Impact of temporal and spatial resolution on atrial feature tracking cardiovascular magnetic resonance imaging.

BACKGROUND: Myocardial deformation assessment by cardiovascular magnetic resonance-feature tracking (CMR-FT) has incremental prognostic value over volumetric analyses. Recently, atrial functional analyses have come to the fore. However, to date recommendations for optimal resolution parameters for accurate atrial functional analyses are still lacking. METHODS: CMR-FT was performed in 12 healthy volunteers and 9 ischemic heart failure (HF) patients. Cine sequences were acquired using different temporal (20, 30, 40 and 50 frames/cardiac cycle) and spatial resolution parameters (high 1.5 × 1.5 mm in plane and 5 mm slice thickness, standard 1.8 × 1.8 × 8 mm and low 3.0 × 3.0 × 10 mm). Inter- and intra-observer reproducibility were calculated. RESULTS: Increasing temporal resolution is associated with higher absolute strain and strain rate (SR) values. Significant changes in strain assessment for left atrial (LA) total strain occurred between 20 and 30 frames/cycle amounting to 2,5-4,4% in absolute changes depending on spatial resolution settings. From 30 frames/cycle onward, absolute strain values remained unchanged. Significant changes of LA strain rate assessment were observed up to the highest temporal resolution of 50 frames/cycle. Effects of spatial resolution on strain assessment were smaller. For LA total strain a general trend emerged for a mild decrease in strain values obtained comparing the lowest to the highest spatial resolution at temporal resolutions of 20, 40 and 50 frames/cycle (p = 0.006-0.046) but not at 30 frames/cycle (p = 0.140). CONCLUSION: Temporal and to a smaller extent spatial resolution affect atrial functional assessment. Consistent strain assessment requires a standard spatial resolution and a temporal resolution of 30 frames/cycle, whilst SR assessment requires even higher settings of at least 50 frames/cycle.

The association between gut microbiome and growth in infants with cystic fibrosis.

BACKGROUND: In cystic fibrosis (CF), pathophysiologic changes in the gastrointestinal tract lead to malnutrition and altered gut microbiome. Microbiome alterations have been linked to linear growth, gut inflammation and respiratory manifestations. Elucidating these gut microbiome alterations may provide insight into future nutritional management in CF. METHODS: Infants were followed for 12-months at four sites in the United States (US-CF) and Australia (AUS-CF). 16S rRNA gene sequencing was performed on longitudinal stool samples. Associations between microbial abundance and age, antibiotic prophylaxis, malnutrition, and breast feeding were evaluated using generalized linear mixed models. Taxonomic and predictive functional features were compared between groups. RESULTS: Infants with CF (N = 78) were enrolled as part of a larger study. AUS-CF infants had higher mean weight-for-age z-scores than US-CF infants (p = 0.02). A subset of participants (CF N = 40, non-CF disease controls N = 10) provided stool samples for microbiome analysis. AUS-CF infants had lower stool alpha diversity compared to US-CF infants (p < 0.001). AUS-CF infants had higher relative abundance of stool Proteobacteria compared to US-CF infants which was associated with antibiotic prophylaxis (p < 0.001). Malnutrition (weight-for-age <10th percentile) was associated with depleted Lactococcus (p < 0.001). Antibiotic prophylaxis (p = 0.002) and malnutrition (p = 0.012) were linked with predicted decreased activity of metabolic pathways responsible for short chain fatty acid processing. CONCLUSIONS: In infants with CF, gut microbiome composition and diversity differed between the two continents. Gut microbial diversity was not linked to growth. The relationship between malnutrition and antibiotic prophylaxis with reduced SCFA fermentation could have implications for gut health and function and warrants additional investigation.

Fluorinated linkers enable the synthesis of flexible MOFs with 1D alkaline earth SBUs and a temperature-induced phase transition.

Fluorination as a functionalization of organic linkers in MOFs has shown surprising effects both on the structure of the linker itself as well as on the topology and properties of the resulting framework materials. 4,4',4''-Benzene-1,3,5-triyl-tris-(benzoate), typically abbreviated to BTB, is a well-known linker in the construction of MOFs. It is expected to be planar due to a complete sp2 hybridisation of its carbon atoms. However, some flexibility is frequently observed by twists of the outer carboxylate groups as well as by the benzoate rings. The latter is mainly influenced by substituents of the inner benzene ring. Herein, we present two novel alkaline earth metal based MOFs [EA(II)5(3F-BTB)3OAc(DMF)5] (EA(II) = Ca, Sr) utilizing a fluorinated derivative of the BTB-linker (perfluorination of the inner benzene ring) with a unique topology, crystalline sponge behaviour and a low temperature induced phase transition.

Structure, substrate recognition and initiation of hyaluronan synthase.

Hyaluronan is an acidic heteropolysaccharide comprising alternating N-acetylglucosamine and glucuronic acid sugars that is ubiquitously expressed in the vertebrate extracellular matrix1. The high-molecular-mass polymer modulates essential physiological processes in health and disease, including cell differentiation, tissue homeostasis and angiogenesis2. Hyaluronan is synthesized by a membrane-embedded processive glycosyltransferase, hyaluronan synthase (HAS), which catalyses the synthesis and membrane translocation of hyaluronan from uridine diphosphate-activated precursors3,4. Here we describe five cryo-electron microscopy structures of a viral HAS homologue at different states during substrate binding and initiation of polymer synthesis. Combined with biochemical analyses and molecular dynamics simulations, our data reveal how HAS selects its substrates, hydrolyses the first substrate to prime the synthesis reaction, opens a hyaluronan-conducting transmembrane channel, ensures alternating substrate polymerization and coordinates hyaluronan inside its transmembrane pore. Our research suggests a detailed model for the formation of an acidic extracellular heteropolysaccharide and provides insights into the biosynthesis of one of the most abundant and essential glycosaminoglycans in the human body.

Chronic Kidney Disease from Polyvinylpyrrolidone Deposition in Persons with Intravenous Drug Use.

BACKGROUND AND OBJECTIVES: Persons with intravenous drug use have a higher risk of developing CKD compared with the general population. In Norway, deposits of polyvinylpyrrolidone have been observed in kidney biopsies taken from persons with opioid addiction and intravenous drug use since 2009. Polyvinylpyrrolidone is an excipient commonly used in pharmaceuticals, and the polyvinylpyrrolidone deposits observed in these patients were caused by intravenous injection of a specific oral methadone syrup containing very high molecular weight polyvinylpyrrolidone. Here, we present the clinicopathologic findings from 28 patients with CKD associated with polyvinylpyrrolidone deposition in the kidney. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: The 28 patients and their kidney biopsies were included when polyvinylpyrrolidone deposition was recognized, either retrospectively or at the time of diagnostic evaluation. Biopsies were taken between 2009 and 2016. We collected laboratory parameters and clinical data from digital patient charts. For each kidney biopsy, the glomerular volume, extent of polyvinylpyrrolidone deposition, and tubulointerstitial area with tubular atrophy were assessed quantitatively. RESULTS: All patients (mean age: 37 years) had CKD (mean eGFR: 33 ml/min per 1.73 m2) and normal urine protein or non-nephrotic-range proteinuria. Biopsies showed moderate to severe tubular atrophy (mean extent: 65%) and interstitial infiltrates of vacuolated macrophages containing polyvinylpyrrolidone (mean share of biopsy area: 1.5%). Underperfused and ischemic glomeruli were common findings. In 22 samples, ultrastructural investigation revealed polyvinylpyrrolidone-containing vacuoles in the mesangial or endothelial cells of glomeruli. At the last follow-up, most patients had stable or improved eGFR. Two patients had developed kidney failure and underwent hemodialysis. CONCLUSIONS: Intravenous injection of a specific oral methadone syrup caused polyvinylpyrrolidone deposition in the kidney in persons with opioid addiction and intravenous drug use. Kidney biopsy findings suggested an association between polyvinylpyrrolidone deposition and tubular atrophy.

International consensus guideline for reporting transmission electron microscopy results in the diagnosis of primary ciliary dyskinesia (BEAT PCD TEM Criteria).

Primary ciliary dyskinesia (PCD) is a heterogeneous genetic condition. European and North American diagnostic guidelines recommend transmission electron microscopy (TEM) as one of a combination of tests to confirm a diagnosis. However, there is no definition of what constitutes a defect or consensus on reporting terminology. The aim of this project was to provide an internationally agreed ultrastructural classification for PCD diagnosis by TEM.A consensus guideline was developed by PCD electron microscopy experts representing 18 centres in 14 countries. An initial meeting and discussion were followed by a Delphi consensus process. The agreed guideline was then tested, modified and retested through exchange of samples and electron micrographs between the 18 diagnostic centres.The final guideline a) provides agreed terminology and a definition of Class 1 defects which are diagnostic for PCD; b) identifies Class 2 defects which can indicate a diagnosis of PCD in combination with other supporting evidence; c) describes features which should be included in a ciliary ultrastructure report to assist multidisciplinary diagnosis of PCD; and d) defines adequacy of a diagnostic sample.This tested and externally validated statement provides a clear guideline for the diagnosis of PCD by TEM which can be used to standardise diagnosis internationally.

Single and dual coil shock efficacy and predictors of shock failure in patients with modern implantable cardioverter defibrillators-a single-center paired randomized study.

PURPOSE: Implantable cardioverter defibrillators (ICDs) can treat life-threatening tachyarrhythmia with high-voltage shocks. The aims were to compare the efficacy of single and dual coil shock vectors in modern ICDs and to identify predictors of shock failure. METHODS: This is a single-center paired randomized study including 216 patients with mixed indications and ICDs from four manufacturers. All patients underwent two implant defibrillation tests using single and dual coil vectors with the test order randomized. Tested shock energy differed slightly between manufacturers because of differences in device programmability: first shock approximately 15 J below maximal output-if failed, second shock approximately 10 J below maximal output-if failed, third shock at maximal output. RESULTS: First shock success rate was 399/432 (92.4%). Comparing single and dual coil vectors, no differences were seen in first shock efficacy (91.7% vs. 93.1%, P = 0.629) or lowest tested succesfully stored energy (27.2 J vs. 27.1 J, P = 0.620). All successive internal shocks failed in 4/432 (0.9%) of inductions requiring external rescue shocks to restore circulation. Multivariate predictors of first shock failure were QRS duration (relative risk 0.81 per 10 ms, P = 0.001), amiodarone treatment (relative risk 3.30, P = 0.003), and body height (relative risk 1.70 per 10 cm, P = 0.019). CONCLUSIONS: Implant defibrillation testing of modern intravenous ICD systems demonstrates high shock efficacy with no difference between single and dual coil vectors.

Effects of marine n-3 fatty acid supplementation in renal transplantation: A randomized controlled trial.

Marine n-3 fatty acids (FAs) may exert beneficial effects on inflammation, fibrosis, and endothelial function, which could preserve renal graft function. In this randomized controlled trial, 132 Norwegian renal transplant recipients received either 2.6 g of marine n-3 FAs or olive oil (control) daily for 44 weeks, in addition to standard care. Thirty patients did not complete the trial. The primary endpoint was change (Δ) in measured glomerular filtration rate (mGFR) during follow-up. We found no significant difference in Δ mGFR between the marine n-3 FA group and controls (6.7 vs 3.8 mL/min per 1.73 m2 , P = .15). Significant beneficial effects from marine n-3 FA supplementation were, however, seen in secondary endpoints plasma triglycerides, plasma high-sensitivity C-reactive protein, and brachial artery flow-mediated dilation. In the per-protocol population, the renal graft indices percent interstitial fibrosis and Chronic Allograft Damage Index also were significantly lower in the marine n-3 FA group. The cumulative incidence of adverse events did not differ between the marine n-3 FA group (n = 218) and controls (n = 240). In conclusion, marine FA supplementation did not improve renal function compared with controls, but was safe, lowered plasma triglyceride and high-sensitivity C-reactive protein levels, and improved endothelial function (Clinical.Trials.gov identifier NCT01744067).

Machine learning for intraoperative prediction of viability in ischemic small intestine.

OBJECTIVE: Evaluation of intestinal viability is essential in surgical decision-making in patients with acute intestinal ischemia. There has been no substantial change in the mortality rate (30%-93%) of patients with acute mesenteric ischemia (AMI) since the 1980s. As the accuracy from the first laparotomy alone is 50%, the gold standard is a second-look laparotomy, increasing the accuracy to 87%-89%. This study investigates the use of machine learning to classify intestinal viability and histological grading in pig jejunum, based on multivariate time-series of bioimpedance sensor data. APPROACH: We have previously used a bioimpedance sensor system to acquire electrical parameters from perfused, ischemic and reperfused pig jejunum (7 + 15 pigs) over 1-16 h of ischemia and 1-8 h of reperfusion following selected durations of ischemia. In this study we compare the accuracy of using end-point bioimpedance measurements with a feedforward neural network (FNN), versus the accuracy when using a recurrent neural network with long short-term memory units (LSTM-RNN) with bioimpedance data history over different periods of time. MAIN RESULTS: Accuracies in the range of what has been reported clinically can be achieved using FNN's on a single bioimpedance measurement, and higher accuracies can be achieved when employing LSTM-RNN on a sequence of data history. SIGNIFICANCE: Intraoperative bioimpedance measurements on intestine of suspect viability combined with machine learning can increase the accuracy of intraoperative assessment of intestinal viability. Increased accuracy in intraoperative assessment of intestinal viability has the potential to reduce the high mortality and morbidity rate of the patients.

Protein-protein interactions in "cis-AT" polyketide synthases.

Covering: up to the end of 2018 Polyketides are a valuable source of bioactive and clinically important molecules. The biosynthesis of these chemically complex molecules has led to the discovery of equally complex polyketide synthase (PKS) pathways. Crystallography has yielded snapshots of individual catalytic domains, di-domains, and multi-domains from a variety of PKS megasynthases, and cryo-EM studies have provided initial views of a PKS module in a series of defined biochemical states. Here, we review the structural and biochemical results that shed light on the protein-protein interactions critical to catalysis by PKS systems with an embedded acyltransferase. Interactions include those that occur both within and between PKS modules, as well as with accessory enzymes.

Application of Native ESI-MS to Characterize Interactions between Compounds Derived from Fragment-Based Discovery Campaigns and Two Pharmaceutically Relevant Proteins.

Native electrospray ionization mass spectrometry (ESI-MS) was applied to analyze the binding of compounds generated during fragment-based drug discovery (FBDD) campaigns against two functionally distinct proteins, the X-linked inhibitor of apoptosis protein (XIAP) and cyclin-dependent kinase 2 (CDK2). Compounds of different molecular weights and a wide range of binding affinities obtained from the hits to leads and lead optimization stages of FBDD campaigns were studied, and their dissociation constants (Kd) were measured by native ESI-MS. We demonstrate that native ESI-MS has the potential to be applied to the stages of an FBDD campaign downstream of primary screening for the detection and quantification of protein-ligand binding. Native ESI-MS was used to derive Kd values for compounds binding to XIAP, and the dissociation of the complex between XIAP and a peptide derived from the second mitochondria-derived activator of caspases (SMAC) protein induced by one of the test compounds was also investigated. Affinities of compounds binding to CDK2 gave Kd values in the low nanomolar to low millimolar range, and Kd values generated by MS and isothermal titration calorimetry (ITC) followed the same trend for both proteins. Practical considerations for the application of native ESI-MS are discussed in detail.

Ischemia/reperfusion injury in porcine intestine - Viability assessment.

AIM: To investigate viability assessment of segmental small bowel ischemia/reperfusion in a porcine model. METHODS: In 15 pigs, five or six 30-cm segments of jejunum were simultaneously made ischemic by clamping the mesenteric arteries and veins for 1 to 16 h. Reperfusion was initiated after different intervals of ischemia (1-8 h) and subsequently monitored for 5-15 h. The intestinal segments were regularly photographed and assessed visually and by palpation. Intraluminal lactate and glycerol concentrations were measured by microdialysis, and samples were collected for light microscopy and transmission electron microscopy. The histological changes were described and graded. RESULTS: Using light microscopy, the jejunum was considered as viable until 6 h of ischemia, while with transmission electron microscopy the ischemic muscularis propria was considered viable until 5 h of ischemia. However, following ≥ 1 h of reperfusion, only segments that had been ischemic for ≤ 3 h appeared viable, suggesting a possible upper limit for viability in the porcine mesenteric occlusion model. Although intraluminal microdialysis allowed us to closely monitor the onset and duration of ischemia and the onset of reperfusion, we were unable to find sufficient level of association between tissue viability and metabolic markers to conclude that microdialysis is clinically relevant for viability assessment. Evaluation of color and motility appears to be poor indicators of intestinal viability. CONCLUSION: Three hours of total ischemia of the small bowel followed by reperfusion appears to be the upper limit for viability in this porcine mesenteric ischemia model.

PKS-NRPS Enzymology and Structural Biology: Considerations in Protein Production.

The structural diversity and complexity of marine natural products have made them a rich and productive source of new bioactive molecules for drug development. The identification of these new compounds has led to extensive study of the protein constituents of the biosynthetic pathways from the producing microbes. Essential processes in the dissection of biosynthesis have been the elucidation of catalytic functions and the determination of 3D structures for enzymes of the polyketide synthases and nonribosomal peptide synthetases that carry out individual reactions. The size and complexity of these proteins present numerous difficulties in the process of going from gene to structure. Here, we review the problems that may be encountered at the various steps of this process and discuss some of the solutions devised in our and other labs for the cloning, production, purification, and structure solution of complex proteins using Escherichia coli as a heterologous host.

Native Mass Spectrometry Gives Insight into the Allosteric Binding Mechanism of M2 Pyruvate Kinase to Fructose-1,6-Bisphosphate.

The various oligomeric states of the M2 isoform of pyruvate kinase (PKM2) were distinguished using native mass spectrometry. The effect of PKM2 concentration on its dimer-tetramer equilibrium was monitored, and a value for the dissociation constant ( Kd) of the two species was estimated to be 0.95 µM. Results of binding of fructose-1,6-bisphosphate (FBP) to PKM2 are shown and provide insight into the allosteric mechanism and changes in the oligomerization status of PKM2. The average Kd for binding of FBP to the PKM2 tetramer was estimated to be 7.5 µM. It is concluded that four molecules of FBP bind to the active PKM2 tetramer whereas binding of FBP to the PKM2 dimer was not observed. It is suggested that either FBP potentiates rapid tetramer formation after binding to apo PKM2 dimers or FBP binds to PKM2 apo tetramers, thus driving the dimer-tetramer equilibrium in the direction of fully FBP-bound tetramer. The binding occurs in a highly positively cooperative manner with a Hill coefficient ( n) of 3.

Negative effect of zoledronic acid on tendon-to-bone healing.

Background and purpose - Outcome after ligament reconstruction or tendon repair depends on secure tendon-to-bone healing. Increased osteoclastic activity resulting in local bone loss may contribute to delayed healing of the tendon-bone interface. The objective of this study was to evaluate the effect of the bisphosphonate zoledronic acid (ZA) on tendon-to-bone healing. Methods - Wistar rats (n = 92) had their right Achilles tendon cut proximally, pulled through a bone tunnel in the distal tibia and sutured anteriorly. After 1 week animals were randomized to receive a single dose of ZA (0.1 mg/kg IV) or control. Healing was evaluated at 3 and 6 weeks by mechanical testing, dual-energy X-ray absorptiometry and histology including immunohistochemical staining of osteoclasts. Results - ZA treatment resulted in 19% (95% CI 5-33%) lower pullout strength and 43% (95% CI 14-72%) lower stiffness of the tendon-bone interface, compared with control (2-way ANOVA; p = 0.009, p = 0.007). Administration of ZA did not affect bone mineral density (BMD) or bone mineral content (BMC). Histological analyses did not reveal differences in callus formation or osteoclasts between the study groups. Interpretation - ZA reduced pullout strength and stiffness of the tendon-bone interface. The study does not provide support for ZA as adjuvant treatment in tendon-to-bone healing.

Kidney allograft subclinical rejection modulates systemic inflammation measured by C-reactive protein at 1 year after transplantation.

Kidney allograft inflammation is associated with proinflammatory modifications of peripheral blood mononuclear cells, suggesting that renal inflammation contributes to systemic inflammation. Thus, the aim of this study was to evaluate the relationship between subclinical inflammation in surveillance biopsies performed at 1 year and systemic inflammation assessed by C-reactive protein (CRP) levels at the time of biopsy. We analyzed 544 surveillance biopsies performed at 1 year that were classified as normal (n = 368), borderline (n = 148), or subclinical rejection (SCR) (n = 28). CRP levels were divided into quartiles. Patients in 1st, 2nd, and 3rd quartile were classified as low CRP (n = 408) and patients in the 4th quartile as high CRP (n = 136). Univariate analysis showed that the proportion of patients with SCR was higher in the high CRP group (10.3% vs 3.4%, P = 0.0067). Multivariate analysis showed that independent predictors of high CRP were body mass index (odds ratio [OR] 1.072 and 95% confidence interval [CI] 1.027-1.119), a positive urine culture at the day of the biopsy (OR 2.760 and 95% CI 1.205-6.323), and the presence of SCR at 1-year surveillance biopsy (OR 7.260 and 95% CI 3.530-14.935). In summary, we describe that subclinical acute rejection constitutes an independent predictor of systemic inflammation as measured by CRP.

Development of Kidney Transplant Fibrosis Is Inversely Associated With Plasma Marine Fatty Acid Level.

OBJECTIVE(S): We assessed associations between plasma levels of polyunsaturated fatty acids (PUFAs) and degree of inflammation and interstitial fibrosis in transplanted kidneys. DESIGN: The design of the study was single center cohort study. SUBJECTS: A study population of 156 patients who received a kidney transplant at Oslo University Hospital during 2010. MAIN OUTCOME MEASURE: Kidney transplant biopsies were obtained at 2 months and 1 year after transplantation. Degree of inflammation and interstitial fibrosis in the cortex of transplanted kidneys were estimated semi-quantitatively. Plasma phospholipid fatty acids levels were measured in a stable phase 2 months posttransplant. We used multivariate linear regression to assess associations between plasma levels of PUFAs and degree of inflammation and interstitial fibrosis at 2 months and 1 year postoperatively and change in degree of interstitial fibrosis during the first year after transplantation, adjusting for inflammation and fibrosis risk factors. RESULTS: Higher plasma marine n-3 PUFA levels were associated with less development of interstitial fibrosis in the kidney transplant (unstandardized ß-coefficient -1.12, standardized ß-coefficient -0.18, P = .03) during the first year after transplantation. Plasma levels of alpha linoleic acid, linoleic acid, and arachidonic acid were not associated with development of interstitial fibrosis. No associations were found between plasma levels of PUFAs and inflammation inside fibrotic areas or outside fibrotic areas in the kidney transplant at neither 2 months nor 1 year postoperatively. Linolenic acid levels in plasma were positively associated with change in renal function during the first year after transplantation. CONCLUSION: The inverse association between plasma marine n-3 PUFA levels and development of interstitial fibrosis during the first year after kidney transplantation suggests that marine fatty acid consumption might halt progression of fibrosis.

Tacrolimus and mycophenolate regimen and subclinical tubulo-interstitial inflammation in low immunological risk renal transplants.

The aim was to evaluate the relationship between maintenance immunosuppression, subclinical tubulo-interstitial inflammation and interstitial fibrosis/tubular atrophy (IF/TA) in surveillance biopsies performed in low immunological risk renal transplants at two transplant centers. The Barcelona cohort consisted of 109 early and 66 late biopsies in patients receiving high tacrolimus (TAC-C0 target at 1-year 6-10 ng/ml) and reduced MMF dose (500 mg bid at 1-year). The Oslo cohort consisted of 262 early and 237 late biopsies performed in patients treated with low TAC-C0 (target 3-7 ng/ml) and standard MMF dose (750 mg bid). Subclinical inflammation, adjusted for confounders, was associated with low TAC-C0 in the early (OR: 0.75, 95% CI: 0.61-0.92; P = 0.006) and late biopsies (OR: 0.69, 95% CI: 0.50-0.95; P = 0.023) from Barcelona. In the Oslo cohort, it was associated with low MMF in early biopsies (OR: 0.90, 95% CI: 0.83-0.98; P = 0.0101) and with low TAC-C0 in late biopsies (OR: 0.77, 95% CI: 0.61-0.97; P = 0.0286). MMF dose was significantly reduced in Oslo between early and late biopsies. IF/TA was not associated with TAC-C0 or MMF dose in the multivariate analysis. Our data suggest that in TAC- and MMF-based regimens, TAC-C0 levels are associated with subclinical inflammation in patients receiving reduced MMF dose.

Inflammation in Early Kidney Allograft Surveillance Biopsies With and Without Associated Tubulointerstitial Chronic Damage as a Predictor of Fibrosis Progression and Development of De Novo Donor Specific Antibodies.

BACKGROUND: Interstitial fibrosis and tubular atrophy (IFTA) associated with interstitial inflammation in nonscarred areas (IFTA+i) is associated with poorer graft outcome than inflammation without IFTA or IFTA without inflammation. METHODS: We evaluated if histological categories at week 6 could predict the development of interstitial fibrosis and de novo donor specific anti-HLA antibodies (dnDSA) at 1 year. Biopsies were classified according to Banff criteria as normal (i+t≤1 and ci+ct≤1), inflammation (i+t≥2 and ci+ct≤1), IFTA (i+t≤1 and ci+ct≥2) or IFTA+i (i+t≥2 and ci+ct≥2). RESULTS: We analyzed 598 standard immunological risk recipients. The histological diagnosis at 6 weeks was: normal (n = 206), inflammation (n = 29), IFTA (n = 255), and IFTA+i (n = 108). Moderate/severe interstitial fibrosis (ci≥2) at 1 year was observed in 4.2% of patients with prior (6 weeks) normal histology, in 3.4% with inflammation, in 13.8% with IFTA, and in 24.5% with IFTA+i (P = 0.0001). Fifty-three recipients (8.9%) had dnDSA at 1 year. Independent predictors of development of dnDSA at 1 year were: HLA-DR mismatches (odds ratio [OR], 1.95; 95% confidence interval [95% CI], 1.09-3.49), the presence of inflammation (OR, 5.49; 95% CI, 1.67-18.03) or IFTA+i (OR, 4.09; 95% CI, 1.67-10.0) in the 6-week surveillance biopsy. CONCLUSIONS: Early subclinical inflammation in surveillance biopsies with or without tubulointerstitial chronic lesions is associated with an increased risk of dnDSA development.