Impact of Subclinical Inflammation on the Development of Interstitial Fibrosis and Tubular Atrophy in Kidney Transplant Recipients

Abstract Background In kidney transplantation, fibrosis represents the final and irreversible consequence of the pathogenic mechanisms that lead to graft failure, and in the late stages it irremediably precedes the loss of renal function. The invasiveness of kidney biopsy prevents this condition from being frequently monitored, while clinical data are rather unspecific. The objective of this study was to find noninvasive biomarkers of kidney rejection. Methods We carried out proteomic analysis of the urinary Extracellular Vesicles (uEVs) from a cohort of kidney transplant recipients (n = 23) classified according to their biopsy-based diagnosis and clinical parameters as interstitial fibrosis and tubular atrophy (IFTA), acute cellular rejection (ACR), calcineurin inhibitors toxicity (CNIT) and normal kidney function (NKF). Results Shotgun mass spectrometry of uEV-proteins identified differential expression of several proteins among these different groups. Up to 23 of these proteins were re-evaluated using targeted proteomics in a new independent cohort of patients (n = 41) classified in the same diagnostic groups. Among other results, we found a differential expression of vitronectin (VTN) in patients displaying chronic interstitial and tubular lesions (ci and ct mean > 2 according to Banff criteria). These results were further confirmed by a pilot study using enzyme-linked immunosorbent assay (ELISA). Conclusion Urinary vitronectin levels are a potential stand-alone biomarker to monitor fibrotic changes in kidney transplant recipients in a non-invasive fashion.

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Urinary MicroRNA-21-5p as Potential Biomarker of Interstitial Fibrosis and Tubular Atrophy (IFTA) in Kidney Transplant Recipients

Diagnostics ◽

10.3390/diagnostics10020113 ◽

2020 ◽

Vol 10 (2) ◽

pp. 113 ◽

Cited By ~ 2

Author(s):

Michal S. Gniewkiewicz ◽

Izabela Paszkowska ◽

Jolanta Gozdowska ◽

Katarzyna Czerwinska ◽

Anna Sadowska-Jakubowicz ◽

...

Keyword(s):

Kidney Transplant ◽

Renal Allograft ◽

Interstitial Fibrosis ◽

Graft Function ◽

Transplant Recipients ◽

Kidney Transplant Recipients ◽

Tubular Atrophy ◽

Expression Levels ◽

Allograft Dysfunction ◽

Potential Biomarker

Chronic renal allograft dysfunction (CAD) is a major limiting factor of long-term graft survival. The hallmarks of progressive CAD are interstitial fibrosis and tubular atrophy (IFTA). MicroRNAs are small, regulatory RNAs involved in many immunological processes. In particular, microRNA-21-5p (miR-21) is considered to be strongly associated with pathogenesis regarding tubulointerstitium. The aim of this study was to assess urinary miR-21 expression levels in the kidney transplant recipients and determine their application in the evaluation of IFTA and kidney allograft function. The expression levels of miR-21 were quantified in the urine of 31 kidney transplant recipients with biopsy-assessed IFTA (IFTA 0 + I: n = 17; IFTA II + III: n = 14) by real-time quantitative PCR. Urine samples were collected at the time of protocolar biopsies performed 1 or 2 years after kidney transplantation. MicroRNA-191-5p was used as reference gene. MiR-21 was significantly up-regulated in IFTA II + III group compared to IFTA 0 + I group (p = 0.003). MiR-21 correlated significantly with serum concentration of creatinine (r = 0.52, p = 0.003) and eGFR (r = −0.45; p = 0.01). ROC analysis determined the diagnostic value of miR-21 with an area under curve (AUC) of 0.80 (p = 0.0002), sensitivity of 0.86 and specificity of 0.71. miR-21 is associated with renal allograft dysfunction and IFTA. Therefore, it could be considered as a potential diagnostic, non-invasive biomarker for monitoring renal graft function.

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The determinants, biomarkers, and consequences of microvascular injury in kidney transplant recipients

AJP Renal Physiology ◽

10.1152/ajprenal.00163.2018 ◽

2019 ◽

Vol 316 (1) ◽

pp. F9-F19 ◽

Cited By ~ 1

Author(s):

Alice Doreille ◽

Mélanie Dieudé ◽

Heloise Cardinal

Keyword(s):

Kidney Disease ◽

Kidney Transplant ◽

Interstitial Fibrosis ◽

Ischemia Reperfusion ◽

Transplant Recipients ◽

Kidney Transplant Recipients ◽

Hla Antibodies ◽

Microvascular Injury ◽

Antibody Mediated Rejection ◽

Peritubular Capillaries

Independent of the initial cause of kidney disease, microvascular injury to the peritubular capillary network appears to play a central role in the development of interstitial fibrosis in both native and transplanted kidney disease. This association is explained by mechanisms such as the upregulation of profibrotic genes and epigenetic changes induced by hypoxia, capillary leakage, endothelial and pericyte transition to interstitial fibroblasts, as well as modifications in the secretome of endothelial cells. Alloimmune injury due to antibody-mediated rejection and ischemia-reperfusion injury are the two main etiologies of microvascular damage in kidney transplant recipients. The presence of circulating donor-specific anti-human leukocyte antigen (HLA) antibodies, histological findings, such as diffuse C4d staining in peritubular capillaries, and the extent and severity of peritubular capillaritis, are commonly used clinically to provide both diagnostic and prognostic information. Complement-dependent assays, circulating non-HLA antibodies, or evaluation of the microvasculature with novel imaging techniques are the subject of ongoing studies.

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

Integrative Journal of Medical Sciences ◽

10.15342/ijms.2021.451 ◽

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.

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Pilot Analysis of Late Conversion to Belatacept in Kidney Transplant Recipients for Biopsy-Proven Chronic Tacrolimus Toxicity

Journal of Transplantation ◽

10.1155/2018/1968029 ◽

2018 ◽

Vol 2018 ◽

pp. 1-6 ◽

Cited By ~ 2

Author(s):

Shruti Gupta ◽

Ivy Rosales ◽

David Wojciechowski

Keyword(s):

Interstitial Fibrosis ◽

Calcineurin Inhibitors ◽

Transplant Recipients ◽

Kidney Transplant Recipients ◽

Tubular Atrophy ◽

Transplant Patients ◽

Number Of Patients ◽

Allograft Function ◽

The Mean ◽

Arteriolar Hyalinosis

Background. Calcineurin inhibitors are associated with chronic nephrotoxicity, manifesting as interstitial fibrosis/tubular atrophy (IF/TA) and arteriolar hyalinosis. Conversion from tacrolimus to belatacept may be one strategy to preserve renal function. Methods. We conducted a retrospective review of renal transplant patients followed at our institution who were converted to belatacept and found to have chronic tacrolimus toxicity on biopsy. The primary outcome was eGFR at conversion as compared to eGFR at 3, 6, 12, and 24 months after conversion. We also assessed incidence of infection and rates of allograft survival at 1 year. Results. The average time between transplant and conversion was 11.9 years. There was no decrease in eGFR at any postconversion time point as compared with preconversion. The mean eGFR at time of preconversion was 32.9 mL/min, as compared with 35.6 mL/min at 3 months (p=0.09), 34.1 mL/min at 6 months (p=0.63), 34.9 mL/min at 12 months (p=0.57), and 39.6 mL/min at 24 months after conversion (p=0.92). Four of 7 patients had increases in their eGFR after conversion. All grafts were functioning at 1 year after conversion. Conclusion. While this study was limited by a small number of patients, belatacept conversion stabilized eGFR at all time points in patients with late allograft function due to chronic tacrolimus toxicity, with a trend towards increased eGFR at 3 months.

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Influence of CYP3A5 genetic differences in tacrolimus on quantitative interstitial fibrosis and long-term graft function in kidney transplant recipients

International Immunopharmacology ◽

10.1016/j.intimp.2018.03.004 ◽

2018 ◽

Vol 58 ◽

pp. 57-63 ◽

Cited By ~ 4

Author(s):

Naoki Komine ◽

Shigeru Satoh ◽

Mitsuru Saito ◽

Kazuyuki Numakura ◽

Takamitsu Inoue ◽

...

Keyword(s):

Kidney Transplant ◽

Interstitial Fibrosis ◽

Graft Function ◽

Genetic Differences ◽

Transplant Recipients ◽

Kidney Transplant Recipients

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Interstitial fibroblasts in donor kidneys predict late posttransplant anemia

Clinical Kidney Journal ◽

10.1093/ckj/sfz122 ◽

2019 ◽

Author(s):

Aki Mafune Hamada ◽

Izumi Yamamoto ◽

Mayuko Kawabe ◽

Haruki Katsumata ◽

Takafumi Yamakawa ◽

...

Keyword(s):

Kidney Transplant ◽

Interstitial Fibrosis ◽

Pathological Finding ◽

University Hospital ◽

Inverse Association ◽

Transplant Recipients ◽

Kidney Transplant Recipients ◽

Operating Characteristics ◽

Donor Factors ◽

Progression Of Kidney Disease

Abstract Background Posttransplant anemia (PTA) is associated with the progression of kidney disease and mortality in kidney transplant recipients. Although the main causes of PTA are recipient factors, donor factors have not been fully investigated. In this study we investigated the association of donor pathological findings with the incidence of PTA in kidney transplant recipients after 3 years of transplantation. Methods We conducted a retrospective cohort study at a single university hospital. A total of 50 consecutive adult recipients and donors were enrolled. To assess the structure of interstitial lesions, immunohistochemical staining of interstitial fibrosis and fibroblasts were assessed in 0-h biopsies for quantitative analysis. Results The incidence of PTA in this cohort was 30%. The mean hemoglobin (Hb) was 11.6 ± 0.8 g/dL in patients with PTA and 14.3 ± 1.5 g/dL in patients without PTA. An inverse association was observed in biopsies between interstitial fibrosis area and interstitial fibroblast area (P < 0.01) and each pathological finding was examined for its association with PTA incidence after multivariate adjustment. For the interstitial fibrosis area, the odds ratio (OR) was 1.94 [95% confidence interval (CI) 1.26–2.99; P < 0.01]. For the interstitial fibroblast area, the OR was 0.01 (95% CI 0.00–0.16; P < 0.01). Receiver operating characteristics curve analysis indicated that the interstitial fibroblast area had high predictive power for the incidence of PTA. Conclusions The presence of interstitial fibroblasts in donor kidneys may play an important role in predicting the incidence of PTA.

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

International Journal of Molecular Sciences ◽

10.3390/ijms22115414 ◽

2021 ◽

Vol 22 (11) ◽

pp. 5414

Author(s):

Erika T. Rhone ◽

Elissa Bardhi ◽

Sai Vineela Bontha ◽

Patrick D. Walker ◽

Jorge A. Almenara ◽

...

Keyword(s):

Molecular Markers ◽

Kidney Transplant ◽

Calcineurin Inhibitor ◽

Interstitial Fibrosis ◽

Immunosuppressive Agents ◽

Mitochondrial Activity ◽

Specific Gene ◽

Transplant Recipients ◽

Kidney Transplant Recipients ◽

Calcineurin Inhibitor Nephrotoxicity

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

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The Spectrum of Histopathological Changes in the Renal Allograft - a 12 Months Protocol Biopsy Study

Open Access Macedonian Journal of Medical Sciences ◽

10.3889/oamjms.2018.162 ◽

2018 ◽

Vol 6 (4) ◽

pp. 606-612

Author(s):

Galina Severova-Andreevska ◽

Ladislava Grcevska ◽

Gordana Petrushevska ◽

Koco Cakalaroski ◽

Aleksandar Sikole ◽

...

Keyword(s):

Kidney Transplant ◽

Cell Activation ◽

Interstitial Fibrosis ◽

Transplant Recipients ◽

Histopathological Changes ◽

Kidney Transplant Recipients ◽

Protocol Biopsy ◽

Antibody Mediated Rejection ◽

Precise Diagnosis

INTRODUCTION: Renal transplantation became a routine and successful medical treatment for Chronic Kidney Disease in the last 30 years all over the world. Introduction of Luminex based Single Antigen Beads (SAB) and recent BANFF consensus of histopathological phenotypes of different forms of rejection enables more precise diagnosis and changes the therapeutic approach. The graft biopsies, protocol or cause, indicated, remain a golden diagnostic tool for clinical follow up of kidney transplant recipients (KTR).AIM: The study aimed to analyse the histopathological changes in renal grafts 12 months after the surgery in KTR with satisfactory kidney function.MATERIAL AND METHODS: A 12-month protocol biopsy study was performed in a cohort of 50 Kidney transplant recipients (42 from living and 8 from deceased donors). Usual work-up for suitable donors and recipients, standard surgical procedure, basic principles of peri and postoperative care and follow up were done in all KTR. Sequential quadruple immunosuppression including induction with Anti-thymocyte globulin (ATG) or Interleukin-2R antagonist (IL-2R), and triple drug maintenance therapy with Calcineurin Inhibitors (CNI), Mycophenolate Mofetil (MMF) and Steroids were prescribed to all pts. Different forms of Glomerulonephritis (16), Hypertension (10), End Stage Renal Disease (13), Hereditary Nephropathies (6), Diabetes (3) and Vesicoureteral Reflux (2) were the underlying diseases. All biopsies were performed under ultrasound guidance. The 16 gauge needles with automated “gun” were used to take 2 cores of tissue. The samples were stained with HE, PAS, Trichrome Masson and Silver and reviewed by the same pathologist. A revised and uploaded BANFF 2013 classification in 6 categories (Cat) was used.RESULTS: Out of 48 biopsies, 15 (31%) were considered as normal, 4 (8%), Borderline (BL-Cat 3), 5 (10%) as Interstitial Fibrosis/Tubular Atrophy (IF/TA-Cat 5), 5 (10%) were classified as non-immunological (Cat 6), 2 as a pure antibody-mediated rejection (ABMR-Cat 2) and T-cell Mediated Rejection (TCMR-Cat 4). The remaining 17 samples were classified as a “mixed” rejection: 7 (41%) ABMR + IF/TA, 5 (29%) ABMR + BL + IF/TA, 2 (11%) BL + IF/TA, 1 (5%) ABMR + BL, 1 (5%) ABMR + TCMR and 1 (5%) TCMR + IF/TA. The mean serum creatinine at the time of the biopsy was 126.7 ± 23.4 µmol/L, while GFR-MDRD 63.4 ± 20.7 ml/min, which means that the majority of the findings were subclinical. Among the non-immunological histological findings (Cat 6), 3 cases belonged to CNI toxicity, 1 to BK nephropathy and 1 to recurrence of the primary disease.CONCLUSION: Our 12-month protocol biopsy study revealed the presence of different forms of mixed subclinical rejection. Use of recent BANFF classification and scoring system enables more precise diagnosis and subsequently different approach to the further treatment of the KTR. More correlative long-term studies including Anti HLA antibodies and Endothelial Cell Activation- Associated Transcripts (ENDAT) are needed.

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