Publications by authors named "Mark Haas"

150 Publications

Does the definition of chronic active T cell-mediated rejection need revisiting?

Am J Transplant 2020 Nov 29. Epub 2020 Nov 29.

Department of Laboratory Medicine & Pathology, University of Alberta, Edmonton, Canada.

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http://dx.doi.org/10.1111/ajt.16419DOI Listing
November 2020

Donor-derived Cell-free DNA Combined With Histology Improves Prediction of Estimated Glomerular Filtration Rate Over Time in Kidney Transplant Recipients Compared With Histology Alone.

Transplant Direct 2020 Aug 15;6(8):e580. Epub 2020 Jul 15.

Department of Pathology and Laboratory Medicine, Cedars-Sinai Medical Center, Los Angeles, CA.

Higher Banff inflammation and chronicity scores on kidney transplant biopsies are associated with poorer graft survival, although histology alone has limitations in predicting outcomes. We investigated if integrating donor-derived cell-free DNA (dd-cfDNA, Allosure; CareDx, Inc.) with Banff biopsy scores into a predictive model for estimated glomerular filtration rate over time can improve prognostic assessment versus histology alone.

Methods: We identified 180 kidney transplant patients with dd-cfDNA assessed within 1 mo of biopsy. Using linear mixed-effects models, a prediction model of Banff histology scores and dd-cfDNA on estimated glomerular filtration rate over time was derived. Nested models were compared using the likelihood-ratio test, Akaike Information Criterion, and Bayesian Information Criterion to assess if inclusion of dd-cfDNA into a model consisting of Banff biopsy scores would improve model fit.

Results: Univariate models identified significant covariate-by-time interactions for cg = 3 versus <3 (coefficient: -1.3 mL/min/1.73 m/mo; 95% confidence interval [CI], -2.4 to -0.2; = 0.02) and ci + ct ≥ 3 versus <3 (coefficient: -0.7 mL/min/1.73 m/mo; 95% CI, -1.3 to -0.1; = 0.03) and a trend toward significant covariate-by-time interaction for dd-cfDNA (coefficient: -0.5 mL/min/1.73 m/mo; 95% CI, -1.0 to 0.1; = 0.08). Addition of acute inflammation (i, t, and v), microvascular inflammation (g and ptc), and inflammation in area of interstitial fibrosis and tubular atrophy scores to chronicity scores (cg ≥ 3 and ci + ct ≥ 3) did not improve model fit. However, a model including dd-cfDNA with cg and ci + ct with covariate-by-time interactions had a better model fit compared with cg and ci + ct alone (likelihood-ratio test statistic = 21.1; df = 2; < 0.001).

Conclusions: Addition of dd-cfDNA to Banff biopsy scores provided better prognostic assessment over biopsy characteristics alone.
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http://dx.doi.org/10.1097/TXD.0000000000001027DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7581058PMC
August 2020

Donor-derived Cell-free DNA and the Prediction of BK Virus-associated Nephropathy.

Transplant Direct 2020 Nov 23;6(11):e622. Epub 2020 Oct 23.

Cedars-Sinai Medical Center, Los Angeles, CA.

Approximately 15% of kidney transplant recipients (KTRs) develop BK viremia (BKV), with 1%-10% developing BK virus-associated nephropathy (BKVAN), which histologically resembles rejection. The Diagnosing Acute Rejection in Kidney Transplant Recipients (DART) study showed that donor-derived cell-free DNA (dd-cfDNA) levels <1% have a negative predictive value of 85% for active allograft rejection. Using data from this study, we evaluated the association of dd-cfDNA with plasma BK viral loads and biopsy findings to determine if dd-cfDNA can distinguish asymptomatic BKV from BKVAN.

Methods: Data on dd-cfDNA, plasma BK viral loads, and biopsy findings from patients from the DART study were retrospectively examined. BKV was defined as 500-10 000 copies/mL. Presumptive BKVAN was defined as BK >10 000 copies/mL.

Results: Of 102 participants with biopsies, 10 patients with BKV and BKVAN had paired dd-cfDNA, and viral loads available for analysis. Patients diagnosed with BKV and BKVAN had a median dd-cfDNA of 0.58% (IQR 0.43-1.15) and 3.38% (IQR 2.3-4.56, = 0.001), respectively. dd-cfDNA titers correlated with BK PCR viral loads (R = 0.874, = 0.01) and the presence of histologic evidence of BKVAN (100% sensitivity, 50% specificity). Five of 7 patients with BKVAN, but only 2 of 7 with BKV, had biopsies meeting Banff criteria for T-cell-mediated rejection. Median dd-cfDNA in nonrejection patients was 0.43% versus 2.84% in rejection patients ( = 0.001).

Conclusion: Higher dd-cfDNA titers were associated with higher BK viral loads, biopsy-diagnosed BVAN, as well histologic changes meeting Banff criteria for as T-cell-mediated rejection. dd-cfDNA may be a useful noninvasive test to assess for progression of BKV to BKVAN.
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http://dx.doi.org/10.1097/TXD.0000000000001061DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7587413PMC
November 2020

Formalin-fixed paraffin-embedded renal biopsy tissues: an underexploited biospecimen resource for gene expression profiling in IgA nephropathy.

Sci Rep 2020 09 16;10(1):15164. Epub 2020 Sep 16.

Schena Foundation, Research Center of Kidney Diseases, Strada Provinciale Valenzano-Casamassima Km. 3.00, 70100, Valenzano, Bari, Italy.

Primary IgA nephropathy (IgAN) diagnosis is based on IgA-dominant glomerular deposits and histological scoring is done on formalin-fixed paraffin embedded tissue (FFPE) sections using the Oxford classification. Our aim was to use this underexploited resource to extract RNA and identify genes that characterize active (endocapillary-extracapillary proliferations) and chronic (tubulo-interstitial) renal lesions in total renal cortex. RNA was extracted from archival FFPE renal biopsies of 52 IgAN patients, 22 non-IgAN and normal renal tissue of 7 kidney living donors (KLD) as controls. Genome-wide gene expression profiles were obtained and biomarker identification was carried out comparing gene expression signatures a subset of IgAN patients with active (N = 8), and chronic (N = 12) renal lesions versus non-IgAN and KLD. Bioinformatic analysis identified transcripts for active (DEFA4, TNFAIP6, FAR2) and chronic (LTB, CXCL6, ITGAX) renal lesions that were validated by RT-PCR and IHC. Finally, two of them (TNFAIP6 for active and CXCL6 for chronic) were confirmed in the urine of an independent cohort of IgAN patients compared with non-IgAN patients and controls. We have integrated transcriptomics with histomorphological scores, identified specific gene expression changes using the invaluable repository of archival renal biopsies and discovered two urinary biomarkers that may be used for specific clinical decision making.
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http://dx.doi.org/10.1038/s41598-020-72026-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7494931PMC
September 2020

Consensus definitions for glomerular lesions by light and electron microscopy: recommendations from a working group of the Renal Pathology Society.

Kidney Int 2020 11 29;98(5):1120-1134. Epub 2020 Aug 29.

Department of Pathology and Laboratory Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.

Over the past 2 decades, scoring systems for multiple glomerular diseases have emerged, as have consortia of pathologists and nephrologists for the study of glomerular diseases, including correlation of pathologic findings with clinical features and outcomes. However, one important limitation faced by members of these consortia and other renal pathologists and nephrologists in both investigative work and routine practice remains a lack of uniformity and precision in clearly defining the morphologic lesions on which the scoring systems are based. In response to this issue, the Renal Pathology Society organized a working group to identify the most frequently identified glomerular lesions observed by light microscopy and electron microscopy, review the literature to capture the published definitions most often used for each, and determine consensus terms and definitions for each lesion in a series of online and in-person meetings. The defined lesions or abnormal findings are not specific for any individual disease or subset of diseases, but rather can be applied across the full spectrum of glomerular diseases and within the context of the different scoring systems used for evaluating and reporting these diseases. In addition to facilitating glomerular disease research, standardized terms and definitions should help harmonize reporting of medical kidney diseases worldwide and lead to more-precise diagnoses and improved patient care.
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http://dx.doi.org/10.1016/j.kint.2020.08.006DOI Listing
November 2020

Late-afternoon communication and patient planning (CAPP) rounds: an intervention to allow early patient discharges.

Hosp Pract (1995) 2021 Feb 3;49(1):56-61. Epub 2020 Sep 3.

Department of Medicine, Tufts Medical Center , Boston, Massachusetts, USA.

Objective: Measure effect of late-afternoon communication and patient planning (CAPP) rounds to increase early electronic discharge orders (EDO).

Methods: We enrolled 4485 patients discharged from six subspecialty medical services. We implemented late-afternoon CAPP rounds to identify patients who could have morning discharge the subsequent day. After an initial successful implementation of the intervention, we identified lack of sustainability. We made changes with sustained implementation of the intervention. This is a before-after study of a quality improvement intervention.

Program Evaluation: Primary measures of intervention effectiveness were percentage of patients who received EDO by 11 am and patients discharged by noon. Additional measure of effectiveness were percent of patients admitted to the correct ward, emergency department (ED)-to-ward transfer time compared between intervention and nonintervention periods. We compared the overall expected LOS and the average weekly discharges to assess for comparability across the control and intervention time periods. We used the readmission rate as balancing measure to ensure that the intervention was not have unintended negative patients consequences.

Results: Expected length of stay based upon discharge diagnosis/comorbidities and readmission rates were similar across the intervention and control time periods. The average weekly discharges were not statistically significant. Percentage of EDO by 11 am was higher in the first intervention period, second intervention period and combined intervention periods (28.9% vs. 21.8%, < 0.001) compared with the respective control periods. Percent discharged before noon increased in the first intervention period, second intervention period and for the combined intervention periods (17 vs. 11.8%, < 0.001). There was no difference in the percent admitted to the correct ward and ED-to-ward transfer time.

Conclusion: Afternoon CAPP rounds to identify early patient discharges the following day led to increase in EDO entered by 11 am and discharges by noon without an adverse change in readmission rates and LOS.
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http://dx.doi.org/10.1080/21548331.2020.1814042DOI Listing
February 2021

The Banff 2019 Kidney Meeting Report (I): Updates on and clarification of criteria for T cell- and antibody-mediated rejection.

Am J Transplant 2020 09 28;20(9):2318-2331. Epub 2020 May 28.

Department of Laboratory Medicine and Pathology, University of Alberta, Edmonton, Canada.

The XV. Banff conference for allograft pathology was held in conjunction with the annual meeting of the American Society for Histocompatibility and Immunogenetics in Pittsburgh, PA (USA) and focused on refining recent updates to the classification, advances from the Banff working groups, and standardization of molecular diagnostics. This report on kidney transplant pathology details clarifications and refinements to the criteria for chronic active (CA) T cell-mediated rejection (TCMR), borderline, and antibody-mediated rejection (ABMR). The main focus of kidney sessions was on how to address biopsies meeting criteria for CA TCMR plus borderline or acute TCMR. Recent studies on the clinical impact of borderline infiltrates were also presented to clarify whether the threshold for interstitial inflammation in diagnosis of borderline should be i0 or i1. Sessions on ABMR focused on biopsies showing microvascular inflammation in the absence of C4d staining or detectable donor-specific antibodies; the potential value of molecular diagnostics in such cases and recommendations for use of the latter in the setting of solid organ transplantation are presented in the accompanying meeting report. Finally, several speakers discussed the capabilities of artificial intelligence and the potential for use of machine learning algorithms in diagnosis and personalized therapeutics in solid organ transplantation.
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http://dx.doi.org/10.1111/ajt.15898DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7496245PMC
September 2020

Banff 2019 Meeting Report: Molecular diagnostics in solid organ transplantation-Consensus for the Banff Human Organ Transplant (B-HOT) gene panel and open source multicenter validation.

Am J Transplant 2020 09 27;20(9):2305-2317. Epub 2020 Jun 27.

Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA.

This meeting report from the XV Banff conference describes the creation of a multiorgan transplant gene panel by the Banff Molecular Diagnostics Working Group (MDWG). This Banff Human Organ Transplant (B-HOT) panel is the culmination of previous work by the MDWG to identify a broadly useful gene panel based on whole transcriptome technology. A data-driven process distilled a gene list from peer-reviewed comprehensive microarray studies that discovered and validated their use in kidney, liver, heart, and lung transplant biopsies. These were supplemented by genes that define relevant cellular pathways and cell types plus 12 reference genes used for normalization. The 770 gene B-HOT panel includes the most pertinent genes related to rejection, tolerance, viral infections, and innate and adaptive immune responses. This commercially available panel uses the NanoString platform, which can quantitate transcripts from formalin-fixed paraffin-embedded samples. The B-HOT panel will facilitate multicenter collaborative clinical research using archival samples and permit the development of an open source large database of standardized analyses, thereby expediting clinical validation studies. The MDWG believes that a pathogenesis and pathway based molecular approach will be valuable for investigators and promote therapeutic decision-making and clinical trials.
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http://dx.doi.org/10.1111/ajt.16059DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7496585PMC
September 2020

The pathologist's view.

Authors:
Mark Haas

Kidney Int 2020 05;97(5):1060

Department of Pathology and Laboratory Medicine, Cedars-Sinai Medical Center, Los Angeles, California, USA. Electronic address:

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http://dx.doi.org/10.1016/j.kint.2020.01.023DOI Listing
May 2020

A Validation of the 2018 Revision of International Society of Nephrology/Renal Pathology Society Classification for Lupus Nephritis: A Cohort Study from China.

Am J Nephrol 2020 22;51(6):483-492. Epub 2020 Apr 22.

Division of Renal, Department of Medicine, Peking University First Hospital, Beijing, China.

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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http://dx.doi.org/10.1159/000507213DOI Listing
April 2020

Immunoglobulin G/albumin staining in tubular protein reabsorption droplets in minimal change disease and focal segmental glomerulosclerosis.

Nephrol Dial Transplant 2020 Mar 19. Epub 2020 Mar 19.

Pathology and Laboratory Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, USA.

Background: Some renal biopsies cannot distinguish minimal change disease (MCD) from primary focal segmental glomerulosclerosis (FSGS) because of inadequate sampling and/or a lack of sampled glomeruli with segmental sclerosis. As protein excretion in MCD has been described as being albumin-selective, we examined whether the ratio of immunoglobulin G (IgG)/albumin staining in protein reabsorption droplets (tPRD) might help distinguish MCD from FSGS.

Methods: Frozen tissue from 144 native renal biopsies from patients with nephrotic syndrome and a diagnosis of MCD or FSGS [73 MCD, 30 FSGS tip variant (FSGS-tip), 38 FSGS-not otherwise specified (FSGS-NOS), 3 FSGS collapsing] was retrospectively stained by direct immunofluorescence for IgG and albumin; none of these samples showed diagnostic lesions of FSGS. IgG and albumin staining of tPRD were graded on a scale of 0 to 3+ based on the distribution and intensity of staining.

Results: Mean (standard deviation) IgG/albumin staining ratios were 0.186 ± 0.239 for MCD, 0.423 ± 0.334 for FSGS-tip (P = 0.0001 versus MCD) and 0.693 ± 0.297 for FSGS-NOS (P < 0.0001 versus MCD; P = 0.0001 versus FSGS-tip). Of 84 biopsies with a ratio ≤0.33, 63 (75%) showed MCD, whereas among 21 with a ratio of 1.0, all but one showed FSGS (15 FSGS-NOS).

Conclusions: In summary, IgG/albumin staining in tPRD was correlated with histologic diagnosis in renal biopsies with MCD and FSGS. A ratio of ≤0.33 was associated with MCD, whereas a ratio of 1.0 was most often seen with FSGS-NOS.
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http://dx.doi.org/10.1093/ndt/gfaa039DOI Listing
March 2020

Uncovering the etiology of CINAC, a complex and mysterious renal syndrome: the invaluable role of histopathology and electron microscopy.

Authors:
Mark Haas

Kidney Int 2020 02;97(2):258-260

Department of Pathology and Laboratory Medicine, Cedars-Sinai Medical Center, Los Angeles, California, USA. Electronic address:

Chronic interstitial nephritis in agricultural communities (CINAC) is a progressive form of tubulointerstitial nephritis affecting agricultural workers in different parts of the world. Its underlying etiology is not known, although a study by Vervaet and coworkers in this issue of Kidney International provides strong evidence that CINAC is a lysosomal tubulopathy induced by toxin exposure. Key to this important discovery is a thorough morphologic analysis of kidney tissue, including ultrastructural as well as histopathologic examination.
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http://dx.doi.org/10.1016/j.kint.2019.10.005DOI Listing
February 2020

Recommended Treatment for Antibody-mediated Rejection After Kidney Transplantation: The 2019 Expert Consensus From the Transplantion Society Working Group.

Transplantation 2020 05;104(5):911-922

Centre for Transplant and Renal Research, Westmead Institute of Medical Research, University of Sydney and Renal Unit, Westmead Hospital, NSW, Australia.

With the development of modern solid-phase assays to detect anti-HLA antibodies and a more precise histological classification, the diagnosis of antibody-mediated rejection (AMR) has become more common and is a major cause of kidney graft loss. Currently, there are no approved therapies and treatment guidelines are based on low-level evidence. The number of prospective randomized trials for the treatment of AMR is small, and the lack of an accepted common standard for care has been an impediment to the development of new therapies. To help alleviate this, The Transplantation Society convened a meeting of international experts to develop a consensus as to what is appropriate treatment for active and chronic active AMR. The aim was to reach a consensus for standard of care treatment against which new therapies could be evaluated. At the meeting, the underlying biology of AMR, the criteria for diagnosis, the clinical phenotypes, and outcomes were discussed. The evidence for different treatments was reviewed, and a consensus for what is acceptable standard of care for the treatment of active and chronic active AMR was presented. While it was agreed that the aims of treatment are to preserve renal function, reduce histological injury, and reduce the titer of donor-specific antibody, there was no conclusive evidence to support any specific therapy. As a result, the treatment recommendations are largely based on expert opinion. It is acknowledged that properly conducted and powered clinical trials of biologically plausible agents are urgently needed to improve patient outcomes.
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http://dx.doi.org/10.1097/TP.0000000000003095DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7176344PMC
May 2020

Eculizumab as Primary Therapy for Active Antibody-mediated Rejection of Renal Allografts: A Matter of Timing, Severity, and Donor-specific Antibodies.

Authors:
Mark Haas

Transplantation 2019 11;103(11):2219-2220

Department of Pathology and Laboratory Medicine, Cedars-Sinai Medical Center, Los Angeles, CA.

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http://dx.doi.org/10.1097/TP.0000000000002640DOI Listing
November 2019

Microangiopathic Lesions in IgA Nephropathy: A Cohort Study.

Am J Kidney Dis 2019 11 15;74(5):629-639. Epub 2019 May 15.

Renal Division, Department of Medicine, Peking University First Hospital, Beijing, China.

Rationale & Objective: Renal arteriolar microangiopathic lesions may occur in immunoglobulin A nephropathy (IgAN), but their role in disease progression remains unclear. We sought to understand the prevalence and character of microangiopathic lesions in IgAN and their role in disease progression.

Study Design: A retrospective cohort study.

Setting & Participants: In this study, we enrolled a Chinese cohort with 944 adult patients with IgAN who had been followed up for at least 1 year.

Predictors: Renal arteriolar microangiopathic lesions.

Outcomes: Composite kidney end point event defined as a>50% reduction in estimated glomerular filtration rate, end-stage kidney disease, or death.

Analytical Approach: All kidney biopsies were independently reviewed by 2 investigators. Renal arteriolar microangiopathic lesions were detected using light microscopy. Multivariable Cox regression analysis was used to test the association between microangiopathic lesions and the outcomes.

Results: Overall, 194 (20.6%) patients had renal arteriolar microangiopathic lesions. Patients with microangiopathic lesions presented with higher blood pressures, more severe proteinuria, and lower estimated glomerular filtration rates (all P<0.001) than patients without microangiopathic lesions. After a median follow-up of 4.2 years, 75 (38.7%) patients with microangiopathic lesions and 83 (11.1%) patients without these lesions reached the composite kidney end point (P<0.001). In a multivariable Cox regression model adjusting for clinical and pathologic variables available at the time of biopsy, the presence of microangiopathic lesions was an independent risk factor for kidney failure (HR, 1.95; 95% CI, 1.34-2.83; P<0.001). Renal vascular sclerosis (arterial intimal fibrosis or arteriolar hyalinosis) was not a risk factor for kidney disease progression (P = 0.5).

Limitations: A single Chinese center's experience, retrospective study, most patients were not tested for hemolytic markers (for example, haptoglobin level, lactate dehydrogenase level, and schistocytes).

Conclusions: Renal arteriolar microangiopathic lesions are frequent in IgAN and their presence is independently associated with progression to kidney failure. If confirmed in other patient cohorts, such lesions could be considered for inclusion in formal classification schemes of IgAN.
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http://dx.doi.org/10.1053/j.ajkd.2019.03.416DOI Listing
November 2019

Transplant Glomerulopathy With Glomerular C3 Deposits: Why the Worse Outcome?

Kidney Int Rep 2019 Apr 25;4(4):516-519. Epub 2019 Feb 25.

Department of Pathology and Laboratory Medicine, Cedars-Sinai Medical Center, Los Angeles, California, USA.

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http://dx.doi.org/10.1016/j.ekir.2019.02.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6451154PMC
April 2019

Clinical Relevance of Posttransplant DSAs in Patients Receiving Desensitization for HLA-incompatible Kidney Transplantation.

Transplantation 2019 12;103(12):2666-2674

Comprehensive Transplant Center, Cedars-Sinai Medical Center, Los Angeles, CA.

Background: Highly HLA-sensitized (HS) patients have an increased risk for the development of donor-specific antibodies (DSA) and antibody-mediated rejection (AMR) posttransplant. Here, we examined the risk for AMR in HS patients transplanted after desensitization (DES) who were DSA+ versus DSA- at transplant. We also examined the incidence and clinical impact of de novo DSAs (dnDSAs) and compared with dnDSA- patients.

Methods: From January 2013 to October 2016, 90 HS patients (PRA > 80%, DSA+ = 50 versus DSA- = 40) received kidney transplantation after DES with IVIG + rituximab ± PLEX (plasma exchange) ± tocilizumab. DSAs were monitored at transplant and at 1, 3, 6, 12, 24, 36, and 48 months posttransplant.

Results: Patients were divided into 4 groups: DSA+/+ (n = 31), DSA+/- (n=19), DSA-/+ (n=10), and DSA-/- (n = 30). Median follow-up time was 2.9 years. DSA-negative patients who developed dnDSA had the highest incidence of AMR (70%) compared with the DSA+/+ (45%), DSA+/- (11%), and DSA-/- (10%) patients (P < 0.0001). Among patients who developed AMR, Banff 2013 AMR scores did not differ among the 4 groups. Graft survival and estimated glomerular filtration rate determinations at 4 years were similar.

Conclusions: Persistence of preexisting DSAs or development of dnDSA after transplant is associated with an increased risk for AMR. Despite this, we did not observe a difference in Banff biopsy scores, graft survival, or patient survival compared with those without DSAs after transplant. Thus, for HS patients undergoing HLA-incompatible kidney transplant, DES therapy and frequent monitoring for dnDSAs appears critical for good long-term survival in at-risk groups.
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http://dx.doi.org/10.1097/TP.0000000000002691DOI Listing
December 2019

Early clinical experience using donor-derived cell-free DNA to detect rejection in kidney transplant recipients.

Am J Transplant 2019 06 29;19(6):1663-1670. Epub 2019 Mar 29.

Division of Nephrology, Department of Medicine, Comprehensive Transplant Center, Cedars-Sinai Medical Center, Los Angeles, California.

Donor-derived cell-free DNA (dd-cfDNA) became Medicare reimbursable in the United States in October 2017 for the detection of rejection in kidney transplant recipients based on results from its pivotal validation trial, but it has not yet been externally validated. We assessed 63 adult kidney transplant recipients with suspicion of rejection with dd-cfDNA and allograft biopsy. Of these, 27 (43%) patients had donor-specific antibodies and 34 (54%) were found to have rejection by biopsy. The percentage of dd-cfDNA was higher among patients with antibody-mediated rejection (ABMR; median 1.35%; interquartile range [IQR]: 1.10%-1.90%) compared to those with no rejection (median 0.38%, IQR: 0.26%-1.10%; P < .001) and cell-mediated rejection (CMR; median: 0.27%, IQR: 0.19%-1.30%; P = .01). The dd-cfDNA test did not discriminate patients with CMR from those without rejection. The area under the ROC curve (AUC) for CMR was 0.42 (95% CI: 0.17-0.66). For ABMR, the AUC was 0.82 (95% CI: 0.71-0.93) and a dd-cfDNA ≥0.74% yielded a sensitivity of 100%, specificity 71.8%, PPV 68.6%, and NPV 100%. The dd-cfDNA test did not discriminate CMR from no rejection among kidney transplant recipients, although performance characteristics were stronger for the discrimination of ABMR.
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http://dx.doi.org/10.1111/ajt.15289DOI Listing
June 2019

Human-Robotic Variable-Stiffness Grasps of Small-Fruit Containers Are Successful Even Under Severely Impaired Sensory Feedback.

Front Neurorobot 2018 31;12:70. Epub 2018 Oct 31.

German Aerospace Center DLR e.V., Institute of Robotics and Mechatronics, Wessling, Germany.

Application areas of robotic grasping extend to delicate objects like groceries. The intrinsic elasticity offered by variable-stiffness actuators (VSA) appears to be promising in terms of being able to adapt to the object shape, to withstand collisions with the environment during the grasp acquisition, and to resist the weight applied to the fingers by a lifted object during the actual grasp. It is hypothesized that these properties are particularly useful in the absence of high-quality sensory feedback, which would otherwise be able to guide the shape adaptation and collision avoidance, and that in this case, VSA hands perform better than hands with fixed stiffness. This hypothesis is tested in an experiment where small-fruit containers are picked and placed using a newly developed variable-stiffness robotic hand. The grasp performance is measured under different sensory feedback conditions: full or impaired visual feedback, full or impaired force feedback. The hand is switched between a variable-stiffness mode and two fixed-stiffness modes. Strategies for modulating the stiffness and exploiting environmental constraints are observed from human operators that control the robotic hand. The results show consistently successful grasps under all stiffness and feedback conditions. However, the performance is affected by the amount of available visual feedback. Different stiffness modes turn out to be beneficial in different feedback conditions and with respect to different performance criteria, but a general advantage of VSA over fixed stiffness cannot be shown for the present task. Guidance of the fingers along cracks and gaps is observed, which may inspire the programming of autonomously grasping robots.
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http://dx.doi.org/10.3389/fnbot.2018.00070DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6220053PMC
October 2018

The relationship between pathologic lesions of active and chronic antibody-mediated rejection in renal allografts.

Authors:
Mark Haas

Am J Transplant 2018 12 24;18(12):2849-2856. Epub 2018 Sep 24.

Department of Pathology and Laboratory Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, USA.

The Banff classification of renal allograft pathology defines specific morphologic lesions that are used in the diagnosis of active (glomerulitis, peritubular capillaritis, endarteritis) and chronic (transplant glomerulopathy, peritubular capillary basement membrane multilayering, transplant arteriopathy) antibody-mediated rejection (ABMR). However, none of these individual lesions are specific for ABMR, and for this reason Banff requires 1 or more additional findings, including C4d deposition in peritubular capillaries, presence of circulating donor-specific antibodies (DSAs), and/or expression in the tissue of transcripts strongly associated with ABMR, for a definitive diagnosis of ABMR to be made. In addition, while animal studies examining serial biopsies have established the progression of morphologic lesions of active to chronic ABMR as well as intermediate forms (chronic active ABMR) exhibiting features of both, clear documentation that lesions of chronic ABMR require the earlier presence of corresponding active and intermediate lesions is less well established in human renal allografts. This review examines temporal relationships between key morphologic lesions of active and chronic ABMR in biopsies of human grafts, likely intermediate forms, and findings for and possibly against direct and potentially interruptible progression from active to chronic lesions.
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http://dx.doi.org/10.1111/ajt.15088DOI Listing
December 2018

A 2018 Reference Guide to the Banff Classification of Renal Allograft Pathology.

Transplantation 2018 11;102(11):1795-1814

Institute of Pathology, University Hospital of Cologne, Cologne, Germany.

The Banff Classification of Allograft Pathology is an international consensus classification for the reporting of biopsies from solid organ transplants. Since its initial conception in 1991 for renal transplants, it has undergone review every 2 years, with attendant updated publications. The rapid expansion of knowledge in the field has led to numerous revisions of the classification. The resultant dispersal of relevant content makes it difficult for novices and experienced pathologists to faithfully apply the classification in routine diagnostic work and in clinical trials. This review shall provide a complete and simple illustrated reference guide of the Banff Classification of Kidney Allograft Pathology based on all publications including the 2017 update. It is intended as a concise desktop reference for pathologists and clinicians, providing definitions, Banff Lesion Scores and Banff Diagnostic Categories. An online website reference guide hosted by the Banff Foundation for Allograft Pathology (www.banfffoundation.org) is being developed, which will be updated with future refinement of the Banff Classification from 2019 onward.
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http://dx.doi.org/10.1097/TP.0000000000002366DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7597974PMC
November 2018

Collagen type III glomerulopathy.

Kidney Int 2018 Jun;93(6):1490

Division of Pediatric Nephrology, Cedars-Sinai Medical Center, Los Angeles, California, USA.

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http://dx.doi.org/10.1016/j.kint.2017.11.002DOI Listing
June 2018

A phase I/II, double-blind, placebo-controlled study assessing safety and efficacy of C1 esterase inhibitor for prevention of delayed graft function in deceased donor kidney transplant recipients.

Am J Transplant 2018 12 14;18(12):2955-2964. Epub 2018 May 14.

Comprehensive Transplant Center, Cedars-Sinai Medical Center, Los Angeles, CA.

Delayed graft function (DGF) is defined as need for dialysis early posttransplant. DGF is related to ischemia-reperfusion injury (IRI) that diminishes allograft function and may be complement dependent. Here, we investigate the ability of C1 esterase inhibitor (C1INH) to prevent IRI/DGF in kidney transplant recipients. Seventy patients receiving deceased donor kidney transplants at risk for DGF were randomized to receive C1INH 50 U/kg (#35) or placebo (#35) intraoperatively and at 24 hours. The primary end point was need for hemodialysis during the first week posttransplant. Assessments of glomerular filtration rate and dialysis dependence were accomplished. Complications and safety of therapy were recorded. Similar characteristics with no significant differences in cold-ischemia time or risk factors for DGF were seen. C1INH did not result in reduction of dialysis sessions at 1 week posttransplant, but significantly fewer dialysis sessions (P = .0232) were required 2 to 4 weeks posttransplant. Patients at highest risk for DGF (Kidney Donor Profile Index ≥85) benefited most from C1INH therapy. Significantly better renal function was seen at 1 year in C1INH patients (P = .006). No significant adverse events were noted with C1INH. Although the primary end point was not met, significant reductions in need for dialysis and improvements in long-term allograft function were seen with C1INH treatment.
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http://dx.doi.org/10.1111/ajt.14767DOI Listing
December 2018

Mesoamerican nephropathy: pathology in search of etiology.

Authors:
Mark Haas

Kidney Int 2018 03;93(3):538-540

Department of Pathology and Laboratory Medicine, Cedars-Sinai Medical Center, Los Angeles, California, USA. Electronic address:

Mesoamerican nephropathy is a progressive, often fatal form of tubulointerstitial nephritis affecting young agricultural laborers in Central America. Initially described as a chronic disease, a study by Fischer and coworkers in this issue of Kidney International suggests that Mesoamerican nephropathy goes through an active, inflammatory phase. Although the pathologic findings are nonspecific and the etiology of Mesoamerican nephropathy remains unclear, inflammatory infiltrates in areas of evolving and established interstitial fibrosis appear to cause progressive kidney injury.
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http://dx.doi.org/10.1016/j.kint.2017.09.025DOI Listing
March 2018

Revision of the International Society of Nephrology/Renal Pathology Society classification for lupus nephritis: clarification of definitions, and modified National Institutes of Health activity and chronicity indices.

Kidney Int 2018 04 16;93(4):789-796. Epub 2018 Feb 16.

Department of Pathology, Vanderbilt University School of Medicine, Nashville, Tennessee, USA.

We present a consensus report pertaining to the improved clarity of definitions and classification of glomerular lesions in lupus nephritis that derived from a meeting of 18 members of an international nephropathology working group in Leiden, Netherlands, in 2016. Here we report detailed recommendations on issues for which we can propose adjustments based on existing evidence and current consensus opinion (phase 1). New definitions are provided for mesangial hypercellularity and for cellular, fibrocellular, and fibrous crescents. The term "endocapillary proliferation" is eliminated and the definition of endocapillary hypercellularity considered in some detail. We also eliminate the class IV-S and IV-G subdivisions of class IV lupus nephritis. The active and chronic designations for class III/IV lesions are replaced by a proposal for activity and chronicity indices that should be applied to all classes. In the activity index, we include fibrinoid necrosis as a specific descriptor. We also make recommendations on issues for which there are limited data at present and that can best be addressed in future studies (phase 2). We propose to proceed to these investigations, with clinicopathologic studies and tests of interobserver reproducibility to evaluate the applications of the proposed definitions and to classify lupus nephritis lesions.
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http://dx.doi.org/10.1016/j.kint.2017.11.023DOI Listing
April 2018

Comments on Famulski and Halloran AJT i-IFTA letter.

Am J Transplant 2018 03 14;18(3):767-768. Epub 2018 Feb 14.

Department of Pathology and Laboratory Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, USA.

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http://dx.doi.org/10.1111/ajt.14664DOI Listing
March 2018

Evolving criteria for the diagnosis of antibody-mediated rejection in renal allografts.

Authors:
Mark Haas

Curr Opin Nephrol Hypertens 2018 05;27(3):137-143

Department of Pathology and Laboratory Medicine, Cedars-Sinai Medical Center, Los Angeles, California, USA.

Purpose Of Review: To review changes in the Banff schema for antibody-mediated renal allograft rejection over the past decade, including key revisions agreed upon during and immediately subsequent to the 2017 Banff Conference on Allograft Pathology.

Recent Findings: The original Banff schema for diagnosis of acute and chronic active antibody-mediated rejection (ABMR) in renal allografts was formulated at the 2001 and 2007 Banff Conferences, and required histologic (primarily microvascular inflammation and transplant glomerulopathy), immunohistologic (C4d in peritubular capillaries), and serologic [circulating donor-specific antibodies (DSA)] evidence for a definitive diagnosis of ABMR. This schema was updated at the 2013 Banff Conference, recognizing C4d-negative ABMR, intimal arteritis as a potential manifestation of ABMR, and revising definitions and thresholds for glomerulitis and transplant glomerulopathy to improve interobserver agreement and correlation with clinical, molecular, and serologic data. Compared with the 2007 criteria, Banff 2013 improved the sensitivity of the classification for diagnosing ABMR and the correlation of ABMR diagnosis with graft outcomes. At the 2017 Banff Conference, new modifications to the classification were discussed and have subsequently been agreed upon, accepting C4d and thoroughly validated molecular classifiers as surrogate markers for DSA.

Summary: From a consensus reached at the 2017 Banff Conference, updated criteria for diagnosis of active and chronic active ABMR have been developed that recognize C4d and molecular classifiers as surrogate markers for DSA. In addition, specific recommendations for the use of molecular diagnostics in the diagnosis of ABMR were developed.
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http://dx.doi.org/10.1097/MNH.0000000000000398DOI Listing
May 2018

Clinical and histopathologic features of antibody-mediated rejection among pediatric renal transplant recipients with preformed vs de novo donor-specific antibodies.

Pediatr Transplant 2017 Dec;21(8)

Comprehensive Transplant Center, Cedars-Sinai Medical Center, Los Angeles, CA, USA.

Preformed and de novo donor specific antibodies (pDSA and dnDSA) are risk factors for ABMR. This study compares the effects of pDSA vs dnDSA in pediatric kidney transplant recipients. Sixteen pediatric patients with biopsy-proven ABMR were evaluated. Strong DSA (MFI >10 000) was recorded at transplant, rejection, and follow-up. DSAs with the highest MFI were termed iDSAs. Allograft biopsies were scored according to Banff 2013 criteria. Seven of 16 (44%) patients had pDSA at transplant; 9 (56%) developed dnDSA. Patients with pDSA developed ABMR earlier (median = 63 vs 1344 days, P = .017), while patients with dnDSA were more likely to have strong Class II iDSA (100% vs 28%, P = .009). Viral infection or non-adherence was more common in patients developing dnDSA (88.8% vs 28.6%, P < .01). Pathology in those with pDSAs demonstrated worse transplant glomerulitis (g score 1.57 ± 0.98 vs 0.56 ± 0.73, P = .031); however, those with dnDSAs exhibited higher C4d+ ABMR (P = .013). Patients developing dnDSAs showed ABMR later post-transplant with predominance of HLA-Class II iDSAs. Inadequate immunosuppression likely contributes to dnDSA formation. Patients with no DSA who have unprotocolized decreases in immunosuppression should be screened for dnDSA as it could lead to early intervention and potentially better outcomes.
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http://dx.doi.org/10.1111/petr.13079DOI Listing
December 2017

Glomerular Disease Pathology in the Era of Proteomics: From Pattern to Pathogenesis.

Authors:
Mark Haas

J Am Soc Nephrol 2018 01 2;29(1):2-4. Epub 2017 Nov 2.

Department of Pathology and Laboratory Medicine, Cedars-Sinai Medical Center, Los Angeles, California

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http://dx.doi.org/10.1681/ASN.2017080881DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5748926PMC
January 2018