on kidney transplantation patients in kidney transplant ward of Imam Khomeini hospital complex affiliated to Tehran University of Medical Sciences, Tehran, Iran. Patients older than 14years old undergoing their first kidney transplantation from a deceased donor were evaluated for eligibility to take part in this study. Fifty-six patients were randomly assigned to L-carnitine or placebo groups. During this trial, 3g of oral L-carnitine or placebo was administered in 3 divided doses each day for 4 consecutive days starting the day before kidney transplantation (i.e., days -1, 0, 1, and 2). The need for dialysis within the first week after transplantation, serum creatinine and urine output were assessed daily. After hospital discharge, patients were followed for 3months regarding organ function. DGF incidence did not differ between the L-carnitine and placebo groups (18.51% vs. 23.8%, respectively; P=.68). Total allograft failure within 3months after kidney transplantation happened in 6 patients in the placebo and 1 patient in the L-carnitine group (P=.05). This study showed no protective effects of oral L-carnitine supplementation against DGF occurrence recipients; however, 3-month graft loss was lower in the L-carnitine supplemented group.

Thyroid hormone changes in early kidney transplantation and its correlation with delayed graft function.

Thyroid hormones affect kidney function and may alter with changes in kidney function, as well. We evaluated changes in serum levels of triiodothyronine (T3), thyroxin (T4), and thyroid-stimulating hormone (TSH) early after kidney transplantation and their relationship with delayed graft function (DGF). Fifty-five consecutive kidney allograft recipients were enrolled in the study. Serum levels of T3, T4, and TSH were measured on the day before transplantation, and also on posttransplant days 1, 3, 7, 14, and 21. Results were compared between patients with a normal allograft function and those with DGF. The mean T3 level decreased from 110.41 +/- 49.79 ng/dL before transplantation to 80.78 +/- 51.42 ng/dL on the 1st day after transplantation (P = .04), while T4 reduction reached a significant level on the 3rd day after transplantation (8.27 +/- 3.27 microg/dL to 5.50 +/- 2.57 microg/dL, P = .004). Patients with DGF experienced a significantly greater decrease in the serum level of T3 at the end of the 1st week after transplantation compared with patients with normal kidney function (P = .02). This significant decrease in T3 continued until the end of the 2nd week. Serum levels of T4 reduced comparably in the two groups, until the end of the 1st week, when it showed a significantly more reduction in the patients with DGF (P = .04). Both T3 and T4 reduced early after kidney transplantation, and this reduction was significantly more prominent in those with DGF. This is compatible with a consequence rather than a cause of DGF, explained in the setting of sick euthyroid syndrome.

Risk factors and consequences of delayed graft function

The impact of delayed graft function (DGF) on the outcome of renal transplantation remains controversial. We analyzed the risk factors for DGF and its impact on graft and patient survival. A total of 354 renal transplants performed between June 1986 and April 2000 were analyzed. Variables analyzed included donor and recipient age, method and duration of renal replacement therapy, HLA mismatch, cold and warm ischemia times, biopsy-confirmed acute rejection, length of stay in the hospital, serum creatinine at the end of first hospitalization as well as graft and patient survival at one, three, five and ten years. The study patients were divided into two groups: patients with DGF (G1) and those without DGF (G2). DGF occurred in 50 patients (14.1%), and it was seen more frequently in patients transplanted from deceased donors (60% vs. 40%, P <0.0001). The cause of DGF was acute tubular necrosis, seen in 98% of the cases. Univariate analysis showed a statistically significant difference between the two groups G1 and G2 in the following parameters: average duration on dialysis (52.3 vs. 36.4 months, P = 0.006), HLA mismatch (44.9% vs. 32.11% P = 0.015), donor age (35.9 vs. 40.2 years, P = 0.026), cold ischemia time (23 vs. 18.2 h, P = 0.0016), warm ischemia time (41.9 vs. 38.6 mn, P = 0.046), length of stay in the hospital during first hospitalization (54.7 vs. 33.2 days, P <0.0001), serum creatinine at the end of first hospitalization (140 vs. 112 μmol/L, P <0.0001) and at three months following transplantation (159 vs. 119 μmol/L, P = 0.0002). Multivariate analysis revealed the following independent risk factors for DGF: deceased donor (RR = 13.2, P <0.0001) and cold ischemia time (RR = 1.17, P = 0.008). The graft survival at one, three, five and ten years was 100%, 93%, 88.3% and 78.3% in G1 versus 100%, 95.9% 92.8% and 82.3% in G2; there was no statistically significant difference. The patient survival at one, three, five and ten years was 100%, 91.3%, 83.6% and 74.4% in G1 versus 100%, 95.9%, 94% and 82.6% in G2 with a statistically significant difference (P = 0.04). Prolonged cold ischemia time and transplantation of kidneys from deceased donors were the main risk factors for DGF in our study. Also, DGF significantly affected patient survival but had no influence on graft survival.

Plasma NGAL Is An Early Biomarker of Graft Function, Calcineurin Inhibitor Nephrotoxicity and Tubular Regeneration in Kidney Transplantation from Extended Criteria Donors

Delayed graft function (DGF) is an early complication of kidney transplantation (KT) usually defined as the need for dialysis in the first week after the procedure. The main cause of DGF is ischemia-reperfusion injury and the incidence of DGF has been increasing in the last years for the use of kidneys from extended criteria donors (ECD). Moreover, DGF is associated with an increased risk of acute rejection due to enhanced tissue immunogenicity and to a premature loss of kidney graft function. Plasma Neutrophil Gelatinase Associated Lipocalin (NGAL) is a 25 kDa protein belonging to the lipocalin family secreted by leukocytes and different epithelia including renal tubular epithelial cells. NGAL has been proposed as early biomarker of ischemic and toxic acute kidney injury and of DGF in kidney graft. The aims of this study were to evaluate: 1) plasma NGAL in 50 patients in the first 24h after KT from ECD; 2) the relationship between plasma NGAL and DGF, slow graft function (SGF) and immediate graft function (IGF); 3) the trend of serum creatinine (sCr) and plasma NGAL in the first 5 days after KT; 4) plasma NGAL before and after the introduction of calcineurin inhibitors (CNI, tacrolimus or cyclosporine); 5) the in vitro role of NGAL in tubular regeneration after ischemic injury. Fifty patients were enrolled in the study (immunosuppression with basiliximab, MMF and steroids: CNI introduced when sCr < 2.5 mg/dl). Patients were divided in 3 groups: DGF, SGF (sCr >3 mg/dl at day 6 after KT) and IGF (sCr < 3 mg/dl at day 6 after KT). Plasma NGAL levels were measured by a fluorimetric method (Alere, San Diego, CA). Protein and mRNA NGAL levels, proliferation and apoptosis were evaluated in isolated human tubular cells cultured under hypoxia or with therapeutic doses of tacrolimus/cyclosporine. Patients' demographics and characteristics were: male 67%, recipient age 57.65 yr, donor age 65 yr, cold ischemia time 16.8 h, HLA mismatches 3.46, recipient BMI 24.2, donor hypertension 64.4%, donor eGFR 88.66 ml/min. The incidence of DGF was 28%: in the 72% of patients without DGF, SGF occurred in 55%, IGF in 45%. Plasma NGAL levels (< 24h after KT) were significantly higher in DGF than in SGF and IGF groups (DGF 654.94 ng/ml; SGF 439.75 ng/ml; IGF 357.37 ng/ml). A decline of plasma NGAL but not of sCr was detectable at day 2 after KT with a further decrease at day 3, 4 and 5. By contrast, NGAL increased after 24 hr from CNI introduction (before CNI: 120.12 ng/ml; after CNI: 188.25 ng/ml). Human tubular cells cultured under hypoxia or in presence of tacrolimus/cyclosporine showed enhanced mRNA/protein levels of NGAL. In addition, recombinant NGAL induced a dosedependent decrease of tubular cell apoptosis via caspase inactivation and triggering of P-Akt/Akt pathway. In conclusion, the results of the present study suggest that NGAL is an early predictor of graft function and CNI nephrotoxicity after KT from ECD. These data sustain the role of NGAL as potential autocrine factor involved in tubular regeneration after ischemia-reperfusion and nephrotoxic injury.

Delayed Graft Function in the Kidney Transplant

Acute kidney injury occurs with kidney transplantation and too frequently progresses to the clinical diagnosis of delayed graft function (DGF). Poor kidney function in the first week of graft life is detrimental to the longevity of the allograft. Challenges to understand the root cause of DGF include several pathologic contributors derived from the donor (ischemic injury, inflammatory signaling) and recipient (reperfusion injury, the innate immune response and the adaptive immune response). Progressive demand for renal allografts has generated new organ categories that continue to carry high risk for DGF for deceased donor organ transplantation. New therapies seek to subdue the inflammatory response in organs with high likelihood to benefit from intervention. Future success in suppressing the development of DGF will require a concerted effort to anticipate and treat tissue injury throughout the arc of the transplantation process.

Impaired metabolism in donor kidney grafts after steroid pretreatment

Summary We recently showed in a randomized control trial that steroid pretreatment of the deceased organ donor suppressed inflammation in the transplant organ but did not reduce the rate or duration of delayed graft function (DGF). This study sought to elucidate such of those factors that caused DGF in the steroid-treated subjects. Genome-wide gene expression profiles were used from 20 steroid-pretreated donor-organs and were analyzed on the level of regulatory protein-protein interaction networks. Significance analysis of microarrays (SAM) yielded 63 significantly down-regulated sequences associated with DGF that could be functionally categorized according to Protein ANalysis THrough Evolutionary Relationships ontologies into two main biologic processes: transport (P < 0.001) and metabolism (P < 0.001). The identified genes suggest hypoxia as the cause of DGF, which cannot be counterbalanced by steroid treatment. Our data showed that molecular pathways affected by ischemia such as transport and metabolism are associated with DGF. Potential interventional targeted therapy based on these findings includes peroxisome proliferator-activated receptor agonists or caspase inhibitors.

Influence of retrieval conditions on renal medulla injury: evaluation by proton NMR spectroscopy in an isolated perfused pig kidney model.

Delayed graft function (DGF) has remained an important complication after renal transplantation. The exact causes of DGF remain to be clarified, particularly the impact of retrieval conditions and preservation factors. In the present investigation, (1)HNMR spectroscopy of urine was assessed in order to detect the influence of retrieval condition on renal medulla damage. The isolated perfused pig kidney (IPK) was used to assess initial renal function from multiorgan donors (MOD) or single organ donors (SOD) after in situ cold flush and 24-h cold storage (CS) preservation with two standard preservation solutions: Euro-Collins (EC) and University of Wisconsin (UW) solutions. Kidneys flushed with cold heparinized saline and immediately perfused were used as the control group. Kidneys were perfused for 90 min at 37.5 degrees C for functional evaluation. During reperfusion, renal perfusion flow rate (PF) was measured. Glomerular filtration rate (GFR), tubular reabsorption of Na(+), and lactate dehydrogenase (LDH) and N-acetyl-beta-d-glucosaminidase (NAG) excretions were determined. Ischemia-reperfusion impairment was also determined by histological techniques and (1)HNMR spectroscopy. PF, GFR, and tubular reabsorption of Na(+) were significantly decreased in experimental groups when compared to the control group but there was no significant difference between experimental SOD groups. GFR was significantly greater in UW-MOD than in EC-MOD and tubular reabsorption of Na(+) was significantly greater in UW-MOD than in EC-MOD after 45 min of reperfusion. The release of LDH in the effluent and the urinary excretion of NAG were not significantly different after 24-h CS in the various experimental groups. The most relevant resonances determined by (1)HNMR spectroscopy were citrate, trimethylamine-N-oxide, lactate, acetate, and amino acids. Excretion of these markers was significantly different when compared to biochemical markers. A resonance (P) detected particularly in EC-MOD after 24-h CS was identified and well correlated to renal dysfunction. Histological study showed that ultrastructural damage and mitochondrial injury were more pronounced in the EC-MOD group. These results show that retrieval condition influences renal medullary damage. NMR spectroscopy, which is a noninvasive and nondestructive technique, is more efficient in assessing renal damage than conventional histology and biochemical analysis.

INCREASED LEVELS OF ALPHA-2,6-SIALYLTRANSFERASE PRE-TRANSPLANT PREDICT DELAYED GRAFT FUNCTION IN KIDNEY TRANSPLANTS.

594 Sialyltransferase is an acute phase reactant whose release from cells can be induced by pro-inflammatory cytokines. The importance of changes in the level of sialyltransferase activity may lie in its regulatory effects on cellular adhesion molecules, in particular in ischemia reperfusion injury through neutrophil adherence to endothelium. Patients with chronic renal failure have high circulating levels of pro-inflammatory cytokines. We hypothesized therefore that patients on the renal transplant waiting list would have high levels of sialyltransferase. High levels of sialyltransferase might adversely affect post-transplant (Tx) events, particularly the development of delayed graft function (DGF). Levels of sialyltransferase were measured in serum samples taken immediately pre-Tx in 70 patients. The mean serum level of sialyltransferase(3162±97 units/ml) was significantly higher than in 19 controls(2569±125 units/ml; p<0.003). We found that patients who required dialysis post-Tx for treatment of DGF (n=20) had significantly higher levels of sialyltransferase pre-Tx (3735±228 units/ml) than patients (n=50) who did not require dialysis (2933±83 units/ml; p< 0.0001). Sialyltransferase activity was also correlated (r= 0.48; p<0.02) with the total prednisone requirement of patients in the first month post-Tx. Using stepwise logistic regression we found that sialyltransferase levels correlated with the length of time on dialysis (r=0.28; p<0.03), were significantly higher in patients with previously failed transplants(3877±345 vs 3095±98; p< 0.02), and in patients whose original cause of renal failure was glomerulonephritis (3294±140 units/ml vs 2966±197; p<0.005). Conclusions: These data suggest that high sialytransferase activity pre-transplant may be a risk factor for the development of DGF. As DGF is a major predictor of long-term graft outcome, an understanding of the cause of DGF and possible contribution of sialyltransferase to this event is important. The assessment and perhaps modulation of a potential transplant recipient's systemic sialyltransferase level may be beneficial.

Influence of cadaveric organ source on delayed renal allograft function.

From 1984 to 1987, 110 locally retrieved cadaveric kidneys were transplanted into 108 local recipients, including 50 kidneys from multiple-organ retrieval (MOR) procedures and 60 from kidney-only (KO) donors. Conventional multiple organ retrieval technique, iced Euro-Collins storage, and cyclosporine-prednisone immunosuppression were employed. Delayed graft function (DGF), defined as dialysis dependence after transplantation, was twice as high in the MOR allografts as in the KO allografts, 46% vs. 22%, P less than 0.01. DGF was associated with longer hospitalization postoperatively and reduced eventual allograft function. The greater concordance of DGF in allograft pairs from the MOR group (25% vs. 7% in the KO group) and the increased incidence of DGF when more complex forms of MOR were used (40% with liver or heart retrieval, 55% with liver and heart retrieval) suggested that retrieval-related factors influenced allograft function. DGF in the MOR allografts was unrelated to other differences in donor, preservation, or recipient characteristics in the comparative groups. Unrecognized warm ischemia during conventional MOR is a plausible cause of DGF in kidneys from multiple-organ donors.