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1.  Non-inferiority of creatinine excretion rate to urinary L-FABP and NGAL as predictors of early renal allograft function 
BMC Nephrology  2014;15:117.
We evaluated accuracy of urinary liver type fatty acid-binding protein (L-FABP) for prediction of early allograft function and compared it to neutrophil gelatinase associated lipocalin (NGAL), diuresis and urinary creatinine excretion rate (UCr).
Urine samples from 71 consecutive patients were taken 4, 10, 24 and 48 h after transplantation. We classified recipients into two groups: immediate graft function (IGF), with more than 70% reduction of serum Cr at 7th day post-transplant, and delayed graft function (DGF)/slow graft function (SGF) group (DGF - the need for hemodialysis procedure in the first week, SGF - less than 70% reduction of serum Cr in the first week).
Thirty-one recipients had IGF and 40 had DGF/SGF. L-FABP was only useful 48 h post-transplant with ROC AUC of 0.85 (95% C.I. 0.74-0.92); NGAL 24 h post-transplant had ROC AUC of 0.82 (0.7-0.91). Sensitivity, specificity, PPV and NPV for prediction of DGF/SGF with L-FABP > 9.5 mg/mmol Cr and NGAL > 33.1 μg/mmol Cr were: 86, 80, 83 and 83% (L-FABP), and 68, 93, 91, and 73% (NGAL). The difference in urine output between the groups was largest 4 h post-transplant (p = 0.001), later on the difference diminished. There were no significant differences in ROC AUC between L-FABP at 48 h, NGAL at 24 h, urine output at 4 h and UCr excretion rate at 10 h post-transplant. UCr < 0.56 mmol/h 10 h post-transplant predicted DGF/SGF with 94% sensitivity, 84% specificity, 89% PPV and 91% NPV, ROC AUC was 0.9. Classification tree with urine output 4 h and UCr 10 h post-transplant accurately predicted 89% of outcomes. When L-FABP or NGAL were added, the prediction was accurate in 92 or 90%, respectively.
L-FABP is comparable to NGAL for prediction of first week allograft function, however UCr and diuresis were non-inferior.
PMCID: PMC4107724  PMID: 25027586
Biomarker; Kidney transplantation; Delayed graft function; Outcome
2.  Comparison of Serum Neutrophil Gelatinase-associated Lipocalin (NGAL) with Serum Creatinine in Prediction of Kidney Recovery after Renal Transplantation 
Background: Because of some insult to kidney during transplantation, assessment of kidney function after the procedure is essential. It would be ideal to find a marker better than creatinine to early predict the acute kidney injury.
Objective: To compare with creatinine the predictive value of serum neutrophil gelatinase-associated lipocalin (NGAL) in detecting kidney recovery after renal transplantation.
Methods: We studied 33 patients who received kidney transplantation (deceased [n=20] and live [n=13]) during a 6-month period in 2010. Serum NGAL and creatinine, hemoglobin, and blood glucose were measured at 0, 12, 24, 48, and 72 hours after transplantation. The need for dialysis and kidney function in one week were studied.
Results: There were 16 men and 17 women with the mean±SD age of 36.3±12.2 (range: 14–58) years. Of the studied patients, 6 had delayed graft function (DGF; hemodialysis within the first week of transplant); 9 had slow graft function (SGF; serum creatinine reduction from transplantation to day 7 <70%), and 23 had immediate graft function (IGF; reduction in serum creatinine ≥70%). At any time, serum NGAL, and creatinine levels were significantly higher among patients with DGF (p=0.024) and SGF (p=0.026) compared with those with IGF. However, in those who got IGF vs non-IGF, serum creatinine levels were not significantly different (p=0.59) but serum NGAL levels differed significantly(p=0.020). Receiver-operating characteristic (ROC) curve and area under curves (AUCs) of serum NGAL and serum creatinine levels on the first post-transplantation day had similar significance in predicting the patient’s need to dialysis in the first week. However, using AUC of serum creatinine was not helpful in predicting non-IGF, compared to serum NGAL. The AUCs of the serum NGAL were 0.70 (95% CI: 0.52–0.89) and 0.76 (95% CI: 0.59–0.93) after 12 and 24 hours, respectively (p<0.05). The highest AUC (0.82) was attributed to serum NGAL of 24 hour (p=0.002).
Conclusion: Serum NGAL level especially 24 hours post-transplantation, seems to be an early accurate predictor of both the need to dialysis and slow graft function within the first week of kidney transplantation.
PMCID: PMC4089298  PMID: 25013643
Transplantation; Dialysis; Serum creatinine; Lipocalins; Serum neutrophil gelatinase-associated lipocalin
3.  rhErythropoietin-b as a tissue protective agent in kidney transplantation: a pilot randomized controlled trial 
BMC Research Notes  2015;8:21.
Extended criteria donor (ECD) and donation after circulatory death (DCD) kidneys are at increased risk of delayed graft function (DGF). Experimental evidence suggests that erythropoietin (EPO) attenuates renal damage in acute kidney injury. This study piloted the administration of high dose recombinant human EPO-beta at implantation of ECD and DCD kidneys, and evaluated biomarkers of kidney injury post-transplant.
Forty patients were randomly assigned to receive either rhEPO-b (100,000 iu) (n = 19 in the intervention group, as 1 patient was un-transplantable post randomisation), or placebo (n = 20) in this, double blind, placebo-controlled trial at Manchester Royal Infirmary from August 2007 to June 2009. Participants received either an ECD (n = 17) or DCD (n = 22) kidney. Adverse events, renal function, haematopoietic markers, and rejections were recorded out to 90 days post-transplant. Biomarkers of kidney injury (neutrophil gelatinase-associated lipocalin, Kidney Injury Molecule-1 and IL-18) were measured in blood and urine during the first post-operative week.
The incidence of DGF (53% vs 55%) (RR = 1.0; CI = 0.5-1.6; p = 0.93) and slow graft function (SGF) (32% vs 25%) (RR = 1.1; CI = 0.5-1.9; p = 0.73) respectively, serum creatinine, eGFR, haemoglobin and haematocrit, blood pressure, and acute rejection were similar in the 2 study arms. High dose rhEPO-b had little effect on the temporal profiles of the biomarkers.
High dose rhEPO-b appears to be safe and well tolerated in the early post- transplant period in this study, but has little effect on delayed or slow graft function in recipients of kidneys from DCD and ECD donors. Comparing the profiles of biomarkers of kidney injury (NGAL, IL-18 and KIM-1) showed little difference between the rhEPO-b treated and placebo groups. A meta-analysis of five trials yielded an overall estimate of the RR for DGF of 0.89 (CI = 0.73; 1.07), a modest effect favouring EPO but not a significant difference. A definitive trial based on this estimate would require 1000-2500 patients per arm for populations with base DGF rates of 50-30% and 90% power. Such a trial is clearly unfeasible.
Trial registration
EudraCT Number 2006-005373-22 ISRCTN ISRCTN85447324 registered 19/08/09.
PMCID: PMC4330593  PMID: 25643790
Ischaemia reperfusion; Delayed graft function; Erythropoietin
4.  Neutrophil Gelatinase-Associated Lipocalin in Kidney Transplantation Is an Early Marker of Graft Dysfunction and Is Associated with One-Year Renal Function 
Journal of Transplantation  2013;2013:650123.
Urinary neutrophil gelatinase-associated lipocalin (uNGAL) has been suggested as potential early marker of delayed graft function (DGF) following kidney transplantation (KTx). We conducted a prospective study in 40 consecutive KTx recipients to evaluate serial changes of uNGAL within the first week after KTx and assess its performance in predicting DGF (dialysis requirement during initial posttransplant week) and graft function throughout first year. Urine samples were collected on post-KTx days 0, 1, 2, 4, and 7. Linear mixed and multivariable regression models, receiver-operating characteristic (ROC), and areas under ROC curves were used. At all-time points, mean uNGAL levels were significantly higher in patients developing DGF (n = 18). Shortly after KTx (3–6 h), uNGAL values were higher in DGF recipients (on average +242 ng/mL, considering mean dialysis time of 4.1 years) and rose further in following days, contrasting with prompt function recipients. Day-1 uNGAL levels accurately predicted DGF (AUC-ROC = 0.93), with a performance higher than serum creatinine (AUC-ROC = 0.76), and similar to cystatin C (AUC-ROC = 0.95). Multivariable analyses revealed that uNGAL levels at days 4 and 7 were strongly associated with one-year serum creatinine. Urinary NGAL is an early marker of graft injury and is independently associated with dialysis requirement within one week after KTx and one-year graft function.
PMCID: PMC3833111  PMID: 24288591
5.  Deceased donor neutrophil gelatinase-associated lipocalin and delayed graft function after kidney transplantation: a prospective study 
Critical Care  2011;15(3):R121.
Expanding the criteria for deceased organ donors increases the risk of delayed graft function (DGF) and complicates kidney transplant outcome. We studied whether donor neutrophil gelatinase-associated lipocalin (NGAL), a novel biomarker for acute kidney injury, could predict DGF after transplantation.
We included 99 consecutive, deceased donors and their 176 kidney recipients. For NGAL detection, donor serum and urine samples were collected before the donor operation. The samples were analyzed using a commercial enzyme-linked immunosorbent assay kit (serum) and the ARCHITECT method (urine).
Mean donor serum NGAL (S-NGAL) concentration was 218 ng/mL (range 27 to 658, standard deviation (SD) 145.1) and mean donor urine NGAL (U-NGAL) concentration was 18 ng/mL (range 0 to 177, SD 27.1). Donor S-NGAL and U-NGAL concentrations correlated directly with donor plasma creatinine levels and indirectly with estimated glomerular filtration rate (eGFR) calculated using the modification of diet in renal disease equation for glomerular filtration rate. In transplantations with high (greater than the mean) donor U-NGAL concentrations, prolonged DGF lasting longer than 14 days occurred more often than in transplantations with low (less than the mean) U-NGAL concentration (23% vs. 11%, P = 0.028), and 1-year graft survival was worse (90.3% vs. 97.4%, P = 0.048). High U-NGAL concentration was also associated with significantly more histological changes in the donor kidney biopsies than the low U-NGAL concentration. In a multivariate analysis, U-NGAL, expanded criteria donor status and eGFR emerged as independent risk factors for prolonged DGF. U-NGAL concentration failed to predict DGF on the basis of receiver operating characteristic curve analysis.
This first report on S-NGAL and U-NGAL levels in deceased donors shows that donor U-NGAL, but not donor S-NGAL, measurements give added value when evaluating the suitability of a potential deceased kidney donor.
PMCID: PMC3218974  PMID: 21545740
6.  Effect of N-Acetylcysteine Pretreatment of Deceased Organ Donors on Renal Allograft Function: A Randomized Controlled Trial 
Transplantation  2015;99(4):746-753.
Antioxidant donor pretreatment is one of the pharmacologic strategy proposed to prevent renal ischemia-reperfusion injuries and delayed graft function (DGF). The aim of the study was to investigate whether a donor pretreatment with N-acetylcysteine (NAC) reduces the incidence of DGF in adult human kidney transplant recipients.
In this randomized, open-label, monocenter trial, 160 deceased heart-beating donors were allowed to perform 236 renal transplantations from September 2005 to December 2010. Donors were randomized to receive, in a single-blind controlled fashion, 600 mg of intravenous NAC 1 hr before and 2 hr after cerebral angiography performed to confirm brain death. Primary endpoint was DGF defined by the need for at least one dialysis session within the first week or a serum creatinine level greater than 200 μmol/L at day 7 after kidney transplantation.
The incidence of DGF was similar between donors pretreated with or without NAC (39/118; 33% vs. 30/118; 25.4%; P = 0.19). Requirement for at least one dialysis session was not different between the NAC and No NAC groups (17/118; 14.4% vs. 14/118; 11.8%, P = 0.56). The two groups had comparable serum creatinine levels, estimated glomerular filtration rates, and daily urine output at days 1, 7, 15, and 30 after kidney transplantation as well as at hospital discharge. No difference in recipient mortality nor in 1-year kidney graft survival was observed.
Donor pretreatment with NAC does not improve delayed graft function after kidney transplantation.
A prospective, randomized, single-blind study of donor treatment with N-acetylcysteine prior to procurement shows that antioxidant treatment does not influence early renal allograft function for organs from brain-dead donors. Alternative approaches will be necessary to prevent delayed graft function.
PMCID: PMC4376274  PMID: 25250647
7.  Prolonged Delayed Graft Function Is Associated with Inferior Patient and Kidney Allograft Survivals 
PLoS ONE  2015;10(12):e0144188.
It is unclear if there is an association between the duration of delayed graft function (DGF) and kidney transplant (KT) outcomes. This study investigated the impact of prolonged DGF on patient and graft survivals, and renal function one year after KT. This single center retrospective analysis included all deceased donor KT performed between Jan/1998 and Dec/2008 (n = 1412). Patients were grouped in quartiles according to duration of DGF (1–5, 6–10, 11–15, and >15 days, designated as prolonged DGF). The overall incidence of DGF was 54.2%. Prolonged DGF was associated with retransplantation (OR 2.110, CI95% 1.064–4.184,p = 0.033) and more than 3 HLA mismatches (OR 1.819, CI95% 1.117–2.962,p = 0.016). The incidence of acute rejection was higher in patients with DGF compared with those without DGF (36.2% vs. 12.2%, p<0.001). Compared to patients without DGF, DGF(1–5), DGF(6–10), and DGF(11–15), patients with prolonged DGF showed inferior one year patient survival (95.2% vs. 95.4% vs. 95.5% vs. 93.4% vs. 88.86%, p = 0.003), graft survival (91% vs. 91.4% vs. 92% vs. 88.7% vs. 70.5%, p<0.001), death-censored graft survival (95.7% vs. 95.4% vs. 96.4% vs. 94% vs. 79.3%, p<0.001), and creatinine clearance (58.0±24.6 vs. 55.8±22.2 vs. 53.8±24.1 vs. 53.0±27.2 vs. 36.8±27.0 mL/min, p<0.001), respectively. Multivariable analysis showed that prolonged DGF was an independent risk factor for graft loss (OR 3.876, CI95% 2.270–6.618, p<0.001), death censored graft loss (OR 4.103, CI95% 2.055–8.193, p<0.001), and death (OR 3.065, CI95% 1.536–6.117, p = 0.001). Prolonged DGF, determined by retransplantation and higher HLA mismatches, was associated with inferior renal function, and patient and graft survivals at one year.
PMCID: PMC4683001  PMID: 26679933
8.  Center-Level Variation in the Development of Delayed Graft Function Following Deceased Donor Kidney Transplantation 
Transplantation  2015;99(5):997-1002.
Patient-level risk factors for delayed graft function (DGF) have been well-described. However, the OPTN definition of DGF is based on dialysis in the first week, which is subject to center-level practice patterns. It remains unclear if there are center-level differences in DGF, and if measurable center characteristics can explain these differences.
Using 2003-2012 SRTR data, we developed a hierarchical (multilevel) model to determine the association between center characteristics and DGF incidence after adjusting for known patient risk factors, and to quantify residual variability across centers after adjustment for these factors.
Of 82,143 deceased donor kidney transplant recipients, 27.0% developed DGF, with a range across centers of 3.2-63.3%. A center’s proportion of preemptive transplants (OR 0.83, per 5% increment; 95%CI:0.74-0.93;P=0.001) and kidneys with >30 hours of cold ischemia time (OR 0.95, per 5% increment; 95%CI:0.92-0.98;P=0.001) were associated with less DGF. A center’s proportion of donation after cardiac death donors (OR 1.12, per 5% increment; 95%CI:1.03-1.17; P<0.001) and imported kidneys (OR 1.06, per 5% increment; 95%CI:1.03-1.10; P<0.001) were associated with more DGF. After patient- and center-level adjustment, only 41.8% of centers had DGF incidences consistent with the national median and 28.2% had incidences above the national median.
Significant heterogeneity in DGF incidences across centers, even after adjusting for patient and center-level characteristics, calls into question the generalizability and validity of the current DGF definition. Enhanced understanding of center-level variability and improving the definition of DGF accordingly may improve DGF’s utility in clinical care and as a surrogate endpoint in clinical trials.
PMCID: PMC4405384  PMID: 25340600
delayed graft function; kidney transplantation; Scientific Registry of Transplant Recipients
9.  Five-year experience with donation after cardiac death kidney transplantation in a Canadian transplant program: Factors affecting outcomes 
Donation after cardiac death (DCD) has led to an increase of up to 40% in the number of kidney transplants in some programs. Unfortunately, the increase in warm ischemic time results in higher rates of delayed graft function (DGF). The purpose of our study was to examine our initial 5-year experience with DCD kidney transplantation and to determine the factors involved in early postoperative function and function at 1 year.
This retrospective study included a review of the recipient and donor charts of 63 DCD kidneys retrieved and transplanted by the London Multi-Organ Transplant Program between July 2006 and October 2011. Comparisons were carried out between our early (n=31, July 2006 to January 2009) and our recent experience (n=32, March 2009 to October 2011). DGF and creatinine clearance at 3, 7 and 365 days were examined with regression analyses.
DGF was seen in 65% of transplanted kidneys. Mean creatinine clearance (CrCl) at 1 year was 66.7 mL/min. Low pre-transplant recipient daily urine output was the most statistically significant predictor of DGF in multivariate analysis (p < 0.001). In comparisons between our early and more recent results, improvements were noted in time from asystole to flush (16.0 vs. 12.0 minutes, p = 0.003), while cold ischemic time increased (464 vs. 725 minutes, p = 0.006). Experience contributed to a significant reduction in hospital length of stay (16 vs. 13 days, p = 0.035) and improved early renal function (CrCl at 3 days 7.8 vs. 11.9 mL/min, p = 0.027). The use of machine cold perfusion and higher recipient preoperative daily urine output predicted improved early renal function, while increasing donor age predicted poorer function at 1 year.
Despite early DGF, our results justify the continued transplantation of kidneys from DCD donors.
PMCID: PMC3526629  PMID: 23282662
10.  AB063. 63 cases of DCD experience in renal transplant recipients 
Translational Andrology and Urology  2015;4(Suppl 1):AB063.
To retrospectively analyze the clinical data of patients with ESRD undergoing cardiac death organ donation free (DCD) renal transplant, summarize the recovery condition after renal transplantation and the influence of DCD donor to recipient and graft postoperative.
There were 32 donors in 63 cases of DCD renal transplantation, including 28 men and four women. Their ages ranged from 3-62 years old, and the average age was 33.5 years. The donors included 28 cases of traumatic brain injury, two cases of cerebral tumor, one case of cerebral vascular accident, five children donors, 16 with preoperative abnormal creatinine (sCr).The 63 recipients included 43 men and 20 women. Their ages ranged from 25-49 years old. The average age was 33.5 years. Recipients were 23 cases of chronic glomerulonephritis original disease, 18 cases of chronic renal insufficiency, and the nine cases of high blood pressure, six cases of nephrotic syndrome, seven other cases. The recipient’s blood type were 13 type A, 30 type B, 20 type O. HLA antigen matching included four cases of five antigen mismatches, 18 cases of four antigen mismatches, 31 cases of three antigen mismatches, two antigen mismatches 11 cases. Minimized or avoided the use of strong contraction of norepinephrine renal artery vasoactive drugs during donor maintenance. Indicators for kidney assessment: clinical data including age, blood pressure, heart rate, urine output, creatinine, primary disease, past history kidney disease, dying time, vasoactive drug use, B-renal morphology and blood flow in B-ultrasound; the warm ischemia time and cold ischemic time of donor renal; color, shape and texture of donor renal; the kidney quality by application life-port renal perfusion assessment instrument; donor kidney biopsy. ARI DCD donor kidney transplant acceptance criteria: no history of chronic kidney disease, negative biopsy, no chronic structural lesions (alternative), age <50 years, occurred during or after the trauma ICU to maintain, obvious inducement, abdominal ultrasound examination without morphological abnormalities, vascular tree clear, common causes: prehospital hypovolemic shock, boosting drugs during ICU, traumatic brain injury lead to lower blood pressure perfusion, rhabdomyolysis myoglobin casts. Caution or waive the standard for kidney: die because of drowning, suffocation longer time; active infection without treatment; ICU treatment time for more than one week; dying more than 1 hour, warm ischemia time over 30 min; appearance “gray”, and after heparin infusion cannot be restored; life-port continuous perfusion RI >0.6, continuous infusion flow rate <50 mL/min; renal transplant biopsy shows a wide range of micro-thrombosis. The adoption of immunosuppressive regimen was ATG + TAC + MMF + Pre.
Forty-seven cases donors had normal sCr, 19 cases had delayed graft function (DGF) after transplantation, accounting for 40.4%. Ten cases dialyzed postoperative, accounting for 21.3%, who had an average of dialysis three times. The sCr recovery the normal time was 10.7 days. There were 16 donors had abnormal sCr (sCr at 184-504 umol/between L). All had DGF postoperative, accounting for 100%. And 11 cases dialyzed postoperative, accounting for 68.7%, an average of 6.7 times. The time of sCr returned to normal was 28.9 days after surgery. There were a total of 63 cases of DCD renal transplantation, including 35 cases of DGF, accounted for 55.6%. And 21 cases, accounting for 33.3%, should do hemodialysis postoperative. Seven cases suffered from acute rejection, 11 cases had different degree of the infection in different parts, one case died, and three cases had renal allograft loss.
Of the 63 cases of DCD renal transplantation in our hospital, through the follow up of 312 months, 94.7% of recipients transplanted kidney maintain good function in the short term. Living donor restrictions, death row organs have been banned, DCD is now an important part of the organ sources in China. Facing the organ shortage, DCD is a very potential solution of organ transplantation.
PMCID: PMC4708700
Organ donation free; renal transplant; creatinine
11.  Similar Outcomes with Different Rates of Delayed Graft Function May Reflect Center Practice, Not Center Performance 
To better understand the implications for considering delayed graft function (DGF) a performance measure, we compared outcomes associated with a 2- to 3-fold difference in the incidence of DGF at 2 transplant centers. We analyzed 5072 kidney transplantations between 1984–2006 at the University of Minnesota Medical Center (UMMC) and Hennepin County Medical Center (HCMC). In logistic regression the adjusted odds ratio for DGF at HCMC versus UMMC was 3.11 (95% Confidence Interval [CI]=2.49–3.89) for deceased donors and 2.24 (CI=1.45–3.47) for living donors. In Cox analysis of 4957 transplantations, slow graft function [SGF; creatinine >3.0 mg/dL (230 μmol/L) on day 5 without dialysis] was associated with graft failure at UMMC (Relative Risk [RR] =1.43, CI=1.25–1.64), but not HCMC (RR=0.99, CI=0.77–1.28). RR’s of DGF were similar at both centers. Thus, the lower incidence of DGF at UMMC likely resulted in a higher incidence and higher risk of SGF compared to HCMC. Indeed, graft survival for recipients with DGF at HCMC was similar (p=0.3741) to that of recipients with SGF at UMMC. We conclude that dialysis per se is likely not a cause of worse graft outcomes. A better definition is needed to measure early graft dysfunction and its effects across transplant programs.
PMCID: PMC2758075  PMID: 19459804
12.  Serum neutrophil gelatinase-associated lipocalin and recovery of kidney graft function after transplantation 
BMC Nephrology  2014;15:123.
Neutrophil gelatinase-associated lipocalin (NGAL) is a marker for acute kidney injury. We studied whether serum NGAL predicts delayed graft function (DGF) and recovery of kidney function after transplantation.
Serum NGAL was analyzed using commercial ELISA and point-of-care (POC) (Triage®, Biosite) methods. Serum samples were collected from 176 consecutive, deceased-donor kidney recipients just before transplant surgery and on day 1 and 14 after transplantation. The first 132 samples were analyzed with both methods and the remaining samples with the POC method.
The correlation between the ELISA and POC methods was 0.89, p < 0.0001 and hence the POC method was used for the remaining analyses. DGF was seen in 66/176 patients. Day 1 sNGAL was significantly higher in DGF (588 ng/ml, SD 189.6) compared to early graft function (355 ng/ml, SD 166.2, p < 0.0001) and this difference persisted on day 14. Day 1 sNGAL predicted DGF with an area under the curve (AUC) of 0.853 (CI 0.792-0.914, p < 0.0001). At the optimal cutoff level of 423 ng/ml the sensitivity was 87% and the specificity 77%. In a multivariate analysis, day 1 sNGAL emerged as an independent predictor of DGF. The sNGAL also predicted DGF lasting longer than 14 days with an AUC of 0.825 (CI 0.751-0.899, p < 0.0001). At the optimal cutoff level of 486 ng/ml, the sensitivity was 80% and specificity 75%.
Serum NGAL predicts clinically significant DGF and is useful in the care of kidney transplant recipients.
PMCID: PMC4122536  PMID: 25066815
Kidney transplantation; Delayed graft function; Serum NGAL; Point-of-care analysis
13.  Kinetic Estimation of GFR Improves Prediction of Dialysis and Recovery after Kidney Transplantation 
PLoS ONE  2015;10(5):e0125669.
The early prediction of delayed graft function (DGF) would facilitate patient management after kidney transplantation.
In a single-centre retrospective analysis, we investigated kinetic estimated GFR under non-steady-state conditions, KeGFR, in prediction of DGF. KeGFRsCr was calculated at 4h, 8h and 12h in 56 recipients of deceased donor kidneys from initial serum creatinine (sCr) concentrations, estimated creatinine production rate, volume of distribution, and the difference between consecutive sCr values. The utility of KeGFRsCr for DGF prediction was compared with, sCr, plasma cystatin C (pCysC), and KeGFRpCysC similarly derived from pCysC concentrations.
At 4h, the KeGFRsCr area under the receiver operator characteristic curve (AUC) for DGF prediction was 0.69 (95% CI: 0.56–0.83), while sCr was not useful (AUC 0.56, (CI: 0.41–0.72). Integrated discrimination improvement analysis showed that the KeGFRsCr improved a validated clinical prediction model at 4h, 8h, and 12h, increasing the AUC from 0.68 (0.52–0.83) to 0.88 (0.78–0.99) at 12h (p = 0.01). KeGFRpCysC also improved DGF prediction. In contrast, sCr provided no improvement at any time point.
Calculation of KeGFR from sCr facilitates early prediction of DGF within 4 hours of renal transplantation.
PMCID: PMC4418565  PMID: 25938452
14.  Gene Expression Profile in Delay Graft Function: Inflammatory Markers Are Associated with Recipient and Donor Risk Factors 
Mediators of Inflammation  2014;2014:167361.
Background. Delayed graft function (DGF) remains an important problem after kidney transplantation and reduced long-term graft survival of the transplanted organ. The aim of the present study was to determine if the development of DGF was associated with a specific pattern of inflammatory gene expression in expanded criteria of deceased donor kidney transplantation. Also, we explored the presence of correlations between DGF risk factors and the profile that was found. Methods. Seven days after kidney transplant, a cDNA microarray was performed on biopsies of graft from patients with and without DGF. Data was confirmed by real-time PCR. Correlations were performed between inflammatory gene expression and clinical risk factors. Results. From a total of 84 genes analyzed, 58 genes were upregulated while only 1 gene was downregulated in patients with DGF compared with no DGF (P = 0.01). The most relevant genes fold changes observed was IFNA1, IL-10, IL-1F7, IL-1R1, HMOX-1, and TGF-β. The results were confirmed for IFNA1, IL-1R1, HMOX-1 and TGF-β. A correlation was observed between TGF-β, donor age, and preablation creatinine, but not body mass index (BMI). Also, TGF-β showed an association with recipient age, while IFNA1 correlated with recipient BMI. Furthermore, TGF-β, IFNA1 and HMOX-1 correlated with several posttransplant kidney function markers, such as diuresis, ultrasound Doppler, and glycemia. Conclusions. Overall, the present study shows that DGF is associated with inflammatory markers, which are correlated with donor and recipient DGF risk factors.
PMCID: PMC4052172  PMID: 24959002
15.  Does Living Donor Hyperoxia Have an Impact on Kidney Graft Function After Transplantation? 
Nephro-urology Monthly  2013;5(3):835-839.
Improvement in the outcome of organ transplantation is related to advances in patient selection criteria, organ preservation, operative techniques, perioperative care and efficacy of immunosuppressive agents.
We aimed to evaluate the effects of higher levels of arterial PaO2 in donors on DGF (delayed graft function).
Patients and Methods
Forty patients over 18 years old with stage 4-5 chronic kidney disease (CKD) who received a kidney from living donors were enrolled. They were randomly grouped in to the case (n = 17) and control (n = 23) groups and were followed for 2 weeks after transplantation. Donors were exposed to 60% oxygen for at least 2 hours with a face-mask (venture mask) for 2 consecutive days before transplantation until arterial oxygen pressure increased in arterial blood gas to 200 mmHg. Neutrophil gelatinase associated lipocalin (NGAL), Interleuk-18 (IL-18), tumor necrosis factor- α (TNF-α) and transforming growth factor–β (TGF-β) could be good biomarkers for early diagnosis of kidney injury in renal transplant recipients; we assessed kidney function with these biomarkers.
Forty living kidney transplantations including 17 cases and 23 controls were performed; female gender was more prevalent in recipients (n = 16, 40%). The mean age of recipients was 36.1 ± 12.4 (18-67) years old. DGF was detected in 2 (5.95%) individuals, from whom one was in the case group and the other one in the control group. In the univariate analysis, there was no significant correlation between age and biomarkers in urine and serum unless for the second serum NGAL (P = 0.02, r = -0.06) and second urine IL 18 (P = 0.03, r = -0.5) which had a negative correlation, and first urine TNF α (P = 0.02, r = 0.7) which had a positive correlation.
Oxygen therapy in the case group had no significant impact on protection from DGF.
PMCID: PMC3830912  PMID: 24282796
Oxygen Inhalation Therapy; Kidney; Transplantation; Delayed Graft Function
16.  Association of pre-transplant statin use with delayed graft function in kidney transplant recipients 
BMC Nephrology  2012;13:111.
Administration of HMG-CoA reductase inhibitors (statins), prior to ischemia or prior to reperfusion has been shown to decrease ischemia-reperfusion renal injury in animal studies. It is unknown whether this protective effect is applicable to renal transplantation in humans. The aim of this study was to determine the relationship between prior statin use in renal transplant recipients and the subsequent risk of delayed graft function.
All patients who underwent deceased or living donor renal transplantation at the Princess Alexandra Hospital between 1 July 2008 and 1 August 2010 were included in this retrospective, observational cohort study. Graft function was classified as immediate graft function (IGF), dialysis-requiring (D-DGF) and non-dialysis-requiring (ND-DGF) delayed graft function. The independent predictors of graft function were evaluated by multivariable logistic regression, adjusting for donor characteristics, recipient characteristics, HLA mismatch and ischaemic times.
Overall, of the 266 renal transplant recipients, 21% exhibited D-DGF, 39% had ND-DGF and 40% had IGF. Statin use prior to renal transplantation was not significantly associated with the risk of D-DGF (adjusted odds ratio [OR] 1.05, 95% CI 0.96 – 1.15, P = 0.28). This finding was not altered when D-DGF and ND-DGF were pooled together (OR 0.98; 95% CI 0.89-1.06, p = 0.56).
The present study did not show a significant, independent association between prior statin use in kidney transplant recipients and the occurrence of delayed graft function.
PMCID: PMC3507677  PMID: 22985048
17.  “Successful Porcine Renal Transplantation after 60 Minutes of Donor Warm Ischemia: Extracorporeal Perfusion And Thrombolytics” 
Donation from uncontrolled circulatory determination of death donors (uDCD) is impractical in America because of the time needed to organize procurement before irreversible organ damage. Salvaging organs after prolonged warm ischemic time (WIT) may address this limitation. We evaluated the combination of extracorporeal support (ECS) and thrombolytics in a porcine uDCD renal transplant model.
Non anti-coagulated uDCD sustained 60min of WIT, and two groups were studied. Rapid recovery (RR-uDCD), kidneys procured using rapid topical cooling; and ECS assisted donation (E-uDCD), 4hr ECS plus thrombolytics for in-situ perfusion prior to procurement. All kidneys were flushed and cold stored, followed by transplantation into healthy nephrectomized recipients without immunosuppression. Delayed graft function (DGF) was defined as creatinine>5.0mg/dL on any postoperative day.
Twelve kidneys in E-uDCD and 6 in RR-uDCD group were transplanted. All 12 E-uDCD recipients had urine production and adequate function in the first 48hr, but two grafts (16.7%) had DGF at 96hr. All 6 recipients from RR-uDCD group had DGF at 48hr and were euthanized. Creatinine and BUN levels were significantly lower in E-uDCD compared to RR-uDCD group at 24hr (2.9±0.7mg/dL vs. 5.2±0.9mg/dL), and 48hr (3.2±0.9mg/dL vs. 7.2±1.0mg/dl); BUN levels at 24hr, (28.3±6.7mg/dL vs. 39.5±7.5mg/dL), and 48hr (23.9±5.0mg/dL vs. 46±12.9mg/dL) respectively.
ECS plus thrombolytics precondition organs in-situ yielding functional kidneys in a porcine model of uDCD with 60 minutes of WIT. This procurement method addresses logistical limitations for uDCD use in the US, and could have a major impact on the organ donor pool.
PMCID: PMC4486602  PMID: 25851315
kidney transplantation; extracorporeal support; organ perfusion; thrombolytics; donation after circulatory determination of death
18.  Short-Time Intermittent Preexposure of Living Human Donors to Hyperoxia Improves Renal Function in Early Posttransplant Period: A Double-Blind Randomized Clinical Trial 
Journal of Transplantation  2011;2011:204843.
The purpose of this human study was to investigate the effect of oxygen pretreatment in living kidney donors on early renal function of transplanted kidney. Sixty living kidney donor individuals were assigned to receive either 8–10 L/min oxygen (Group I) by a non-rebreather mask with reservoir bag intermittently for one hour at four times (20, 16, 12, and 1 hours before transplantation) or air (Group II). After kidney transplantation, urine output, blood urea nitrogen (BUN), serum creatinine, need to additional diuretics (NTADs) in the first 24 hours after transplantation, delayed graft function (DGF), the creatinine clearance (CrCL) on 10th day, and duration of hospital stay from the first posttransplant day till normalization of renal function was recorded and compared in two groups. Mean CrCL in posttransplant day 10, NTAD after 24 hours of transplantation, and urine output during 6 hours after operation were significantly better in Group I compared with Group II (P < .05). Also, DGF during the first week after operation and duration of hospital stay was less in Group I compared with Group II. Intermittent exposure of human living kidney donor to hyperoxic environment may improve renal function following kidney transplantation.
PMCID: PMC3087885  PMID: 21559250
19.  Risk factors and long-term outcomes of delayed graft function in deceased donor renal transplantation 
The purpose of this study was to analyze the risk factors for delayed graft function (DGF) and determine its impact on the outcomes of deceased donor (DD) kidney transplantation (KT).
Between January 2000 and December 2011, we performed 195 DD renal transplants. After the exclusion of primary nonfunctional grafts (n = 4), the study recipients were divided into two groups-group I, DGF (n = 31, 16.2%); group II, non-DGF (n = 160, 83.8%). The following variables were compared: donor and recipient characteristics, patient and graft survival, postoperative renal function, acute rejection (AR) episodes, and the rates of surgical and infectious complications.
Donor-related variables that showed significant differences included hypertension (P = 0.042), diabetes (P = 0.025), and prerecovery serum creatinine levels (P < 0.001). However, there were no significant differences in recipient-related factors. One significantly different transplant-related factor was positive panel reactive antibody (PRA > 20%, P = 0.008). On multivariate analysis, only the prerecovery serum creatinine level (P < 0.001; hazard ratio [HR], 1.814) was an independent risk factor for the development of DGF. A Cox multivariate analysis of risk factors for graft survival identified these independent risk factors for graft survival: nephron mass (donor kidney weight to recipient body weight ratio) index (P = 0.026; HR, 2.328), CMV infection (P = 0.038; HR, 0.114), and AR episode (P = 0.038; HR, 0.166).
In DD KT, an independent risk factor for DGF was the prerecovery serum creatinine level. Although there was a significant difference in graft survival between the DGF and non-DGF groups, DGF was not an independent risk factor for graft failure in this study.
PMCID: PMC4595821  PMID: 26446498
Delayed graft function; Deceased donor renal transplantation
20.  Is Delayed Graft Function Causally Associated with Long-Term Outcomes after Kidney Transplantation? Instrumental Variable Analysis1 
Transplantation  2013;95(8):1008-1014.
While some studies have found an association between delayed graft function (DGF) after kidney transplantation and worse long-term outcomes, a causal relationship remains controversial. We investigated this relationship using an instrumental variables model (IVM), a quasi-randomization technique for drawing causal inferences.
We identified 80,690 adult, deceased-donor, kidney-only transplant recipients from the Scientific Registry of Transplant Recipients between 1997 and 2010. We used cold ischemia time (CIT) as an instrument to test the hypothesis that DGF causes death-censored graft loss and mortality at 1 and 5 years post-transplant, controlling for an array of characteristics known to affect patient and graft survival. We compared our IVM results to a multivariable linear probability model (LPM).
DGF occurred in 27% of our sample. Graft loss rates at 1 and 5 years were 6% and 22%, respectively, and 1-year and 5-year mortality rates were 5% and 20%, respectively. In the LPM, DGF was associated with increased risk of both graft loss and mortality at 1 and 5 years (p<0.001). In the IVM, we found evidence suggesting a causal relationship between DGF and death-censored graft loss at both 1 year (13.5% increase; p<0.001) and 5 years (16.2% increase; p<0.001), and between DGF and mortality at both 1 year (7.1% increase; p<0.001) and 5 years (11.0% increase; p<0.01). Results were robust to exclusion of lower-quality as well as pumped kidneys and use of a creatinine-based definition for DGF.
Instrumental variables analysis supports a causal relationship between DGF and both graft loss and mortality.
PMCID: PMC3629374  PMID: 23591726
delayed graft function; kidney transplantation; outcomes; cold ischemia time; allograft failure
21.  Neutrophil Gelatinase Associated Lipocalin Is an Early and Accurate Biomarker of Graft Function and Tissue Regeneration in Kidney Transplantation from Extended Criteria Donors 
PLoS ONE  2015;10(6):e0129279.
Delayed graft function (DGF) is an early complication of kidney transplantation (KT) associated with increased risk of early loss of graft function. DGF increases using kidneys from extended criteria donors (ECD). NGAL is a 25KDa protein proposed as biomarker of acute kidney injury. The aim of this study was to investigate the role of NGAL as an early and accurate indicator of DGF and Tacrolimus (Tac) toxicity and as a mediator of tissue regeneration in KT from ECD.
We evaluated plasma levels of NGAL in 50 KT patients from ECD in the first 4 days after surgery or after Tac introduction.
Plasma levels of NGAL at day 1 were significantly higher in DGF group. In the non DGF group, NGAL discriminated between slow or immediate graft function and decreased more rapidly than serum creatinine. NGAL increased after Tac introduction, suggesting a role as marker of drug toxicity. In vitro, hypoxia and Tac induced NGAL release from tubular epithelial cells (TEC) favoring an autocrine loop that sustains proliferation and inhibits apoptosis (decrease of caspases and Bax/Bcl-2 ratio).
NGAL is an early and accurate biomarker of graft function in KT from ECD favoring TEC regeneration after ischemic and nephrotoxic injury.
PMCID: PMC4488380  PMID: 26125566
22.  Association between the Perioperative Antioxidative Ability of Platelets and Early Post-Transplant Function of Kidney Allografts: A Pilot Study 
PLoS ONE  2012;7(1):e29779.
Recent studies have demonstrated that the actions of platelets may unfavorably influence post-transplant function of organ allografts. In this study, the association between post-transplant graft function and the perioperative activity of platelet antioxidants was examined among kidney recipients divided into early (EGF), slow (SGF), and delayed graft function (DGF) groups.
Methodology/Principal Findings
Activities of superoxide dismutase, catalase, glutathione transferase (GST), glutathione peroxidase, and glucose-6-phosphate dehydrogenase (G6P) were determined and levels of glutathione, oxidized glutathione, and isoprostane were measured in blood samples collected immediately before and during the first and fifth minutes of renal allograft reperfusion. Our results demonstrated a significant increase in isoprostane levels in all groups. Interestingly, in DGF patients, significantly lower levels of perioperative activity of catalase (p<0.02) and GST (p<0.02) were observed. Moreover, in our study, the activity of platelet antioxidants was associated with intensity of perioperative oxidative stress. For discriminating SGF/DGF from EGF, sensitivity, specificity, and positive and negative predictive values of platelet antioxidants were 81–91%, 50–58%, 32–37%, and 90–90.5%, respectively.
During renal transplantation, significant changes occur in the activity of platelet antioxidants. These changes seem to be associated with post-transplant graft function and can be potentially used to differentiate between EGF and SGF/DGF. To the best of our knowledge, this is the first study to reveal the potential protective role of platelets in the human transplantation setting.
PMCID: PMC3261166  PMID: 22279544
23.  Pretransplant Transcriptome Profiles Identify among Kidneys with Delayed Graft Function Those with Poorer Quality and Outcome 
Molecular Medicine  2011;17(11-12):1311-1322.
Robust biomarkers are needed to identify donor kidneys with poor quality associated with inferior early and longer-term outcome. The occurrence of delayed graft function (DGF) is most often used as a clinical outcome marker to capture poor kidney quality. Gene expression profiles of 92 preimplantation biopsies were evaluated in relation to DGF and estimated glomerular filtration rate (eGFR) to identify preoperative gene transcript changes associated with short-term function. Patients were stratified into those who required dialysis during the first week (DGF group) versus those without (noDGF group) and subclassified according to 1-month eGFR of >45 mL/min (eGFRhi) versus eGFR of ≤45 mL/min (eGFRlo). The groups and subgroups were compared in relation to clinical donor and recipient variables and transcriptome-associated biological pathways. A validation set was used to confirm target genes. Donor and recipient characteristics were similar between the DGF versus noDGF groups. A total of 206 probe sets were significant between groups (P < 0.01), but the gene functional analyses failed to identify any significantly affected pathways. However, the subclassification of the DGF and noDGF groups identified 283 probe sets to be significant among groups and associated with biological pathways. Kidneys that developed postoperative DGF and sustained an impaired 1-month function (DGFlo group) showed a transcriptome profile of significant immune activation already preimplant. In addition, these kidneys maintained a poorer transplant function throughout the first-year posttransplant. In conclusion, DGF is a poor marker for organ quality and transplant outcome. In contrast, preimplant gene expression profiles identify “poor quality” grafts and may eventually improve organ allocation.
PMCID: PMC3321827  PMID: 21912807
24.  Diagnosis of kidney damage using novel acute kidney injury biomarkers: assessment of kidney function alone is insufficient 
Critical Care  2011;15(4):170.
Acute kidney injury (AKI) is a syndrome that is associated with a major burden of morbidity and mortality in a variety of high risk patient populations, many of them cared for by intensivists. Following renal transplantation, delayed graft function (DGF) caused by severe acute tubular necrosis (ATN), defined by a requirement for dialysis during the initial post-transplant week, complicates postoperative management, and if prolonged (>14 days), adversely affects allograft survival. Neutrophil gelatinase-associated lipocalin (NGAL) and other novel biomarkers can detect AKI earlier than serum creatinine, and can predict AKI severity in high risk patient populations, including kidney transplant recipients. Hollmen and colleagues now demonstrate that elevated urine NGAL in deceased kidney donors is a significant risk factor for prolonged post-transplant DGF in recipients. These findings have clear implications with regard to potentially improved assessment of deceased donor suitability for potential renal allograft donation. These findings are also consistent with the growing evidence that severe ATN diagnosed by markedly elevated levels of AKI biomarkers is a useful predictor of the requirement for acute renal replacement therapy in AKI patients.
PMCID: PMC3226312  PMID: 21740601
25.  Urinary cystatin C as an early biomarker of acute kidney injury following adult cardiothoracic surgery 
Kidney international  2008;74(8):1059-1069.
There is a need to develop early biomarkers of acute kidney injury following cardiac surgery, where morbidity and mortality are increased by its presence. Plasma cystatin C (CyC) and plasma and urine Neutrophil Gelatinase Associated Lipocalin (NGAL) have been shown to detect kidney injury earlier than changes in plasma creatinine in critically ill patients. In order to determine the utility of urinary CyC levels as a measure of kidney injury, we prospectively collected plasma and urine from 72 adults undergoing elective cardiac surgery for analysis. Acute kidney injury was defined as a 25% or greater increase in plasma creatinine or renal replacement therapy within the first 72 hours following surgery. Plasma CyC and NGAL were not useful predictors of acute kidney injury within the first 6 hours following surgery. In contrast, both urinary CyC and NGAL were elevated in the 34 patients who later developed acute kidney injury, compared to those with no injury. The urinary NGAL at the time of ICU arrival and the urinary CyC level 6 hours after ICU admission were most useful for predicting acute kidney injury. A composite time point consisting of the maximum urinary CyC achieved in the first 6 hours following surgery outperformed all individual time points. Our study suggests that urinary CyC and NGAL are superior to conventional and novel plasma markers in the early diagnosis of acute kidney injury following adult cardiac surgery.
PMCID: PMC2745082  PMID: 18650797
cystatin C; acute kidney injury; biomarker; cardiac surgery; Neutrophil Gelatinase Associated Lipocalin

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