1-year Protocol Biopsies Research Articles

The Importance of 1-Year Protocol Biopsy in the Long-Term Prognosis of Kidney Transplants—5-Years Follow-Up

Protocol biopsies are performed to detect subclinical pathologies that may lead to future graft dysfunction. However, they are not routinely performed interventions in every transplant center. There is no established regimen for performing them. The study aimed to evaluate if protocol biopsies can improve long-term patient outcomes after detecting early disorders and modifying treatment. Our observational study included 61 patients who underwent protocol biopsy 12 months after the transplantation. Based on the biopsy results, patients with abnormal histologic material (n=37) were divided into 3 study groups as follows: patients with mild inflammatory lesions (n=21), patients with interstitial fibrosis and tubular atrophy (IFTA) grade II to III (n=12), and patients with BK virus nephropathy (n=4). The control group (n=24) included kidney recipients with IFTA 0 to I grade. Outcomes after 5-year follow-up were evaluated. Five years after the biopsy, patients in the control group had stable graft function (5-year change in serum creatinine was -0.09 mg/dL). An increase in serum creatinine levels was observed in patients with IFTA II to III compared with the control group (0.14 mg/dL, P=.04). Immunosuppressive treatment was modified in the group with mild inflammatory changes and in the BKV group after the biopsy result. In the group with mild inflammatory lesions, renal function was stable (change of serum creatinine was -0.01 mg/dL, P=.51). In the BKV nephropathy group, there was a significant reduction in serum creatine levels (-0.48 mg/dL, P=.016). The analysis showed no diagnostic value for serum creatinine concentration (95% CI 0.49-0.78, P=.08). Protocol biopsies are useful for detecting early pathologies and preventing allograft failure. They greatly benefit patients with detectable pathology that can be treated or in whom therapy modification is possible.

Potential utility of urinary chemokine CCL2 to creatinine ratio in prognosis of 5-year graft failure and mortality post 1-year protocol biopsy in kidney transplant recipients.

Chemokines (chemotactic cytokines) are small proteins which are engaged in many pathophysiological processes, including inflammation and homeostasis. In recent years, application of chemokines in transplant medicine was intensively studied. The aim of this study was to determine the utility of urinary chemokines CCL2 (C-C motif ligand 2) and CXCL10 (C-X-C motif chemokine ligand 10) in prognosis of 5-year graft failure and mortality post 1-year protocol biopsy in renal transplant recipients. Forty patients who had a protocol biopsy 1 year after renal transplantation were included. Concentrations of CCL2 and CXCL10 in urine with reference to urine creatinine were measured. All patients were under the supervision of one transplant center. Long-term outcomes within 5 years after 1-year posttransplant biopsy were analyzed. Urinary CCL2:Cr at the time of biopsy was significantly increased in patients who died or had graft failure. CCL2:Cr was proven to be a significant predictor of 5-year graft failure and mortality (odds ratio [OR]:1.09, 95% confidence interval [CI]: 1.02-1.19, p = .02; OR: 1.08, 95% CI: 1.02-1.16, p = .04; respectively). Chemokines are easily detected by current methods. In the era of personalized medicine, urinary CCL2:Cr can be considered as a factor providing complementary information regarding risk of graft failure or increased mortality.

Vesicoureteral Reflux Causes Interstitial Inflammation in Pediatric Kidney Allograft: A Clinicopathological Analysis of 1-Year Protocol Biopsies

Introduction: At present, there is limited evidence of the histological impact of vesicoureteral reflux (VUR) on pediatric kidney allografts. In this study, we aimed to investigate the relationship between VUR diagnosed by voiding cystourethrography (VCUG) and 1-year protocol biopsy results. Methods: One hundred thirty-eight pediatric kidney transplantations were performed in Toho University Omori Medical Center between 2009 and 2019. We included 87 pediatric transplant recipients who were evaluated for VUR by VCUG prior to or at the time of the 1-year protocol biopsy and underwent a 1-year protocol biopsy after transplantation. We evaluated the clinicopathological findings of the VUR and non-VUR groups, and histological scores were evaluated using the Banff score. Tamm-Horsfall protein (THP) within the interstitium was identified by light microscopy. Results: Of the 87 transplant recipients, 18 cases (20.7%) were diagnosed with VUR by VCUG. The clinical background and findings were not significantly different between the VUR and non-VUR groups. The pathological findings revealed a significantly higher Banff total interstitial inflammation (ti) score in the VUR group than in the non-VUR group. Multivariate analysis indicated a significant relationship between the Banff ti score and THP within the interstitium, and VUR. The 3-year protocol biopsy results (n = 68) revealed a significantly higher Banff interstitial fibrosis (ci) score in the VUR group than in the non-VUR group. Conclusion: VUR caused interstitial fibrosis in the 1-year pediatric protocol biopsies, and interstitial inflammation at the 1-year protocol biopsy may affect interstitial fibrosis at the 3-year protocol biopsy.

Outcomes of dual kidney transplants from high KDPI kidneys are superior compared to single kidney high KDPI transplants at 1 year.

Dual kidney transplantation (DKT), utilizing two adult kidneys from the same donor for one recipient, has been used as a way to expand the available donor pool. These kidneys often come from high Kidney Donor Profile Index donors (KDPI>85%). Data comparing outcomes between high KDPI DKT and single kidney transplants (SKT) remain limited. We assessed outcomes of 336 high KDPI kidney transplants performed at our center; 11.0% (n=37) were DKT. Recipients of DKT were older (P=.02) and donors had a higher KDPI score (median 96%vs. 91%, P<.0001). DKT operative time was higher compared to SKT (+1.4hours, P<.0001). There were no differences in delayed graft function (54.1%vs. 51.5%, P=.77) and hospital length of stay (median 4.0vs. 3.0 days, P=.21) between DKT and SKT. Grade I Clavien-Dindo complications occurred in 8.1% of DKT and 13.7% of SKT (P=.008). There were no grade IVa, IVb, or V complications in either group. DKT had more glomerulosclerosis (P=.04), interstitial fibrosis (P=.02), tubular atrophy (P=.01), and arterial thickening (P=.03) on 1-year protocol biopsies. Estimated glomerular filtration was higher for DKT at 1- (P=.004) and 2-years post-transplant (P=.01). There were no differences in patient (HR 1.3, 95% CI .5-3.3, P=.58) or graft (HR 1.1, 95% CI .5-2.3, P=.83) survival. Good outcomes can be achieved with DKT using high KDPI kidneys with moderate chronic changes. DKT is a good option to help further utilize high KDPI kidneys and minimize discard.

Effects of antirejection therapies for early subclinical acute rejection in renal transplant protocol biopsies

BackgroundAlthough recently strengthened immunosuppression protocols have decreased the incidence of clinical acute rejection of renal transplants, subclinical acute rejection and borderline changes remain problematic. This study was performed to evaluate the effects of antirejection therapies for early subclinical acute rejection and borderline changes.MethodsIn total, 269 renal transplant patients who received 3-month and 1-year protocol biopsies after renal transplantation were enrolled this study and divided into those with normal findings (Group A) and those with ≥ borderline changes (Group B) according to the 3-month pathological results. Pathological changes, graft function, and graft survival were evaluated at 1 year.ResultsThe 3-month protocol biopsy revealed normal findings in 166 patients (Group A) and borderline changes and subclinical acute rejection in 103 patients (Group B). In Group A, 65.1% (n = 108) of the patients maintained normal findings at 1 year, while 30.1% (n = 50) deteriorated to ≥ borderline changes. In Group B, 52.4% (n = 54) of patients improved to normal. Among patients with subclinical acute rejection, 25.0% (n = 5) maintained subclinical acute rejection at 1 year despite antirejection therapy. The mean estimated glomerular filtration rate decreased from 60.4 ± 24.5 to 58.3 ± 19.0 mL/min/1.73 m2 in Group A and from 57.2 ± 28.2 to 53.7 ± 20.3 mL/min/1.73 m2 in Group B (p = 0.417). The 3-, 5-, and 7-year graft survival rates were 99.4%, 99.4%, and 97.6% in Group A and 100.0%, 98.6%, and 98.6% in Group B, respectively (p = 0.709).ConclusionsSubclinical acute rejection is likely to recur. However, intervention for subclinical acute rejection in the early period after transplantation may help to prevent subsequent histological changes.

Outcomes of Everolimus Plus Standard-Dose Tacrolimus Immunosuppression in De Novo Kidney Transplant: A Retrospective, Single-Center Study of 225 Transplants.

In this study, our aim was to compare the outcomes of everolimus versus mycophenolate mofetil plus standard-dose tacrolimus immunosuppression in patients who received de novo kidney transplant at our center in Fukuoka, Japan. In this retrospective, observational, single-center, inverse probability of treatment weighting analysis study, 225 recipients who underwent kidney transplant at our center between January 2013 and December 2018 were included. The variables considered were recipient age/sex, duration of dialysis, cytomegalovirus mismatch (seronegative recipient and seropositive donor), cause of end-stage renal disease, donor age/sex, and number of HLA mismatches. Our analyses included 85 transplant recipients in the everolimus group and 141 transplant recipients in the mycophenolate mofetil group (n = 226 overall). There were no significant differences between the groups at 1 year for incidence of patient death and allograft loss, biopsy-proven acute rejection, BK virus-associated nephropathy, surgical complications, delayed graft function, and posttransplant diabetes mellitus. Incidence of cytomegalovirus infection and estimated glomerular filtration rate were significantly lower in the everolimus group than in the mycophenolate mofetil group. Posttransplant triglyceride and low-density lipoprotein were higher in the everolimus group than in the mycophenolate mofetil group. Multivariate ordered logistic analysis showed that older donor age and an acute rejection episode, but not induction with everolimus or mean tacrolimus trough concentration throughoutthe firstpostoperative year,were significant risk factors for severity of interstitial fibrosis/tubular atrophy at the 1-year protocol biopsy (P = .004 and P < .001,respectively). Short-term outcomes with everolimus plus standard-dose tacrolimus in recipients of de novo kidney transplant were comparable to those with mycophenolate mofetil plus standard-dose tacrolimus.

Third-party bone marrow–derived mesenchymal stromal cell infusion before liver transplantation: A randomized controlled trial

Mesenchymal stromal cells (MSC) have emerged as a promising therapy to minimize the immunosuppressive regimen or induce tolerance in solid organ transplantation. In this randomized open-label phase Ib/IIa clinical trial, 20 liver transplant patients were randomly allocated (1:1) to receive a single pretransplant intravenous infusion of third-party bone marrow–derived MSC or standard of care alone. The primary endpoint was the safety profile of MSC administration during the 1-year follow-up. In all, 19 patients completed the study, and none of those who received MSC experienced infusion-related complications. The incidence of serious and non-serious adverse events was similar in the two groups. Circulating Treg/memory Treg and tolerant NK subset of CD56bright NK cells increased slightly over baseline, albeit not to a statistically significant extent, in MSC-treated patients but not in the control group. Graft function and survival, as well as histologic parameters and intragraft expression of tolerance-associated transcripts in 1-year protocol biopsies were similar in the two groups. In conclusion, pretransplant MSC infusion in liver transplant recipients was safe and induced mild positive changes in immunoregulatory T and NK cells in the peripheral blood. This study opens the way for a trial on possible tolerogenic efficacy of MSC in liver transplantation. ClinicalTrials.gov identifier: NCT02260375.

Feasibility and safety of 2-week protocol biopsy after kidney transplantation

Background: Protocol biopsies to detect and treat subclinical rejection early after kidney transplantation are useful for improv ing outcomes. However, there have been few studies on the optimal timing of early protocol biopsy. In this study, the results of 2-week and 1-year biopsies were analyzed in terms of technical feasibility, complications, and outcomes. Methods: Allograft protocol biopsies were performed in 916 adult recipients of kidney transplantation between 2012 and 2019 in our center. Retrospective analysis of complications and clinical outcomes of 880 2-week biopsies and 556 1-year biopsies were performed. Results: There were no significant difference between the median number of biopsy cores and sampled glomeruli of 2-week biopsies and 1-year biopsies. All allograft biopsies were technically successful. Total complication rates of 2-week and 1-year biopsies were 27.5% (242/880) and 15.5% (86/556). Major complication (Clavien-Dindo grading III-IV) rates of 2-week and 1-year biopsies were 0.23% (2/880) and 0.18% (1/556). There were only two major complication cases in 2-week biopsies: bleeding requiring surgical exploration (n=1) and bleeding requiring radiological intervention (n=1), and was only one major complication case in 1-year biopsies: allograft failure (n=1). There was no significant risk factor for major complication, even though immuno logic factors, pre-biopsy laboratory results, basic characteristics are analyzed with univariate and multivariate analysis. Detection rates of subclinical rejection was 16.5% (145/880) for 2-week biopsies and 32.9% (183/556) for 1-year biopsies. Conclusions: The 2-week protocol biopsy is as feasible and safe as the 1-year protocol biopsy in kidney transplant. It contributes to early detection of a significant number of subclinical rejection after kidney transplantation.

Clinicopathological Analysis of Medullary Ray Injury in 1-Year Protocol Paediatric Renal Allograft Biopsies

Aim: Medullary ray injury was recently reported in renal transplant biopsies. This study was performed to clarify the clinicopathological features of medullary ray injury in paediatric living renal transplant recipients. Methods: Paediatric recipients who completed a 5-year follow-up after living renal transplantation were enroled. We evaluated the clinical and pathological parameters of the presence or absence of medullary ray injury in their 1-year protocol biopsies. Results: Of 48 1-year protocol biopsies, 18 (37.5%) showed histological evidence of medullary ray injury. The 48 paediatric recipients were classified as those with medullary ray injury (n = 18; MRI-1Y [+] group) and those without medullary ray injury (n = 30; MRI-1Y [−] group) in the 1-year protocol biopsies. The prevalence of histological evidence of calcineurin inhibitor (CNI) nephrotoxicity, chronic obstruction or reflux nephropathy, and imaging findings of vesicoureteral reflux was 66.7, 22.2, and 7.7% in the MRI-1Y (+) group and 33.3, 13.3, and 15.4% in the MRI-1Y (−) group, respectively. Only the prevalence of CNI nephrotoxicity was significantly different between the 2 groups. There was no significant difference in the mean estimated glomerular filtration rate at 1, 3, or 5 years after transplantation between the 2 groups. Conclusion: In total, 37.5% of 1-year protocol biopsies showed histological evidence of medullary ray injury. This finding suggests that CNI nephrotoxicity might be the main contributor to medullary ray injury in 1-year protocol biopsies. The presence of medullary ray injury had little influence on renal function, at least during the first 5 years after transplantation.

Activation of final complement components after kidney transplantation as a marker of delayed graft function severity

BackgroundIschaemia–reperfusion (I/R) damage is a relevant cause of delayed graft function (DGF). Complement activation is involved in experimental I/R injury, but few data are available from kidney transplant (KT) patients. We studied the dynamics of membrane attack complex (C5b-9) as a soluble fraction (SC5b-9) and the histological deposit pattern of C3b, complement Factor H (FH) and C5b-9 in DGF patients.MethodsWe evaluated SC5b-9 levels in 59 recipients: 38 with immediate graft function and 21 with DGF. The SC5b-9 was measured at admission for KT and 7 days after KT. DGF-kidney biopsies (n = 12) and a control group of 1-year protocol biopsies without tissue damage (n = 4) were stained for C5b-9, C3b and FH.ResultsSC5b-9 increased significantly in DGF patients (Day 0: 6621 ± 2202 mAU/L versus Day 7: 9626 ± 4142 mAU/L; P = 0.006), while it remained stable in non-DGF patients. Days 0–7 increase >5% was the better cut-off associated with DGF versus non-DGF patient discrimination (sensitivity = 81%). In addition, SC5b-9 increase was related to DGF duration and worse graft function, and independently associated with DGF occurrence. SC5b-9, C3b and FH stains were observed in tubular epithelial cells basal membrane. DGF-kidney biopsies showed a more frequently high-intensity stain, a higher number of tubules with positive stain and larger perimeter of tubules with positive stains for SC5b-9, C3b and FH than control patients.ConclusionsBoth SC5b-9 levels and SC5b-9, C3b and FH deposits in tubular epithelial cells basal membrane are highly expressed in patients experiencing DGF. SC5b-9 levels increase could be useful as a marker of DGF severity.

1 -YEAR PROTOCOL BIOPSIES IN PEDIATRIC KIDNEY TRANSPLANT CHILDREN: ARE UNFAVORABLE HISTOLOGICAL LESIONS RELATED TO NO ADHERENCE?

Introduction: In adult recipients histological findings in surveillance biopsies at 1-year post kidney transplantation (KT) correlate independently with short and long-term graft survival. Donor specific antibodies (dnDSA) are associated with antibody- mediated rejection. Non-adherence (NOA) to treatment, is a risk factor for dnDSA. Studies in children with KT with protocol biopsies are scarce. Objective: To evaluate the prevalence of favorable (FAV) and unfavorable (UNFAV) histological lesions (FAV) for graft survival in 1-year protocol biopsies of KT children and to identify risk variables for these lesions. Methods: Prospective cohort study in all recipients of a 1st KT between 06/01/2018 and 05/30/2019. (TABLE 1) According to their histological risk, lesions were grouped in “FAV” and “UNFAV”. “FAV” lesions were: 1) minor morphological changes, with absence of inflammation and / or fibrosis and / or chronic glomerulopathy or glomerulonephritis, 2) Acute Interstitial inflammation without interstitial fibrosis or glomerular changes 3) Mild Interstitial fibrosis with absence of interstitial inflammation. “UNFAV” lesions were: 1) moderate-severe interstitial fibrosis without inflammation 2) acute or chronic active rejection mediated by antibodies or T cells 3) de novo glomerular disease 4) polyoma virus-associated nephropathy. dn-DSA were sought simultaneously with kidney biopsy. TAC and / or SRL variation coefficient (VC) >25% was considered a surrogate of NOA. Results: 38 children were included. 29 had “FAV” lesions (76%): 23, Minimal morphological changes, and 6 mild fibrosis. Nine had “UNFAV” histology (24%): One had disease recurrence, three acute vascular rejection, (2/3 subclinical rejection; 1/3 DSA+) and four had moderate fibrosis (2 had graft hydronephrosis and 2 had previous AR,1DSA+). Mean eGFR in patients with “UNFAV” lesions was 39 ± 12.1 ml / min/ 1.73m2 vs 65.3 ± 18 ml / min / 1.73m2 in those with “FAV” (p=0.0003). Both groups had similar pre KT clinical and demographic characteristics. (TABLE2). UNFAV patients had higher incidence of previous Acute Rejection (TABLE2). TAC or SRL VC was: < 25% in 71% of patients (n= 27), and > 25% in 19% of patients (n=11), those with irregular intake. Children with VC> 25% had higher risk of an “UNFAV” lesion in protocol biopsy (OR: 4.8; p=0,04) and higher prevalence of dnDSA (18% vs 0%; p=0.02) Conclusion: In this cohort, FAV lesions were the most prevalent and were associated with negative dnDSA and TAC or SRL VC <25%. Children with UNFAV lesions had lower eGFR. Those with TAC or SRL VC>25% had higher risk of an “UNFAV” lesion, and higher prevalence of dnDSA. Follow-up of this cohort is imperative.

Significance of revised criteria for chronic active T cell-mediated rejection in the 2017 Banff classification: Surveillance by 1-year protocol biopsies for kidney transplantation.

Diagnostic criteria for chronic active T cell-mediated rejection (CA-TCMR) were revised in the Banff 2017 consensus, but it is unknown whether the new criteria predict graft prognosis of kidney transplantation. We enrolled 406 kidney allograft recipients who underwent a 1-year protocol biopsy (PB) and investigated the diagnostic significance of Banff 2017. Interobserver reproducibility of the 3 diagnosticians showed a substantial agreement rate of 0.68 in Fleiss's kappa coefficient. Thirty-three patients (8%) were classified as CA-TCMR according to Banff 2017, and 6 were previously diagnosed as normal, 12 as acute TCMR, 10 with borderline changes, and 5 as CA-TCMR according to Banff 2015 criteria. Determinant factors of CA-TCMR were cyclosporine use (vs tacrolimus), previous acute rejection, and BK polyomavirus-associated nephropathy. In survival analysis, the new diagnosis of CA-TCMR predicted a composite graft endpoint defined as doubling serum creatinine or death-censored graft loss (log-rank test, P<.001). In multivariate analysis, CA-TCMR was associated with the second highest risk of the composite endpoint (hazard ratio: 5.42; 95% confidence interval, 2.02-14.61; P<.001 vs normal) behind antibody-mediated rejection. In conclusion, diagnosis of CA-TCMR in Banff 2017 may facilitate detecting an unfavorable prognosis of kidney allograft recipients who undergo a 1-year PB.

One-year Outcome of Everolimus With Standard-dose Tacrolimus Immunosuppression in De Novo ABO-incompatible Living Donor Kidney Transplantation: A Retrospective, Single-center, Propensity Score Matching Comparison With Mycophenolate in 42 Transplants.

Background.Despite improvement in immunosuppressive therapy, long-term kidney allograft survival remains a major challenge. The outcomes of therapy with everolimus (EVR) and standard-dose tacrolimus (Tac) have not been compared with those of mycophenolate mofetil (MMF) and standard-dose Tac in recipients of de novo ABO-incompatible (ABOi) living donor kidney transplantation (LDKT).Methods.This retrospective, observational, single-center, propensity score matching (PSM) study compared the outcomes of EVR and standard-dose Tac with those of MMF and standard-dose Tac following de novo ABOi LDKT. In total, 153 recipients of ABOi LDKT between January 2008 and March 2018 were screened for inclusion in the study. The variables considered for PSM were: recipient age/sex, duration of dialysis, cytomegalovirus mismatch (seronegative recipient and seropositive donor), cause of kidney disease, donor age/sex, and numbers of mismatches (HLA-A, HLA-B, and HLA-DR). After PSM, there were 21 patients in each group (n = 42 overall).Results.Four patients in the EVR group and 1 patient in the MMF group were withdrawn because of adverse effects. There were no significant differences between the 2 groups in 1-year outcomes regarding patient death, graft loss, delayed graft function, biopsy-proven acute rejection, infection requiring hospital admission, or estimated glomerular filtration rate. The 1-year protocol biopsy showed that the severity of interstitial fibrosis/tubular atrophy was significantly milder in the EVR group than in the MMF group.Conclusions.The findings suggest that the renal efficacy and safety of EVR and standard-dose Tac in recipients of de novo ABOi LDKT are comparable with those of MMF and standard-dose Tac.

Cirrhosis risk score of the donor organ predicts early fibrosis progression after liver transplantation.

Fibrosis progression (FP) after liver transplantation (LT) increases morbidity and mortality. Biomarkers are needed for early prediction of FP. A recipient's seven-gene cirrhosis risk score (CRS) has been associated with FP, especially in non-transplant cohorts. A broader validation of CRS, including the genotype of the donor-organ and HCV-negative patients is lacking. We therefore analyzed the impact of donor- and recipient-specific genotypes on FP after LT in a large cohort of HCV-positive and -negative patients. Genotyping from liver biopsies (n=201 donors) and peripheral blood (n=442 recipients) was performed. Cirrhosis risk score was correlated with FP at 1 and 5 years after LT. Fibrosis >/=F2 was documented in 26.5% of the recipients' CRS group (R-CRS) (defined by recipient's genotype) and in 23.4% of the donors' CRS- group (D-CRS) (defined by donor's genotype). Cumulative incidence for fibrosis >/=F2 was higher in patients with D-CRS >0.7 (p=0.03). While the R-CRS showed no prognostic relevance, D-CRS >0.7 was associated with higher hazard ratios (HRs) for fibrosis >/=F2 (HR=2.04; p=0.01), especially in HCV-negative patients (HR=2.59, p=0.03). Donors' CRS >0.7 was associated with higher risk for >/=F2 in 1-year protocol biopsies (p<0.001). Among the patients in whom both the recipient's and donor's CRS were available, fibrosis >/=F2 was encountered more frequently in patients with a D-CRS >0.7, in combination with any R-CRS, compared to patients with D-CRS scores </=0.7 (p=0.034). Donors' AZIN1, STXBP5L, TRPM5 genotypes carried a higher risk for fibrosis >/=F2 in subgroups. High D-CRS >0.7 predicted early FP after LT, especially in HCV negative patients.

Cirrhosis Risk Score of the Donor Organ Predicts Early Fibrosis Progression after Liver Transplantation

Background &amp; Aims: Fibrosis progression (FP) after liver transplantation (LT) increases morbidity and mortality. Biomarkers are needed for early prediction of FP. A recipient’s seven-gene cirrhosis risk score (CRS) has been associated with FP, especially in non-transplant cohorts. A broader validation of CRS, including the genotype of the donor-organ and HCV-negative patients is lacking. We therefore analyzed the impact of donor- and recipient-specific genotypes on FP after LT in a large cohort of HCV-positive and -negative patients.Method: Genotyping from liver biopsies (n=201 donors) and peripheral blood (n=442 recipients) was performed. Cirrhosis risk score was correlated with FP at 1 and 5 years after LT.Results: Fibrosis ≥F2 was documented in 26.5% of the recipients’ CRS group (R-CRS) (defined by recipient’s genotype) and in 23.4% of the donors’ CRS- group (D-CRS) (defined by donor’s genotype). Cumulative incidence for fibrosis ≥F2 was higher in patients with D-CRS &gt;0.7 (p=0.03). While the R-CRS showed no prognostic relevance, D-CRS &gt;0.7 was associated with higher hazard ratios (HRs) for fibrosis ≥F2 (HR=2.04; p=0.01), especially in HCV-negative patients (HR=2.59, p=0.03). Donors’ CRS &gt;0.7 was associated with higher risk for ≥F2 in 1-year protocol biopsies (p&lt;0.001). Among the patients in whom both the recipient’s and donor’s CRS were available, fibrosis ≥F2 was encountered more frequently in patients with a D-CRS &gt;0.7, in combination with any R-CRS, compared to patients with D-CRS scores ≤0.7 (p=0.034). Donors’ AZIN1, STXBP5L, TRPM5 genotypes carried a higher risk for fibrosis ≥F2 in subgroups.Conclusion: High D-CRS &gt;0.7 predicted early FP after LT, especially in HCV negative patients.

Accelerated podocyte detachment early after kidney transplantation is related to long-term allograft loss of function.

Kidney allograft half-life has not improved despite excellent short-term survival. Recent long-term surveillance biopsy studies identify accumulating glomerulosclerosis (GS) to be associated with late allograft loss. While podocyte depletion is well known to drive proteinuria and GS in animal models and human glomerular diseases, its role in renal allograft loss of function is generally not recognized. To address these questions, we collected urine from 125 kidney allograft recipients in the first posttransplant year for urine pellet messenger RNA (mRNA) and protein analysis, with a median follow up of 4.5years. Using multivariable linear models adjusted for proteinuria, transplant, recipient and donor factors, we observed that the average urine pellet podocin mRNA normalized to urine creatinine (UPodCR) in the first posttransplant year was significantly associated with an estimated glomerular filtration rate (eGFR) decline (P = 0.001). The relationship between UPodCR and eGFR decline persisted even among recipients who were nonproteinuric and who had no recurrent or de novo glomerular disease identified on 1-year protocol biopsy. Finally, we identified recipient, donor and recipient:donor body surface area mismatch ratio to be independently associated with UPodCR early after transplantation. A larger donor was protective, while a larger recipient and increased recipient:donor size mismatch ratio were associated with increased UPodCR. These findings support the concept that in kidney allografts, accelerated podocyte loss precedes proteinuria and is associated with inferior long-term allograft outcomes as measured by eGFR decline and may be initiated by recipient:donor size mismatch. Modulating factors driving early podocyte detachment after kidney transplantation may help improve long-term outcomes.

Relationship Between the Histological Findings Obtained by 1-Year Protocol Biopsies and Kidney Transplant Failure Score (KTFS)

Background Progressive reduction in acute rejection rates has led to an improvement of kidney graft survival throughout the first year, but long-term graft attrition rates remain stable beyond this point. Predicting the outcomes of kidney transplant recipients at 1-year would be useful in order to identify those for whom interventions may be needed. On one hand, it is known that allograft histology obtained by 1-year protocol biopsies is independently related to death-censored graft survival. On the other hand, several clinical risk scores, such as Kidney Transplant Failure Score (KTFS), have shown a good ability to predict long-term graft outcome. The aim of our study was to analyze the relationship between 1-year histologic findings of protocol biopsies and KTFS. Methods/Materials Between 2012 and 2016, 85 protocol biopsies were performed at 1-year post-transplant in our center and each biopsy was scored according to Banff criteria. KTFS was calculated taking into account 8 pre- and post-transplant clinical and analytical variables. Results Mean KTFS was 6.3 ± 1.7. KTFS related to t (r = 0.256, p = 0.018), i (r = 0.299, p = 0.005), ci (r = 0.326, p = 0.002), ct (r = 0.341, p = 0.001) and ah (r = 0.265, p = 0.014), but not with g, v, cg, cv, ptc or mm. Mean KTFS values were higher in patients with higher scores of t (p = 0.046), i (p = 0.008), ct (p = 0.007) and ci (p = 0.009). After multivariate linear regression analysis, both i (β 0.507, 95%CI 0.011-1.004, p = 0.045) and ci (β 0.460, 95%CI 0.034-0.886, p = 0.035) related to higher KTFS, but only 14.7% of total variation in KTFS was explained by histologic scores. Conclusion A clinical scoring system predictive of long-term kidney graft survival such as KTFS relates to both acute and chronic histologic findings in 1-year protocol biopsies, although the degree of correlation was weak. Both clinical scores and histologic variables provide additional information to predict renal graft outcome.

Unique clinical conditions associated with different acinar regions of fibrosis in long-term surviving pediatric liver grafts.

In the majority of long-term survivors after PLTx, graft fibrosis has been identified. Recently, subtypes of graft fibrosis have been described based on their predominant acinar localization. We aimed to evaluate whether the development of portal, perisinusoidal, and centrilobular distribution of graft fibrosis is related to patient or transplantation-related parameters. We reviewed the histological features in protocol liver biopsies taken at 1 and 5years after PLTx of 47 children on a tacrolimus-based immunosuppressive regimen. Fibrosis was assessed according to the LAFSc. The prevalence of portal fibrosis increased from 31% to 62%, sinusoidal from 68% to 79%, and centrilobular from 76% to 85%. The presence of portal fibrosis was associated with total bilirubin and γGT levels (each P<.02) and tended to be associated with biliary complications (P=.06). Sinusoidal fibrosis was associated with prior rejection episodes (P<.02) and centrilobular fibrosis with the presence of HLA mismatches (P=.02). In conclusion, using the LAFSc, we found a high incidence of progressive fibrosis in the 1-year and 5-year protocol biopsies after PLTx. Progression of fibrosis was observed in all acinar compartments, and each of the three locations is associated with different clinical conditions.

Relationship Between Albuminuria During the First Year and Antibody-Mediated Rejection in Protocol Biopsies in Kidney Transplant Recipients

BackgroundAntibody-mediated rejection is the main cause of deterioration of kidney transplants and frequently is detected only by means of protocol biopsies. The aim of this study was to relate the presence of albuminuria throughout the 1st year to the histologic findings detected by 1-year protocol biopsies in kidney graft recipients. MethodsRetrospective observational study of 86 protocol biopsies 1 year after transplantation. Albuminuria was measured at 3, 6, 9, and 12 months in urine samples and expressed as albumin/creatinine (mg/g). ResultsAnalysis of biopsies, reflected according to the Banff criteria, the following categories: fibrosis and tubular atrophy, 35 (40.7%); cellular rejection, 13 (15.1%); antibody-mediated rejection, 8 (9.3%); chronic glomerulopathy, 10 (11.6%); normal, 14 (16.3%); recurrence, 1 (1.2%); and other, 5 (5.8%). The proportions of patients with albuminuria for Banff scale scores (0 vs ≥1, respectively) at 6 and 12 months, respectively, after transplantation, were: for marker glomerulitis, 45.5% versus 59.3% (P = .021) and 36.4% versus 70.4% (P < .001); for marker glomerulopathy, 49.1% versus 50.0% (P = .051) and 42.1% versus 58.3% (P = .019); for marker peritubular capillaritis, 45.8% versus 60.9% (P = .047) and 39.0% versus 69.6% (P = .276); and for marker C4d, 49.2% versus 56.3% (P = .894) and 46.2% versus 56.3% (P = .774). ConclusionsThe presence of albuminuria after renal transplantation is common, especially in patients with proteinuria. Persistent albuminuria after transplantation, even at low levels, can be indicative of subclinical antibody-mediated rejection. Additional broader studies to relate the albuminuria to histologic changes observed in protocol biopsies are required.

Clinical Outcomes and Results of Pathological Findings of 1-year Protocol Biopsy in Recipients of ABO-Incompatible Living Donor Kidney Transplantants

ObjectivesABO-incompatible kidney transplantation has increased the possibility of finding suitable living donors for patients with renal failure. However, there are inevitable immunological risks, including a high risk of early post-transplantation complications. The purpose of this study was to evaluate recipient outcomes following ABO-incompatible kidney transplantation. MethodsSeventy-one patients who had undergone living-donor kidney transplantation (LDKT) at our center between January 2008 and December 2013 were divided into ABO-incompatible (ABOi; n = 21) and ABO-compatible (ABOc; n = 50) groups. Baseline data, graft function, immunosuppressant use, and the results of biopsy 1 year after LDKT were compared between the groups. ResultsRecipient preemptive LDKT rates were significantly different between groups (P = .017). Graft function, incidence of infection, and rates of T-cell-mediated rejection and borderline changes requiring medication were not significantly different. There was no acute antibody-mediated rejection. Selectivity of the immunosuppressant, tacrolimus, was significantly different between groups (P < .01); however, steroid withdrawal rates, mycophenolate mofetil doses, and calcineurin inhibitor trough levels were not different. Regarding biopsy data, interstitial fibrosis scores were significantly different between groups (P = .011), as were interstitial fibrosis and tubular atrophy scores (P = .045) and arteriolar hyalinosis score (P = .022). ConclusionABOi LDKT was relatively safe, with no significant difference in the incidence of rejection compared to ABOc LDKT. Managing chronic pathological changes and arteriolar hyalinosis prophylaxis after ABOi LDKT may result in more successful outcomes.