AJKD Atlas of Renal Pathology: Kidney Transplant Interstitial Fibrosis/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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A Validation of the 2018 Revision of International Society of Nephrology/Renal Pathology Society Classification for Lupus Nephritis: A Cohort Study from China

American Journal of Nephrology ◽

10.1159/000507213 ◽

2020 ◽

Vol 51 (6) ◽

pp. 483-492 ◽

Cited By ~ 2

Author(s):

Juan Tao ◽

Hui Wang ◽

Xiao-Juan Yu ◽

Ying Tan ◽

Feng Yu ◽

...

Keyword(s):

Lupus Nephritis ◽

Renal Biopsy ◽

International Society ◽

Interstitial Fibrosis ◽

Activity Index ◽

Renal Pathology ◽

Tubular Atrophy ◽

Female Ratio ◽

Renal Outcomes

Background: A revision of the International Society of Nephrology/Renal Pathology Society (ISN/RPS) classification for lupus nephritis has been published in 2018. The current study aimed to verify the utility of this system. Materials and Methods: A total of 101 lupus nephritis patients from a large Chinese cohort who underwent renal biopsy in Peking University First Hospital were reevaluated by 2 renal pathologists, who had no knowledge of the clinical findings. The association between clinical data at the time of initial renal biopsy and follow-up and pathological features were further analyzed on all patients selected. Results: The mean age of the cohort was 33 years with a male/female ratio of 1:9, and a median follow-up period of 128 months. The presence and extent of mesangial hypercellularity, endocapillary hypercellularity, global and segmental glomerulosclerosis, neutrophil exudation/karyorrhexis, glomerular hyaline deposits, extracapillary proliferation (crescents), tubular atrophy/interstitial fibrosis, and interstitial inflammation were significantly correlated with several clinical renal injury indices (systemic lupus erythematosus disease activity index, serum creatinine value, proteinuria, and C3 level) at the time of biopsy. By multivariable Cox hazard analysis, fibrous crescents, tubular atrophy/interstitial fibrosis, and the modified National Institutes of Health chronicity index were independent risk factors for patients’ composite renal outcomes (hazard ratio [HR] 4.100 [95% CI 1.544–10.890], p = 0.005; HR 8.584 [95% CI 2.509–29.367], p = 0.001; and HR 3.218 [95% CI 1.138–9.099], p = 0.028; respectively). Conclusions: The 2018 revision of the ISN/RPS classification for lupus nephritis has utility for prediction of clinical renal outcomes.

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Interpreting CD56+ and CD163+ Infiltrates in Early versus Late Renal Transplant Biopsies

American Journal of Nephrology ◽

10.1159/000430473 ◽

2015 ◽

Vol 41 (4-5) ◽

pp. 362-369 ◽

Cited By ~ 10

Author(s):

Sung Shin ◽

Young Hoon Kim ◽

Yong Mee Cho ◽

Yangsoon Park ◽

Seungbong Han ◽

...

Keyword(s):

Kidney Transplant ◽

Graft Failure ◽

Interstitial Fibrosis ◽

Human Kidney ◽

The Other ◽

Cell Infiltration ◽

Tubular Atrophy ◽

Antibody Mediated Rejection ◽

Other Hand ◽

Histologic Lesion

Background: CD56+ and CD163+ cell infiltration in human kidney transplant biopsies have not been fully evaluated. Methods: We investigated the association of CD56+ and CD163+ cell infiltration with human kidney transplant biopsies with antibody- or T-cell-mediated rejection (TCMR) and other histologic lesions. One hundred and seventy four clinically indicated transplant biopsies were included in this analysis. Immunohistochemical staining for C4d, CD56 and CD163 was performed. Results: One hundred and seventy four indication biopsies were divided into early (≤1 year posttransplant; n = 49) and late (>1 year posttransplant; n = 125) biopsies. High numbers of CD56+ cells were uncommon in early biopsies except for those with antibody-mediated rejection (AMR) only. On the other hand, high numbers of CD56+ cells were observed in late biopsies diagnosed as TCMR only, AMR only, and TCMR combined with AMR. In early biopsies, both CD56+ and CD163+ infiltrates correlated strongly with interstitial inflammation, tubulitis, and peritubular capillaritis (ptc) scores. The ci and ct scores, however, were correlated only with the number of CD56+ cells. In late biopsies, on the other hand, the number of CD56+ infiltrates was correlated only with ptc, while the number of CD163+ infiltrates was weakly correlated with any histologic lesion. Multivariable analyses showed that chronic active AMR and the number of CD56+ cells/10 HPF were independently associated with death-censored graft failure post-biopsy. The number of CD163+ cells was not correlated with any pathologic lesion and post-biopsy graft failure. CD56+ infiltrates were also associated with interstitial fibrosis and tubular atrophy. Conclusions: Intragraft CD56+ cell infiltrates were significantly associated with AMR and subsequent poor clinical outcomes.

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Urinary vitronectin identifies patients with high levels of fibrosis in kidney grafts

Journal of Nephrology ◽

10.1007/s40620-020-00886-y ◽

2020 ◽

Author(s):

Laura Carreras-Planella ◽

David Cucchiari ◽

Laura Cañas ◽

Javier Juega ◽

Marcella Franquesa ◽

...

Keyword(s):

Differential Expression ◽

Kidney Transplant ◽

Interstitial Fibrosis ◽

Calcineurin Inhibitors ◽

Enzyme Linked Immunosorbent Assay ◽

Transplant Recipients ◽

Kidney Transplant Recipients ◽

Tubular Atrophy ◽

Non Invasive ◽

Noninvasive Biomarkers

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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Is Late Conversion To Everolimus Beneficial in Kidney Transplant Patients With Interstitial Fibrosis Tubular Atrophy?

Transplantation Journal ◽

10.1097/00007890-201407151-00019 ◽

2014 ◽

Vol 98 ◽

pp. 8

Author(s):

S. Gulati ◽

A. Sabhiki ◽

U. Gupta ◽

V. Kalra ◽

S. Tiwari ◽

...

Keyword(s):

Kidney Transplant ◽

Interstitial Fibrosis ◽

Tubular Atrophy ◽

Transplant Patients ◽

Kidney Transplant Patients

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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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IgE-Mediated Immune Response and Antibody-Mediated Rejection

Clinical Journal of the American Society of Nephrology ◽

10.2215/cjn.02870320 ◽

2020 ◽

Vol 15 (10) ◽

pp. 1474-1483 ◽

Cited By ~ 1

Author(s):

Federica Rascio ◽

Paola Pontrelli ◽

Giuseppe Stefano Netti ◽

Elisabetta Manno ◽

Barbara Infante ◽

...

Keyword(s):

Immune Response ◽

Mast Cells ◽

Kidney Transplant ◽

Interstitial Fibrosis ◽

Graft Function ◽

Specific Marker ◽

Tubular Atrophy ◽

Antibody Mediated Rejection ◽

Ige Mediated ◽

Study Participants

Background and objectivesActive antibody-mediated rejection is the main cause of kidney transplant loss, sharing with SLE the alloimmune response and the systemic activation of the IFN-α pathway. IgE-mediated immune response plays a key role in the development of SLE nephritis and is associated with IFN-α secretion. The aim of our study was to investigate IgE-mediated immune response in antibody-mediated rejection.Design, setting, participants, & measurementsThis was a cross-sectional study of 56 biopsy-proven antibody-mediated rejection study participants, 80 recipients with normal graft function/histology (control), 16 study participants with interstitial fibrosis/tubular atrophy, and six participants with SLE. We evaluated graft IgE deposition, tryptase (a mast cell marker), and CD203 (a specific marker of activated basophils) by immunofluorescence/confocal microscopy. In addition, we measured serum concentration of human myxovirus resistance protein 1, an IFN-α–induced protein, and anti-HLA IgE.ResultsWe observed a significantly higher IgE deposition in tubules and glomeruli in antibody-mediated rejection (1766±79 pixels) and SLE (1495±43 pixels) compared with interstitial fibrosis/tubular atrophy (582±122 pixels) and control (253±50 pixels). Patients with antibody-mediated rejection, but not control patients and patients with interstitial fibrosis/tubular atrophy, presented circulating anti-HLA IgE antibodies, although with a low mean fluorescence intensity. In addition, immunofluorescence revealed the presence of both mast cells and activated basophils in antibody-mediated rejection but not in control and interstitial fibrosis/tubular atrophy. The concentration of circulating basophils was significantly higher in antibody-mediated rejection compared with control and interstitial fibrosis/tubular atrophy. MxA serum levels were significantly higher in antibody-mediated rejection compared with control and correlated with the extent of IgE deposition.ConclusionsOur data suggest that IgE deposition and the subsequent recruitment of basophils and mast cells within the kidney transplant might play a role in antibody-mediated rejection.

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Genetic background determines renal response to chronic lithium treatment in female mice

Physiological Genomics ◽

10.1152/physiolgenomics.00149.2020 ◽

2021 ◽

Author(s):

Theun de Groot ◽

Rosalinda Doty ◽

Lars Damen ◽

Ruben Baumgarten ◽

Steffi Bressers ◽

...

Keyword(s):

Genetic Background ◽

Interstitial Fibrosis ◽

Lithium Treatment ◽

Renal Pathology ◽

Glomerular Injury ◽

Duration Of Treatment ◽

Tubular Atrophy ◽

Female Mice ◽

Renal Histology ◽

Urine Production

Background Chronic lithium treatment for bipolar disease causes mainly side effects in the kidney. A subset of lithium users develops nephrogenic diabetes insipidus (NDI), a urinary concentrating disorder, and chronic kidney disease (CKD). Age, lithium dose and duration of treatment are important risk factors, while genetic background might also play an important role. Methods In order to investigate the role of genetics, female mice of 29 different inbred strains were treated for one year with control or lithium chow and urine, blood and kidneys were analysed. Results Chronic lithium treatment increased urine production and/or reduced urine osmolality in 21 strains. Renal histology showed that lithium increased interstitial fibrosis and/or tubular atrophy in eight strains, while in none of the strains glomerular injury was induced. Interestingly, lithium did not elevate urinary albumin-creatinine ratio (ACR) in any strain, while eight strains even demonstrated a lowered ACR. The protective effect on ACR coincided with a similar decrease in urinary IgG levels, a marker of glomerular function, while the adverse effect of lithium on interstitial fibrosis/tubular atrophy coincided with a severe increase in urinary β2-microglobulin (B2M) levels, an indicator of proximal tubule damage. Conclusion Genetic background plays an important role in the development of lithium-induced NDI and chronic renal pathology in female mice. The strong correlation of renal pathology with urinary B2M levels indicates B2M as a promising biomarker for chronic renal damage induced by lithium.

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