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Article ; Online: AJKD Atlas of Renal Pathology: IgA-Dominant Infection-Related Glomerulonephritis.

Paueksakon, Paisit / Najafian, Behzad / Alpers, Charles E / Fogo, Agnes B

American journal of kidney diseases : the official journal of the National Kidney Foundation

2023 Volume 83, Issue 1, Page(s) e1–e2

MeSH term(s)	Humans ; Kidney ; Glomerulonephritis, IGA ; Immunoglobulin A ; Glomerulonephritis
Chemical Substances	Immunoglobulin A
Language	English
Publishing date	2023-12-01
Publishing country	United States
Document type	Journal Article
ZDB-ID	604539-x
ISSN	1523-6838 ; 0272-6386
ISSN (online)	1523-6838
ISSN	0272-6386
DOI	10.1053/j.ajkd.2023.05.009
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Zs.A 1669: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (1.OG) ab Jg. 2022: Lesesaal (EG)
Zs.MO 468: Show issues

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Article ; Online: Approach to Kidney Biopsy: Core Curriculum 2022.

Najafian, Behzad / Lusco, Mark A / Alpers, Charles E / Fogo, Agnes B

American journal of kidney diseases : the official journal of the National Kidney Foundation

2022 Volume 80, Issue 1, Page(s) 119–131

Abstract: The kidney biopsy is an essential tool for diagnosis of many kidney diseases. Obtaining an adequate biopsy sample with appropriate allocation for various studies is essential. Nephrologists should understand key lesions and their interpretation because ... ...

Abstract	The kidney biopsy is an essential tool for diagnosis of many kidney diseases. Obtaining an adequate biopsy sample with appropriate allocation for various studies is essential. Nephrologists should understand key lesions and their interpretation because these are essential elements underlying optimal approaches for interventions. This installment in the AJKD Core Curriculum in Nephrology will review these topics. We will first briefly discuss considerations for allocation and processing of kidney biopsies. We will then present in outline form the differential diagnoses of a spectrum of patterns of injury and consideration for interpretation of specific lesions. Lesions are presented according to anatomic site as glomerular, vascular, or tubulointerstitial. Native and transplant kidney biopsy lesions are included. These lesions and differential diagnoses and specific diseases are then linked to detailed clinicopathologic discussion of specific diseases presented in the AJKD Atlas of Kidney Pathology II. Correlation with immunofluorescence, electron microscopy, and clinical findings are emphasized to reach a differential diagnosis and the final diagnosis.
MeSH term(s)	Biopsy ; Curriculum ; Humans ; Kidney/pathology ; Kidney Diseases/diagnosis ; Kidney Diseases/pathology ; Kidney Glomerulus/pathology
Language	English
Publishing date	2022-02-04
Publishing country	United States
Document type	Journal Article ; Review
ZDB-ID	604539-x
ISSN	1523-6838 ; 0272-6386
ISSN (online)	1523-6838
ISSN	0272-6386
DOI	10.1053/j.ajkd.2021.08.024
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Zs.A 1669: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (1.OG) ab Jg. 2022: Lesesaal (EG)
Zs.MO 468: Show issues

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Article: Cardiomyocyte Globotriaosylceramide Accumulation in Adult Male Patients with Fabry Disease and IVS4 + 919G>A GLA Mutation is Progressive with Age and Correlates with Left Ventricular Hypertrophy and Reduced Left Ventricular Ejection Fraction.

Chang, Fu-Pang / Hsu, Ting-Rong / Hung, Sheng-Che / Sung, Shih-Hsien / Yu, Wen-Chung / Niu, Dau-Ming / Najafian, Behzad

medRxiv : the preprint server for health sciences

2023

Abstract: Background: While cardiovascular complications are the most common cause of mortality in Fabry disease, the relationship between globotriaosylceramide (GL-3) accumulation, the hallmark of Fabry cardiomyopathy, and cardiac hypertrophy has not been fully ... ...

Abstract	Background: While cardiovascular complications are the most common cause of mortality in Fabry disease, the relationship between globotriaosylceramide (GL-3) accumulation, the hallmark of Fabry cardiomyopathy, and cardiac hypertrophy has not been fully elucidated. Methods: We developed unbiased stereology protocols to quantify the ultrastrcture of Fabry cardiomyopathy. Endomyocardial biopsies from 10 adult male enzyme replacement therapy naïve Fabry patients with IVS4 + 919G>A GLA mutation were studied. The findings were correlated with cardiac MRI and clinical data. Results: Ultrastructural parameters showed significant relationships with key imaging and clinical and functional variables. Average cardiomyocyte volume and GL-3 volume per cardiomyocyte were progressively increased with age. Eighty-four percent of left ventricular mass index (LVMI) variability was explained by cardiomyocyte nuclear volume, age and plasma globotriaosylsphingosine with cardiomyocyte nuclear volume being the only independent predictor of LVMI. Septal thickness was directly and left ventricular ejection fraction (LVEF) was inversely correlated with cardiomyocyte GL-3 accumulation. Sixty-five percent of left ventricular ejection fraction (LVEF) variability was explained by cardiomyocyte GL3 volume, serum α-galactosidase-A activity and age with cardiomyocyte GL3 volume being the only independent predictor of LVEF. Residual α-galactosidase-A activity was directly correlated with myocardial microvasculature density. Conclusions: The unbiased stereological methods introduced in this study unraveled novel relationships between cardiomyocyte structure and important imaging and clinical parameters. These novel tools can help better understand Fabry cardiomyopathy pathophysiology.
Language	English
Publishing date	2023-12-11
Publishing country	United States
Document type	Preprint
DOI	10.1101/2023.12.09.23298489
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Article ; Online: Development of an automated estimation of foot process width using deep learning in kidney biopsies from patients with Fabry, minimal change, and diabetic kidney diseases.

Smerkous, David / Mauer, Michael / Tøndel, Camilla / Svarstad, Einar / Gubler, Marie-Claire / Nelson, Robert G / Oliveira, João-Paulo / Sargolzaeiaval, Forough / Najafian, Behzad

Kidney international

2023 Volume 105, Issue 1, Page(s) 165–176

Abstract: Podocyte injury plays a key role in pathogenesis of many kidney diseases with increased podocyte foot process width (FPW), an important measure of podocyte injury. Unfortunately, there is no consensus on the best way to estimate FPW and unbiased ... ...

Abstract	Podocyte injury plays a key role in pathogenesis of many kidney diseases with increased podocyte foot process width (FPW), an important measure of podocyte injury. Unfortunately, there is no consensus on the best way to estimate FPW and unbiased stereology, the current gold standard, is time consuming and not widely available. To address this, we developed an automated FPW estimation technique using deep learning. A U-Net architecture variant model was trained to semantically segment the podocyte-glomerular basement membrane interface and filtration slits. Additionally, we employed a post-processing computer vision approach to accurately estimate FPW. A custom segmentation utility was also created to manually classify these structures on digital electron microscopy (EM) images and to prepare a training dataset. The model was applied to EM images of kidney biopsies from 56 patients with Fabry disease, 15 with type 2 diabetes, 10 with minimal change disease, and 17 normal individuals. The results were compared with unbiased stereology measurements performed by expert technicians unaware of the clinical information. FPW measured by deep learning and by the expert technicians were highly correlated and not statistically different in any of the studied groups. A Bland-Altman plot confirmed interchangeability of the methods. FPW measurement time per biopsy was substantially reduced by deep learning. Thus, we have developed a novel validated deep learning model for FPW measurement on EM images. The model is accessible through a cloud-based application making calculation of this important biomarker more widely accessible for research and clinical applications.
MeSH term(s)	Humans ; Diabetic Nephropathies/diagnosis ; Diabetic Nephropathies/pathology ; Diabetes Mellitus, Type 2 ; Deep Learning ; Glomerular Basement Membrane/pathology ; Biopsy
Language	English
Publishing date	2023-09-27
Publishing country	United States
Document type	Journal Article
ZDB-ID	120573-0
ISSN	1523-1755 ; 0085-2538
ISSN (online)	1523-1755
ISSN	0085-2538
DOI	10.1016/j.kint.2023.09.011
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Zs.A 797: Show issues

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Article: Divergent Impact of Enzyme Replacement Therapy on Human Cardiomyocytes and Enterocytes Affected by Fabry Disease: Correlation with Mannose-6-phosphate Receptor Expression.

Frustaci, Andrea / Najafian, Behzad / Donato, Giuseppe / Verardo, Romina / Chimenti, Cristina / Sansone, Luigi / Belli, Manuel / Vernucci, Enza / Russo, Matteo Antonio

Journal of clinical medicine

2022 Volume 11, Issue 5

Abstract: Background: The impact of enzyme replacement therapy (ERT) on cardiomyocytes and intestinal cells, affected by Fabry disease (FD), is still unclear. Methods: Six patients with FD, including five family members with GLA mutation c.666delC and one with GLA ...

Abstract	Background: The impact of enzyme replacement therapy (ERT) on cardiomyocytes and intestinal cells, affected by Fabry disease (FD), is still unclear. Methods: Six patients with FD, including five family members with GLA mutation c.666delC and one with GLA mutation c.658C > T, manifesting cardiomyopathy and intestinal symptoms (abdominal pain, diarrhea and malabsorption) were included in the study. Clinical outcome, cardiac magnetic resonance (CMR), endomyocardial and gastro-intestinal biopsies were evaluated before and after 2 years of treatment with agalsidase-α (0.2 mg/kg every other week). Immunohistochemistry and Western blot assessments of mannose-6-phosphate receptors (IGF-II-R) on intestinal and myocardial frozen tissue were obtained at diagnosis and after 2 years of ERT. Results: After ERT left ventricular maximal wall thickness, ranging from pre (<10.5 mm) to mild (<15 mm) and moderate hypertrophy (16 mm), was not associated with significant changes at CMR. Degree of dyspnea, mean cardiomyocyte diameter and % vacuolated areas of cardiomyocytes, representing intracellular GL3, remained unmodified. In contrast, intestinal symptoms improved with disappearance of diarrhea, recovery of anemia and weight gain, correlating with near complete clearance of the enterocytes from GL3 inclusions. IGF-II-R expression was remarkably higher even at histochemistry in intestinal tissue compared with myocardium (p < 0.001) either at baseline and after ERT, thus justifying intestinal recovery. Conclusions: Human cells affected by FD may respond differently to ERT: while cardiomyocytes retain their GL3 content after 2 years of treatment, gastro-intestinal cells show GL3 removal with recovery of function. This divergent response may be related to differences in cellular turnover, as well as tissue IGF-II-R expression.
Language	English
Publishing date	2022-02-28
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2662592-1
ISSN	2077-0383
ISSN	2077-0383
DOI	10.3390/jcm11051344
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Article ; Online: Structural Lesions on Kidney Biopsy in Youth-Onset and Adult-Onset Type 2 Diabetes.

Looker, Helen C / Pyle, Laura / Vigers, Tim / Severn, Cameron / Saulnier, Pierre J / Najafian, Behzad / Mauer, Michael / Nelson, Robert G / Bjornstad, Petter

Diabetes care

2022 Volume 45, Issue 2, Page(s) 436–443

Abstract: Objective: Type 2 diabetes (T2D) is a leading cause of end-stage kidney disease worldwide. Recent studies suggest a more aggressive clinical course of diabetic kidney disease in youth-onset compared with adult-onset T2D. We compared kidney structural ... ...

Abstract	Objective: Type 2 diabetes (T2D) is a leading cause of end-stage kidney disease worldwide. Recent studies suggest a more aggressive clinical course of diabetic kidney disease in youth-onset compared with adult-onset T2D. We compared kidney structural lesions in youth- and adult-onset T2D to determine if youth onset was associated with greater early tissue injury. Research design and methods: Quantitative microscopy was performed on kidney tissue obtained from research kidney biopsies in 161 Pima Indians (117 women, 44 men) with T2D. Onset of T2D was established by serial oral glucose tolerance testing, and participants were stratified as youth onset (age <25 years) or adult onset (age ≥25 years). Associations between clinical and morphometric parameters and age at onset were tested using linear models. Results: At biopsy, the 52 participants with youth-onset T2D were younger than the 109 with adult-onset T2D (39.1 ± 9.9 vs. 51.4 ± 10.2 years; P < 0.0001), but their diabetes duration was similar (19.3 ± 8.1 vs. 17.0 ± 7.8 years; P = 0.09). Median urine albumin-to-creatinine ratio was higher in the youth-onset group (58 [25th-75th percentile 17-470] vs. 27 [13-73] mg/g; P = 0.02). Youth-onset participants had greater glomerular basement membrane (GBM) width (552 ± 128 vs. 490 ± 114 nm; P = 0.002) and mesangial fractional volume (0.31 ± 0.10 vs. 0.27 ± 0.08; P = 0.001) than adult-onset participants. Glomerular sclerosis percentage, glomerular volume, mesangial fractional volume, and GBM width were also inversely associated with age at diabetes onset as a continuous variable. Conclusions: Younger age at T2D onset strongly associates with more severe kidney structural lesions. Studies are underway to elucidate the pathways underlying these associations.
MeSH term(s)	Adolescent ; Adult ; Biopsy/adverse effects ; Child, Preschool ; Diabetes Mellitus, Type 2/complications ; Diabetic Nephropathies/etiology ; Female ; Glomerular Filtration Rate ; Humans ; Kidney ; Kidney Function Tests ; Male
Language	English
Publishing date	2022-01-10
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, N.I.H., Intramural ; Research Support, Non-U.S. Gov't
ZDB-ID	441231-x
ISSN	1935-5548 ; 0149-5992
ISSN (online)	1935-5548
ISSN	0149-5992
DOI	10.2337/dc21-1688
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Zs.A 1434: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (1.OG) ab Jg. 2022: Lesesaal (EG)
Zs.MO 365: Show issues

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Article ; Online: A novel unbiased method reveals progressive podocyte globotriaosylceramide accumulation and loss with age in females with Fabry disease.

Najafian, Behzad / Silvestroni, Aurelio / Sokolovskiy, Alexey / Tøndel, Camilla / Svarstad, Einar / Obrisca, Bogdan / Ismail, Gener / Holida, Myrl D / Mauer, Michael

Kidney international

2022 Volume 102, Issue 1, Page(s) 173–182

Abstract: While females can suffer serious complications of Fabry disease, most studies are limited to males to avoid confounding by mosaicism. Here, we developed a novel unbiased method for quantifying globotriaosylceramide (GL3) inclusion volume in affected ... ...

Abstract	While females can suffer serious complications of Fabry disease, most studies are limited to males to avoid confounding by mosaicism. Here, we developed a novel unbiased method for quantifying globotriaosylceramide (GL3) inclusion volume in affected podocytes (F+) in females with Fabry disease independent of mosaicism leading to important new observations. All podocytes in male patients with Fabry are F+. The probability of observing random profiles from F+ podocytes without GL3 inclusions (estimation error) was modeled from electron microscopic studies of 99 glomeruli from 40 treatment-naïve males and this model was applied to 28 treatment-naïve females. Also, podocyte structural parameters were compared in 16 age-matched treatment-naïve males and females with classic Fabry disease and 11 normal individuals. A 4
MeSH term(s)	Fabry Disease/complications ; Female ; Humans ; Male ; Podocytes ; Proteinuria/etiology ; Trihexosylceramides
Chemical Substances	Trihexosylceramides ; globotriaosylceramide (71965-57-6)
Language	English
Publishing date	2022-04-26
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	120573-0
ISSN	1523-1755 ; 0085-2538
ISSN (online)	1523-1755
ISSN	0085-2538
DOI	10.1016/j.kint.2022.03.023
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Zs.A 797: Show issues

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Article ; Online: Accumulation of Globotriaosylceramide in Podocytes in Fabry Nephropathy Is Associated with Progressive Podocyte Loss.

Najafian, Behzad / Tøndel, Camilla / Svarstad, Einar / Gubler, Marie-Claire / Oliveira, João-Paulo / Mauer, Michael

Journal of the American Society of Nephrology : JASN

2020 Volume 31, Issue 4, Page(s) 865–875

Abstract: Background: In males with classic Fabry disease, the processes leading to the frequent outcome of ESKD are poorly understood. Defects in the gene encoding : Methods: In this study of 55 males (mean age 27 years) with classic Fabry disease genotype ... ...

Abstract	Background: In males with classic Fabry disease, the processes leading to the frequent outcome of ESKD are poorly understood. Defects in the gene encoding Methods: In this study of 55 males (mean age 27 years) with classic Fabry disease genotype and/or phenotype, we performed unbiased quantitative morphometric electron microscopic studies of biopsied kidney samples from patients and seven living transplant donors (to serve as controls). We extracted clinical information from medical records and clinical trial databases. Results: Podocyte GL3 volume fraction (proportion of podocyte cytoplasm occupied by GL3) increased with age up to about age 27, suggesting that increasing podocyte GL3 volume fraction beyond a threshold may compromise survival of these cells. GL3 accumulation was associated with podocyte injury and loss, as evidenced by increased foot process width (a generally accepted structural marker of podocyte stress and injury) and with decreased podocyte number density per glomerular volume. Worsening podocyte structural parameters (increasing podocyte GL3 volume fraction and foot process width) was also associated with increasing urinary protein excretion-a strong prognosticator of adverse renal outcomes in Fabry disease-as well as with decreasing GFR. Conclusions: Given the known association between podocyte loss and irreversible FSGS and global glomerulosclerosis, this study points to an important role for podocyte injury and loss in the progression of Fabry nephropathy and indicates a need for therapeutic intervention before critical podocyte loss occurs.
MeSH term(s)	Adolescent ; Adult ; Age Factors ; Case-Control Studies ; Child ; Child, Preschool ; Fabry Disease/metabolism ; Fabry Disease/pathology ; Glomerular Filtration Rate ; Humans ; Kidney Glomerulus/metabolism ; Kidney Glomerulus/pathology ; Male ; Middle Aged ; Podocytes/metabolism ; Podocytes/pathology ; Trihexosylceramides/metabolism ; Young Adult
Chemical Substances	Trihexosylceramides ; globotriaosylceramide (71965-57-6)
Language	English
Publishing date	2020-03-03
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	1085942-1
ISSN	1533-3450 ; 1046-6673
ISSN (online)	1533-3450
ISSN	1046-6673
DOI	10.1681/ASN.2019050497
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Zs.A 3344: Show issues

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Article ; Online: AJKD Atlas of Renal Pathology: Pierson Syndrome.

Lusco, Mark A / Najafian, Behzad / Alpers, Charles E / Fogo, Agnes B

American journal of kidney diseases : the official journal of the National Kidney Foundation

2018 Volume 71, Issue 4, Page(s) e3–e4

MeSH term(s)	Abnormalities, Multiple/pathology ; Diagnosis, Differential ; Eye Abnormalities/pathology ; Humans ; Kidney/pathology ; Nephrotic Syndrome/pathology ; Periodicals as Topic ; Pupil Disorders/pathology
Language	English
Publishing date	2018-03-22
Publishing country	United States
Document type	Journal Article ; Review
ZDB-ID	604539-x
ISSN	1523-6838 ; 0272-6386
ISSN (online)	1523-6838
ISSN	0272-6386
DOI	10.1053/j.ajkd.2018.02.001
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Zs.A 1669: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (1.OG) ab Jg. 2022: Lesesaal (EG)
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Article ; Online: Predilection of segmental glomerulosclerosis lesions for the glomerulotubular junction area in type 1 diabetic patients: a novel mapping method.

Najafian, Behzad / Mauer, Michael

PloS one

2013 Volume 8, Issue 7, Page(s) e69253

Abstract: The location of segmental glomerular lesions in relation to the vascular or tubular pole may have diagnostic or prognostic significance. We have developed a model-based method to estimate the distance from a glomerular lesion to a given landmark ( ... ...

Abstract	The location of segmental glomerular lesions in relation to the vascular or tubular pole may have diagnostic or prognostic significance. We have developed a model-based method to estimate the distance from a glomerular lesion to a given landmark (vascular or tubular pole) or the glomerular center and applied this to biopsies from 5 microalbuminuric, 5 normoalbuminuric and 7 proteinuric type 1 diabetic patients and 5 normal controls. The distance from each glomerular adhesion to the glomerulotubular junction was measured and divided by the glomerular radius, allowing comparability among different glomeruli, assuming a spherical shape for Bowman's capsule, an assumption which was validated. The frequency of adhesions in 6 glomerular zones with equal height (zone I adjacent to the glomerulotubular junction and zones II-VI progressively farther away) was determined: 59% of adhesions were in zone I, 15% in zone II, 16% in zone III, 7% in zone IV and 3% in zone VI (adjacent to the hilus). In glomeruli with only one adhesion, 82% of these were in zone I. This new method accurately localizes segmental lesions within glomeruli and revealed a marked predilection in type 1 diabetic patients for segmental sclerosis to develop at the glomerulotubular junction.
MeSH term(s)	Adolescent ; Biopsy ; Case-Control Studies ; Diabetes Mellitus, Type 1/pathology ; Diabetes Mellitus, Type 1/urine ; Diabetic Nephropathies/pathology ; Diabetic Nephropathies/urine ; Female ; Glomerulosclerosis, Focal Segmental/pathology ; Glomerulosclerosis, Focal Segmental/urine ; Histocytochemistry ; Humans ; Kidney Glomerulus/pathology ; Kidney Tubules/pathology ; Male ; Middle Aged ; Proteinuria/pathology ; Proteinuria/urine
Language	English
Publishing date	2013-07-25
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ISSN	1932-6203
ISSN (online)	1932-6203
DOI	10.1371/journal.pone.0069253
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