scholarly journals Association study of long-term kidney transplant rejection using whole-exome sequencing

2018 ◽  
Author(s):  
Louis Gioia ◽  
Sunil Kurian ◽  
Tony S. Mondala ◽  
Laia Bassaganyas ◽  
Pui-Yan Kwok ◽  
...  
Keyword(s):  
Interstitial Fibrosis ◽  
Transplant Rejection ◽  
Study Data ◽  
First Year ◽  
Post Transplantation ◽  
Tubular Atrophy ◽  
Association Analyses ◽  
Analysis Workflow ◽  
Meta Analyses

AbstractLong-term renal allograft rejection is the most common outcome in kidney transplantation. Continuing the crusade to extend allograft function after the first year post-transplantation, we attempted to associate genetic factors that might contribute to long-term allograft outcomes by sequencing the exomes of patients diagnosed with chronic allograft nephropathy/interstitial fibrosis and tubular atrophy. A variety of association analyses were employed, but these analyses failed to identify statistically significant associations. The study was underpowered to detect the association of rare genomic variants with small effect sizes. However, it confirmed previous reports of the absence of large effects from common variants. We have made both the study data and analysis workflow available for public use, and we hope that these resources will help to power future meta-analyses that may detect smaller effects.

Intragraft Tubular Vimentin and CD44 Expression Correlate With Long-Term Renal Allograft Function and Interstitial Fibrosis and Tubular Atrophy

2010 ◽  
Vol 90 (5) ◽  
pp. 502-509 ◽  
Author(s):  
Jesper Kers ◽  
Yi-Chun Xu-Dubois ◽  
Eric Rondeau ◽  
Nike Claessen ◽  
Mirza M. Idu ◽  
...  
Keyword(s):  
Renal Allograft ◽  
Interstitial Fibrosis ◽  
Tubular Atrophy ◽  
Cd44 Expression ◽  
Allograft Function

scholarly journals Long-Term Outcomes in 831 Kidney Transplant Recipients with 20 Years of Graft Function

2021 ◽  
Vol 8 ◽  
Author(s):  
Varvara Kirchner ◽  
Kristen Gillingham ◽  
Oscar Serrano ◽  
Srinath Chinnakotla ◽  
Ty Dunn ◽  
...  
Keyword(s):  
Kidney Transplant ◽  
Graft Survival ◽  
Interstitial Fibrosis ◽  
Graft Loss ◽  
Graft Function ◽  
Solid Organ ◽  
Kidney Transplant Recipients ◽  
Long Term Outcomes ◽  
Tubular Atrophy

An understanding of long-term outcomes for kidney transplant(KTx) recipients who survive with graft function beyond a specific time posttransplant is the first step in creating protocols to optimize care for current and improve outcomes for future recipients. We studied 831KTx recipients-580 living donor(LD); 251 deceased donor(DD)—with graft survival(GS) >20 years.  For primary LD recipients, 25-year patient survival(PS) was 83%; 35-year, 59%.  Their 25-year death-censored graft survival(DCGS) was 89%; 35-year, 72%.   DD recipients had lower PS(P<0.01), DCGS(P<0.01).   After 20 years, two major causes of graft loss(GL) were death with function(DwF)(58%, LD; 58%, DD) and interstitial fibrosis and tubular atrophy(IFTA)(22%, LD; 23%, DD).  Two major causes of DwF were cancer(31%, LD; 31%, DD) and cardiovascular disease(CVD)(19%, LD;17%, DD).  Per multivariate analysis(MVA), risk factors for GL after 20 years in pre–calcineurin inhibitor(CNI) era were human leukocyte antigen(HLA) mismatches >3 antigens, pretransplant type 1 diabetes mellitus(DM1); in CNI era, a history of rejection, female gender.  New comorbidities after 20 years were common: CVD(13%, non-DM1;18%, DM1), infections(27%, non-DM1;37%, DM1), 20-29 years posttransplant.  Cancer after 20 years included: nonmelanotic skin cancer,22%; solid organ,7%; post-transplant lymphoproliferative disease(PTLD),2%.  To improve long-term outcomes, clinical trials on prevention, recognition, and treatment of new comorbidities are needed.

scholarly journals Analyses of AUC(0–12) and C0 Compliances within Therapeutic Ranges in Kidney Recipients Receiving Cyclosporine or Tacrolimus

2020 ◽  
Vol 9 (12) ◽  
pp. 3903
Author(s):  
Aurelija Radzevičienė ◽  
Pierre Marquet ◽  
Rima Maslauskienė ◽  
Rūta Vaičiūnienė ◽  
Edmundas Kaduševičius ◽  
...  
Keyword(s):  
Interstitial Fibrosis ◽  
Characteristic Curve ◽  
Bayesian Estimator ◽  
Therapeutic Drug ◽  
Clinical Effects ◽  
Post Transplantation ◽  
Tubular Atrophy ◽  
Time Curve ◽  
Kidney Recipients ◽  
Concentration Time

The AUC (area under the concentration time curve) is considered the pharmacokinetic exposure parameter best associated with clinical effects. Unfortunately, no prospective studies of clinical outcomes have been conducted in adult transplant recipients to investigate properly the potential benefits of AUC(0–12) monitoring compared to the C0-guided therapy. The aim of the present study was to compare two methods, C0 (through level) and AUC(0–12) (area under the concentration time curve), for assessing cyclosporine and tacrolimus concentrations. The study included 340 kidney recipients. The AUC(0–12) was estimated using a Bayesian estimator and a three-point limited sampling strategy. Therapeutic drug monitoring of tacrolimus performed by using AUC(0–12) and C0 showed that tacrolimus in most cases is overdosed when considering C0, while determination of the AUC(0–12) showed that tacrolimus is effectively dosed for 27.8–40.0% of patients receiving only tacrolimus and for 25.0–31.9% of patients receiving tacrolimus with MMF (mycophenolate mofetil). In the 1–5 years post-transplantation group, 10% higher CsA (cyclosporine) dose was observed, which was proportionate with a 10% higher AUC(0–12) exposure value. This indicates good compatibility of the dosage and the AUC(0–12) method. The Bland–Altman plot demonstrated that C0 and AUC(0–12) might be interchangeable methods, while the ROC (receiver operating characteristic) curve analysis of the C0/AUC(0–12) ratio in the tacrolimus-receiving patient group demonstrated reliable performance to predict IFTA (interstitial fibrosis and tubular atrophy) after kidney transplantation, with an ROC curve of 0.660 (95% confidence interval (CI): 0.576–0.736), p < 0.01. Moreover, AUC(0–12) and C0 of tacrolimus depend on concomitant medication and adjustment of the therapeutic range for AUC(0–12) might influence the results.

scholarly journals Ischemia and Reperfusion Injury in Kidney Transplantation: Relevant Mechanisms in Injury and Repair

2020 ◽  
Vol 9 (1) ◽  
pp. 253 ◽  
Author(s):  
Gertrude J. Nieuwenhuijs-Moeke ◽  
Søren E. Pischke ◽  
Stefan P. Berger ◽  
Jan Stephan F. Sanders ◽  
Robert A. Pol ◽  
...  
Keyword(s):  
Kidney Transplantation ◽  
Reperfusion Injury ◽  
Interstitial Fibrosis ◽  
Molecular Pathways ◽  
Ischemia And Reperfusion ◽  
Ischemia And Reperfusion Injury ◽  
Tubular Atrophy ◽  
Chronic Graft Dysfunction ◽  
Injury And Repair

Ischemia and reperfusion injury (IRI) is a complex pathophysiological phenomenon, inevitable in kidney transplantation and one of the most important mechanisms for non- or delayed function immediately after transplantation. Long term, it is associated with acute rejection and chronic graft dysfunction due to interstitial fibrosis and tubular atrophy. Recently, more insight has been gained in the underlying molecular pathways and signalling cascades involved, which opens the door to new therapeutic opportunities aiming to reduce IRI and improve graft survival. This review systemically discusses the specific molecular pathways involved in the pathophysiology of IRI and highlights new therapeutic strategies targeting these pathways.

Objective Measures of Pre-Transplant Physiologic Fitness Are Strong Predictors of Very-Short Term Transplantation Related Mortality

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 2205-2205
Author(s):  
Joshua A Fein ◽  
Roni Shouval ◽  
Noga Shem-Tov ◽  
Ivetta Danylesko ◽  
Ronit Yerushalmi ◽  
...  
Keyword(s):  
Creatinine Clearance ◽  
Cumulative Incidence ◽  
First Year ◽  
Post Transplantation ◽  
Laboratory Markers ◽  
Hazard Ratios ◽  
Laboratory Biomarkers ◽  
Time Of Admission ◽  
Related Mortality

Abstract Background Allogeneic hematopoietic stem cell transplantation (HSCT) is a potentially curative therapy for many hematological malignancies, however high mortality associated with the procedure remains a significant obstacle. Predictors of intermediate- and long-term treatment-related mortality (TRM) have been established, including two well-validated scoring systems (HCT-CI, Sorror 2005; EBMT, Gratwohl 2012). These scores reflect overall comorbidity burden (HCT-CI) and disease status together with specifics of the transplant procedure (EBMT). Early mortality post-HSCT may be related closely to the patient's immediate physiological state at the time of HSCT. We hypothesized that clinical laboratory values taken at the time of admission for HSCT may give a useful representation of physiological age and fitness for transplant, and thus be highly predictive of early (100 day) and very-early (30 day) treatment-related mortality (TRM). Methods This was a retrospective study on a cohort of patients who underwent HSCT at a single center for any indication between 2000 and 2014. Hematology and chemistry laboratory data were collected from the time of admission for transplantation, prior to the initiation of conditioning regimens. Variables representing bone marrow function (neutrophils, platelets, hemoglobin), kidney function (creatinine clearance estimated by EPI), liver function (total bilirubin, AST, ALT), nutritional status (albumin) as well as age were included in a Fine & Gray Competing Risk regression at time-points of 30, 100 and 365 days. Cumulative incidence curves were constructed for variables deemed significant at each time-point. Results A total of 1,045 patients were included in this study. The median patient age was 52 (IQR 39-60). Myeloablative conditioning was used for 274 patients (26.2%) while reduced-intensity conditioning was used for 765 patients (73.2%). 568 (54.4%) patients received transplants from sibling donors, and 477 (45.6%) patients received grafts from unrelated donors. Risk associated with individual laboratory biomarkers changed over the course of the first year post-transplantation. Creatinine clearance, albumin and total bilirubin were strong predictors of early mortality (p < 0.01) at 30 days, with hazard ratios of 4.5, 3 and 2.6 respectively. Notably, the prognostic weight of these variables decreased over time. In contrast, the prognostic role of age became evident only later in the first year (table 1). Cumulative incidence of TRM in patients with creatinine clearance < 60 mL/min (fig. 1a) and with albumin < 3.5 g/dL (fig. 1b) showed markedly poorer outcomes over time, with especially strong effect in the immediate aftermath of transplantation. Conclusions Our study demonstrates that common laboratory biomarkers of physiological fitness and biological age are strong determinants of early transplantation-related mortality. These markers are complimentary to existing prognostic models, which utilize broader comorbidity categories (HCT-CI) or specifics of the transplantation procedure (EBMT score) to predict medium and long-term survival trends. Laboratory variables are readily-available objective measures, and may be of particular importance when assessing fitness for the initial transplantation procedure. Table 1 Hazard ratios of the key laboratory markers at 30, 100 and 365 days post-transplantation Table 1. Hazard ratios of the key laboratory markers at 30, 100 and 365 days post-transplantation Figure 1 Cumulative incidence curves stratified by (a) estimated creatinine clearance and (b) albumin pre-transplantation Figure 1. Cumulative incidence curves stratified by (a) estimated creatinine clearance and (b) albumin pre-transplantation Disclosures No relevant conflicts of interest to declare.

PROGRESSION OF INTERSTITIAL FIBROSIS AND TUBULAR ATROPHY IN THE FIRST YEAR AFTER RENAL TRANSPLANTATION: EARLY PROGRESSION ESPECIALLY IN NON-HEART BEATING KIDNEYS

2008 ◽  
Vol 86 (Supplement) ◽  
pp. 60
Author(s):  
M H.L. Christiaans ◽  
M A.C.J. Gelens ◽  
F M.E.G. Steegh ◽  
J P. van Hooff ◽  
R J. van Suylen ◽  
...  
Keyword(s):  
Renal Transplantation ◽  
Interstitial Fibrosis ◽  
First Year ◽  
Tubular Atrophy ◽  
Heart Beating ◽  
Early Progression

scholarly journals P1741TACROLIMUS FAST METABOLIZERS SHOW A HIGHER PROGRESSION OF INTERTITIAL FIBROSIS AND TUBULAR ATROPHY DURING THE FIRST YEAR AFTER RENAL TRASPLANTATION

2020 ◽  
Vol 35 (Supplement_3) ◽  
Author(s):  
Betty Chamoun Huacon ◽  
Irina Torres ◽  
Alejandra Gabaldon ◽  
Néstor Toapanta ◽  
Joana Sellares ◽  
...  
Keyword(s):  
Interstitial Fibrosis ◽  
Univariate Analysis ◽  
First Year ◽  
Prolonged Release ◽  
Dose Ratio ◽  
Tubular Atrophy ◽  
Protocol Biopsies ◽  
The Difference ◽  
Independent Association ◽  
Allograft Loss

Abstract Background and Aims Fast tacrolimus metabolizers (expressed as the blood concentration/ dose ratio; C / D; ng / mL * mg) showed poorer renal function at 2 years, a higher incidence of nephrotoxicity and BK polyomavirus infection. Greater variability of tacrolimus trough levels (CV) from six to twelve months is associated with the appearance of HLA antibodies, interstitial fibrosis / tubular atrophy (IFTA) progression and allograft loss. We evaluate the relationship between C / D, CV and IFTA progression. Method We evaluated a cohort of 87 low immunological risk renal transplants treated with prolonged-release tacrolimus, mycophenolate mofetil and steroids. We analyzed paired protocol biopsies at 4 and 18 months. Biopsies were evaluated according to the Banff classification and the progression of IFTA was defined as the difference of ci + ct score&gt; 0 between 18 and 4 months. The C / D ratio was calculated as the average of the value recorded at 3, 6 and 12 months of follow-up. The tacrolimus CV between 6 and 12 months was calculated using all the available determinations. Results IFTA progression was observed in 36 cases (41%). In the univariate analysis, it was found that the progression of IFTA was associated with the ci + ct score at 4 months (0.92 ± 0.94 for progressors vs. 1.89 ± 1.26 not progressors, p = 0.0003), and with the average of the C / D ratio (1.70 ± 0.73 for progressors vs. 2.28 ± 1.25 not progressors; p = 0.0144, table 1). An independent association between the C/D ratio and the progression of IFTA was observed in the multivariate analysis (OR: 0.42; 95% CI: 0.22-0.82, p = 0.027). Conclusion The results of our work suggest that fast tacrolimus metabolizers (lower C / D ratio) are more susceptible to the nephrotoxic effect of tacrolimus.

Per-protocol repeat kidney biopsy portends relapse and long-term outcome in incident cases of proliferative lupus nephritis

Rheumatology ◽  
2020 ◽  
Vol 59 (11) ◽  
pp. 3424-3434 ◽  
Author(s):  
Ioannis Parodis ◽  
Christina Adamichou ◽  
Selda Aydin ◽  
Alvaro Gomez ◽  
Nathalie Demoulin ◽  
...  
Keyword(s):  
Interstitial Fibrosis ◽  
Activity Index ◽  
Repeat Biopsy ◽  
Class Iii ◽  
Tubular Atrophy ◽  
Term Outcome ◽  
Long Term Outcome ◽  
Chronicity Index ◽  
Incident Cases

Abstract Objectives In patients with LN, clinical and histological responses to treatment have been shown to be discordant. We investigated whether per-protocol repeat kidney biopsies are predictive of LN relapses and long-term renal function impairment. Methods Forty-two patients with incident biopsy-proven active proliferative (class III/IV±V) LN from the database of the UCLouvain were included in this retrospective study. Per-protocol repeat biopsies were performed after a median [interquartile range (IQR)] time of 24.3 (21.3–26.2) months. The National Institutes of Health activity index (AI) and chronicity index (CI) scores were assessed in all biopsies. Results Despite a moderate correlation between urinary protein/creatinine ratios (UPCR) and AI scores at repeat biopsy (r = 0.48; P = 0.001), 10 patients (23.8%) with UPCR &lt; 1.0 g/g still had a high degree of histological activity (AI &gt; 3). High AI scores (continuous) in repeat biopsies were associated with an increased probability and/or shorter time to renal relapse (n = 11) following the repeat biopsy [hazard ratio (HR) = 1.2, 95% CI: 1.1, 1.3; P = 0.007], independently of proteinuria levels. High CI scores (continuous) in repeat biopsies were associated with a sustained increase in serum creatinine levels corresponding to ≥120% of the baseline value (HR = 1.8, 95% CI: 1.1, 2.9; P = 0.016) through a median (IQR) follow-up time of 131.5 (73.8–178.2) months, being also the case for acute tubulointerstitial inflammation and interstitial fibrosis/tubular atrophy in repeat but not baseline biopsies. Conclusion Our results highlight the usefulness of per-protocol repeat biopsies, herein performed after a median time of 24 months from baseline, as an integral part of the treatment evaluation, also in patients showing adequate clinical response.

scholarly journals Lithium-Associated Kidney Microcysts

2008 ◽  
Vol 8 ◽  
pp. 828-829 ◽  
Author(s):  
Jennifer Tuazon ◽  
David Casalino ◽  
Ehteshamuddin Syed ◽  
Daniel Batlle
Keyword(s):  
Chronic Kidney Disease ◽  
Kidney Disease ◽  
Mr Imaging ◽  
Interstitial Fibrosis ◽  
Renal Cysts ◽  
Lithium Therapy ◽  
Tubular Atrophy ◽  
Advanced Chronic Kidney Disease ◽  
Tubulointerstitial Nephropathy

Long-term lithium therapy is associated with impairment in concentrating ability and, occasionally, progression to advanced chronic kidney disease from tubulointerstitial nephropathy. Biopsy findings in patients with lithium-induced chronic tubulointerstitial nephropathy include tubular atrophy and interstitial fibrosis interspersed with tubular cysts and dilatations. Recent studies have shown that cysts are seen in 33––62.5% of the patients undergoing lithium therapy. MR imaging is highly capable of defining renal morphological features and has been demonstrated to be superior to US and CT scan for the visualization of small renal cysts. The microcysts are found in both cortex and medulla, particularly in the regions with extensive atrophy and fibrosis, and can be multiple and bilateral. They tend to be sparse and do not normally exceed 1–2 mm in diameter. The renal microcysts in the image here reported are subtle, but consistent with lithium-induced chronic nephropathy. An MRI of the kidneys provides noninvasive evidence that strengthens the diagnosis of lithium-induced nephropathy.

scholarly journals Impact of the relationship between hemoglobin levels and renal interstitial fibrosis on long-term outcomes in type 2 diabetes with biopsy-proven diabetic nephropathy

2021 ◽  
Vol 22 (1) ◽  
Author(s):  
Miho Shimizu ◽  
Kengo Furuichi ◽  
Shinji Kitajima ◽  
Tadashi Toyama ◽  
Megumi Oshima ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Diabetic Nephropathy ◽  
Interstitial Fibrosis ◽  
Long Term Outcomes ◽  
Renal Interstitial Fibrosis ◽  
Tubular Atrophy ◽  
Tubulointerstitial Lesions ◽  
The Impact

Abstract Background Progression of renal anemia has been shown to be associated with advanced renal tubulointerstitial lesions. This retrospective study investigated the impact of lower hemoglobin (Hb) levels and renal interstitial fibrosis and tubular atrophy (IFTA) on long-term outcomes in type 2 diabetes with biopsy-proven diabetic nephropathy. Methods A total of 233 patients were enrolled. The severity of IFTA was scored according to the classification by the Renal Pathology Society. Patients were stratified according to baseline Hb tertiles by IFTA status. The outcomes were the first occurrence of renal events (requirement for dialysis or 50 % decline in estimated glomerular filtration rate from baseline) and all-cause mortality. Results At baseline, 151 patients had severe IFTA. There were no patients who have been received erythropoiesis-stimulating agents at the time of renal biopsy. The severity of IFTA was the independent pathological factor of lower Hb levels. During the mean follow-up period of 8.6 years (maximum, 32.4 years), 119 renal events and 42 deaths were observed. Compared with the combined influence of the highest tertile of Hb and mild IFTA, the risks of renal events were higher for the middle tertile and for the lowest tertile of Hb in severe IFTA, whereas the risk of renal events was higher for the lowest tertile of Hb in mild IFTA. The risk of mortality was higher for the lowest tertile of Hb only in severe IFTA. There were significant interactions of tertile of Hb and IFTA in renal events and mortality. Conclusions Impacts of lower Hb levels on long-term outcomes of diabetic nephropathy were greater in severe IFTA than in mild IFTA.

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