Core Curriculum in Nephrology

Approach to Kidney Biopsy: Core

Curriculum 2022
Behzad Najafian, Mark A. Lusco, Charles E. Alpers, and Agnes B. Fogo

The kidney biopsy is an essential tool for diagnosis of many kidney diseases. Obtaining an adequate Complete author and article
biopsy sample with appropriate allocation for various studies is essential. Nephrologists should un- information provided at end
of article.
derstand 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 Am J Kidney Dis.
these topics. We will first briefly discuss considerations for allocation and processing of kidney bi- 80(1):119-131. Published
online February 4, 2022.
opsies. 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 doi: 10.1053/
site as glomerular, vascular, or tubulointerstitial. Native and transplant kidney biopsy lesions are j.ajkd.2021.08.024
included. These lesions and differential diagnoses and specific diseases are then linked to detailed © 2021 by the National
clinicopathologic discussion of specific diseases presented in the AJKD Atlas of Kidney Pathology II. Kidney Foundation, Inc.
Correlation with immunofluorescence, electron microscopy, and clinical findings are emphasized to
reach a differential diagnosis and the final diagnosis.

lesions. For lesions that are segmental, pre- FEATURE EDITOR

Introduction Asghar Rastegar
paring serial sections and levels is critical to
This installment of AJKD’s Core Curriculum in
increase the likelihood that any such lesions
Nephrology consists of 2 parts, which ADVISORY BOARD
represented in the biopsy core will be identi- Ursula C. Brewster
together constitute an update and extension to
fied in the histologic sections, especially when Michael Choi
a 2003 Core Curriculum installment,
the number of available glomeruli is limited. Ann O’Hare
“Approach to Renal Biopsy.” The first part is Biff F. Palmer
The minimum sample size for diagnosis varies
in the form of a brief narrative description of
greatly with the specific diagnosis; for
approaches to allocate and process kidney bi- The Core Curriculum
instance, membranous nephropathy can be
opsies. The second part presents in outline aims to give trainees
diagnosed from a single glomerulus although in nephrology a
form the differential diagnoses of a spectrum
even this disorder requires a greater number strong knowledge
of patterns of injury and consideration for
of glomeruli to fully characterize the lesion base in core topics in
interpretation of specific lesions. These lesions the specialty by
and the extent of chronicity or scarring that
and specific diseases are then linked to detailed providing an over-
may be present. Transplant diagnoses are most
clinicopathologic discussion of specific disease view of the topic and
accurate when the sample includes a mini- citing key references,
presented in the Atlas of Renal Pathology II.
mum of 7 glomeruli from 2 separate sites of including the founda-
cortex. For most LM assessments to adequately tional literature that
Tissue Sampling, Allocation, and assess the severity and distribution of lesions, led to current clinical
Processing 8 to 10 glomeruli are needed. approaches.

Sampling
Sample Size Sample Location
An adequate sample size must be obtained for Subcapsular cortical samples have over-
diagnosis. Considerations regarding biopsy representation of global sclerosis related to
indications, procedure, and relative and ab- aging/hypertension and nonspecific scarring.
solute contraindications are discussed in detail Juxtamedullary glomeruli are the earliest to be
in Core Curriculum “Update on the Native involved with segmental sclerosis in focal
Kidney Biopsy.” Needle gauge has dramatic segmental glomerulosclerosis (FSGS). This
impact on the sample obtained. Although 18- region should be included in the sample for
or 19-gauge needles are commonly used and optimal detection. Some processes are better
usually provide samples that are diagnostic, represented in the corticomedullary or
they provide very small, narrow samples and medullary regions (eg, polyomavirus
may have inadequate representation of vessels. nephropathy).
For focal lesions involving a small number of
glomeruli, 25 glomeruli may be needed for Dividing the Tissue
light microscopy (LM) examination to have a A dissecting microscope can be used to iden-
greater than 95% chance of detecting those tify cortical parenchyma containing glomeruli,

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or without any visual guidance one can remove 1-mm to the laboratory. Tissue is stable at room temperature for
cubes from each end of each core and place them in express mailing to central laboratories in this medium.
glutaraldehyde for electron microscopy (EM). The
remaining cores can then be divided into 2 pieces, placing Immunohistochemistry
the larger of each core, about two-thirds of the core In some laboratories, IHC on formalin-fixed tissue, instead
length, in fixative for LM, and the smaller section of each of IF on frozen tissue, is used with good results for
core in tissue-transport media for immunofluorescence identification of deposited immunoglobulins and com-
(IF). If immunohistochemistry (IHC) on formalin-fixed plement. Success with this technique requires expert
tissue is used in place of IF, then the remaining tissue af- histotechnologists and may not work optimally if tissue
ter EM allocation is allocated in toto for combined LM and has been in fixative or paraffin-embedded for a long period
IHC. Allocation should be done on a clean surface (such as of time.
a wax cutting board) with a sharp razor or blade to avoid
crushing parts of the biopsy sample. Electron Microscopy
Small, 1-mm cubes of cortex are allocated for EM and
Handling of Tissue optimally are placed directly in glutaraldehyde.
To avoid crush artifacts, forceps should not be used. The
tissue can be manipulated by allowing it to adhere to a thin Tissue Processing
wooden stick that then is placed in the fixative or transport Light Microscopy
medium, respectively. Avoid touching the tissue with a Tissue for LM is processed, dehydrated, and embedded in a
fixative-contaminated scalpel or razor blade (this con- paraffin block, and multiple serial sections at 2.5-3 μm
taminates the tissue for IF and could result in false-negative thickness are obtained and stained. Usual stains include
IF results). hematoxylin and eosin (H&E), periodic acid–Schiff (PAS),
silver methenamine (Jones), and Masson trichrome.
Allocation and Fixatives Additional unstained slides are produced to allow addi-
An adequate assessment of native kidney biopsies includes tional special studies as needed. Five hours of processing,
LM, IF or IHC, and EM. For transplant biopsy, LM and IF or sectioning, and staining time are typically needed to pro-
IHC are considered the standard, with repeat biopsies only duce LM slides.
needing LM in many cases and C4d staining, best done
from frozen tissue by IF. However, we recommend that Immunofluorescence Microscopy
transplant biopsies include allocation of tissue for EM in Tissue for IF is surrounded with optimal cutting temper-
first biopsies because often the primary disease process is ature (OCT) compound and frozen in a cryomicrotome (if
unknown and EM may provide unexpected value in not directly frozen after biopsy). Sections are produced,
assessment of kidney graft dysfunction. In follow-up fixed with acetone and stained with fluorescein-tagged
transplant biopsies, allocation for EM may depend on the antibodies against IgG, IgA, IgM, complement pathway
clinical situation (eg, proteinuria, concern for recurrent or components C3 (junction of all 3 complement pathways)
de novo deposit-related disease). When possible, alloca- and C1q and/or C4 (classical pathway), κ and λ light
tion of small pieces for EM (which can be saved and chain, fibrinogen, and albumin. Some laboratories use
processed later as clinically indicated) provides the best properdin as a marker for alternative complement pathway
opportunities for diagnosis in complex cases. activation. Complement product C4d, a marker of classical
and mannose-binding lectin pathways, optimally is stained
Light Microscopy on frozen tissue, with less sensitivity if staining is per-
For most differential diagnoses, the largest portion of formed on paraffin-block tissue. One to 2 hours of pro-
cortex should be placed in fixative for LM. These fixatives cessing, sectioning, and staining time are needed for
include formalin, paraformaldehyde, or, less commonly, production of IF slides.
alcoholic Bouin or Zenker fixative. Although formalin may
not allow some morphologic details to be as defined as Electron Microscopy
with Zenker fixative, the use of formalin allows much EM tissue is processed and embedded in a plastic, hard
greater IHC ancillary testing to be done, as indicated in medium, and scout sections (so-called thick sections) are
individual cases. If observation of urate crystals is intended, stained with toluidine blue to identify the specific area to
ethanol is preferred. be cut for thin sections to be placed on a grid for EM
examination. Typically, 2 working days are needed to
Immunofluorescence Microscopy process the specimen and produce thin sections for ultra-
IF tissue should include a small piece of cortex, usually 3 to structural examination. Microwave processing can hasten
4 mm. Tissue for IF can be directly frozen or placed in polymerization and cut down this processing time, but
tissue transport medium (such as Michel) and transported morphology may be suboptimal.

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Salvage Techniques monotypic immunoglobulin deposits. Kidney Int.

If there is inadequate tissue in any of the media, sometimes 2015;88: 867-873.
results can still be obtained as described in the following. ➢ Nankivell BJ, Renthawa J, Shingde M, Khan A. The
Salvage LM from frozen tissue. The remaining frozen importance of kidney medullary tissue for the accurate
tissue after IF may be retrieved and fixed in formalin and diagnosis of BK virus allograft nephropathy. Clin J Am Soc
processed for LM. This approach, while associated with Nephrol. 2020;15(7):1015-1023.
some freezing artifacts and some loss of morphologic ➢ Nasr SH, Galgano SJ, Markowitz GS, et al. Immuno-
detail, can provide invaluable information when the fluorescence on pronase-digested paraffin sections: a
original LM sample is inadequate. valuable salvage technique for renal biopsies. Kidney Int.
Salvage EM from paraffin-embedded tissue. EM 2006;70:2148-2151.
study can be done by processing remaining tissue from the ➢ Seemayer CA, Gaspert A, Nickeleit V, Mihatsch MJ. C4d
LM sample from the paraffin block for EM. Of note, staining of renal allograft biopsies: a comparative
glomerular basement membranes (GBM) are artefactually analysis of different staining techniques. Nephrol Dial
thinner with such processing, precluding accurate GBM Transplant. 2007;22(2):568-576.
measures. Reprocessing the frozen tissue (for IF) for EM is
possible; however, the outcome quality is variable and
Tissue Examination
may be associated with significant artifacts. Salvage EM
from frozen tissue has major artefacts and is not We will now provide an overview of approaches to assess
recommended. injury and localize pathologic alterations to the specific
Salvage IF from paraffin tissue. Immunofluorescence anatomic compartment. Injuries are categorized as active
done on fixed, paraffin-embedded tissue sections after versus chronic lesions. In addition, injuries are categorized
pronase or proteinase K digestion can yield diagnostic as involving predominantly glomeruli, vessels, or the
information when glomeruli are not present in the original tubulointerstitium, recognizing that eventually injury in
IF sample. Sensitivity for detection of deposits varies. IgA any one of these anatomical compartments may affect
deposits are robustly detected by this method, whereas other anatomical sites. We have organized discussion of
anti-GBM staining is not detected, and the results for specific lesions according to these anatomical
membranous nephropathy are variable. Crystalline light compartments.
chain deposits are not reliably detected by frozen section IF
and by contrast are robustly detected after pronase/pro- Active Versus Chronic Lesions
teinase digestion of formalin-fixed paraffin-embedded Active lesions of glomeruli include hypercellularity (either
(FFPE) sections. Some deposits that are masked (the epi- mesangial or endocapillary, the latter including influx of
topes targeted by the antibodies are hidden due to leukocytes), fibrinoid necrosis with destruction of archi-
conformational changes) and not detectable by routine IF tecture, rupture of GBMs, and karyorrhexis. Crescents are a
on frozen tissue can become detectable after pronase response to injury that breaks the capillary wall. The early
digestion. This technique is of use in assessment of C3 lesion consists predominantly of proliferation of parietal
glomerulopathies and to assess possible clonality of de- epithelial cells with later influx of inflammatory cells and
posits (see the separate sections). fibrous organization. Crescents are classified as cellular
(active), fibrocellular (both active and chronic), or fibrous
Additional Readings (chronic). Tubulointerstitial active lesions are character-
➢ Corwin HL, Schwartz MM, Lewis EJ. The importance of ized by edema, inflammatory infiltrates, often with tubu-
sample size in the interpretation of the renal biopsy. Am litis, with variable lymphocytes, plasma cells, and/or
J Nephrol. 1988;8:85-89. +ESSENTIAL READING polymorphonuclear leukocytes. Active lesions of vessels
➢ Luciano RL, Moeckel GW. Update on the native kidney include intimal swelling necrosis, thrombosis, and
biopsy: core curriculum 2019. Am J Kidney Dis. inflammation (vasculitis).
2019;73:404-415. +ESSENTIAL READING Chronic lesions of glomeruli include sclerosis, either
➢ Messias NC, Walker PD, Larsen CP. Paraffin immuno- segmental or global, and fibrous crescents. The pattern of
fluorescence in the renal pathology laboratory: sclerosis gives hints to the underlying etiology, in
more than a salvage technique. Mod Pathol. conjunction with IF and EM examination, integrated with
2015;28:854-860. +ESSENTIAL READING clinical findings. Chronic changes of the GBMs include
➢ Hou J, Markowitz GS, Bomback AS, et al. Toward a thickening and duplication of the basement membrane
working definition of C3 glomerulopathy by matrices. Fibrous crescents are chronic lesions whereas
immunofluorescence. Kidney Int. 2014;85(2):450- fibrocellular crescentic lesions are a mixture of active and
456. chronic. Chronic tubulointerstitial lesions are interstitial
➢ Larsen CP, Messias NC, Walker PD, et al. Mem- fibrosis and tubular atrophy, which usually develop in
branoproliferative glomerulonephritis with masked parallel. Lymphocytic infiltration occurs in fibrosed areas

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as part of the scarring process. Neutrophils within these Outline of Native Kidney–Specific Lesions
areas suggest additional or other etiologies. Chronic lesions
of vessels include medial thickening, hyalinosis, and I. Glomerular lesions
intimal or medial fibrosis. Concentric intimal proliferation A. Thickened GBM appearance by LM
(“onion-skin” lesion) indicates injury related to chronic i. Thick appearance of GBM by LM with negative
endothelial injury seen in for example scleroderma or se- IF.
vere hypertension. a. No double contour by silver stain, thick lam-
ina densa by EM:
Types of Lesions 1. Diabetic nephropathy.
Examination by IF (or IHC), EM, and LM is essential to 2. Idiopathic nodular glomerulosclerosis.
determine the nature and pathogenesis of lesions. A group b. Double contour by silver stain:
of pathologists from the Renal Pathology Society has 1. Chronic (thrombotic) microangiopathy.
recently proposed precise definitions for use of a spectrum Note: Microangiopathy may or may not
of morphologic lesion descriptions, aimed to provide have thrombosis detected at this stage;
uniformity in reporting. when thrombosis is absent, it is better
Special stains are useful for determining if thickened termed “chronic microangiopathy.”
GBMs are likely due to immune-complex deposits or Note: In some cases of chronic thrombotic
not because deposits and cells do not stain with Jones microangiopathy (TMA), some endocapil-
silver stain. Some stains such as PAS can highlight lary/mesangial hypercellularity may be
large confluent deposits or intracapillary accumulations present, and the differential diagnosis of
of immune complexes such as those that may be membranoproliferative glomerulonephritis
encountered in lupus nephritis or cryoglobulinemic (MPGN) pattern is then considered (see
glomerulonephritis (GN). Assessment by IF then de- section on MPGN pattern).
termines whether lesions are mediated by immune 2. Transplant glomerulopathy (see “Outline
complexes or other deposits or not. EM aids in of Transplant Kidney Lesions” section and
determination of specific localization of any deposits, Chronic Antibody-Mediated Rejection Atlas
nature of any deposits, GBM abnormalities, foot pro- installment).
cess effacement, and other specific abnormalities of, c. -Irregular by silver stain, basketweaving by
for example, tubules or interstitium. Correlation of LM EM: hereditary nephritis (Alport syndrome).
with IF and EM and clinical history is needed for d. Variable spikes or double contour by silver
optimal interpretation. stain: may be due to masked deposits on
In the remainder of this Core Curriculum, we give in- standard frozen tissue IF, with subsequent IF
tegrated differential diagnosis for a spectrum of lesions/ on paraffin-embedded tissue after pronase
patterns of injury, with illustrations provided in the digestion positive after this unmasking of
hyperlinked disease-specific installments of the AJKD Atlas deposits (deposits also visualized by EM, see
of Renal Pathology II. specific sections according to findings).
ii. Thick appearance of GBM by LM with positive IF:
Additional Readings a. Granular capillary loop IgG polyclonal and C3
➢ Bajema IM, Wilhelmus S, Alpers CE, et al. Revision of staining by IF, spikes by Jones stain, subepithelial
the International Society of Nephrology/ Renal Pa- deposits by EM: membranous nephropathy.
thology Society classification for lupus nephritis: clar- Note: Diagnosis of specific etiology is aided by
ification of definitions, and modified National Institutes integration with IF, EM, and clinical history and
of Health activity and chronicity indices. Kidney Int. staining for novel antigens found in membranous
2018;93(4):789-796. nephropathy (eg, PLA2R [phospholipase A2 re-
➢ Haas M, Seshan SV, Barisoni L, et al. Consensus defi- ceptor], THSD7A [thrombospondin type 1
nitions for glomerular lesions by light and electron domain-containing 7A], EXT1/2 [exostosin 1/
microscopy: recommendations from a working group 2], NELL-1 [neuroepidermal growth factor-like
of the Renal Pathology Society. Kidney Int. 1], and others).
2020;98(5):1120-1134. +ESSENTIAL READING b. Molded, sausage-shaped contour of deposits
➢ Sethi S, D’Agati VD, Nast CC, et al. A proposal for along capillary loop, mesangial granular de-
standardized grading of chronic changes in native posits, GBM double contour by silver stain,
kidney biopsy specimens. Kidney Int. 2017;91(4):787- subendothelial deposits by EM: MPGN due to
789. deposits.
➢ Sethi S, Haas M, Markowitz GS, et al. Mayo Clinic/ The nature of the deposits must then be
Renal Pathology Society consensus report on pathologic defined, whether C3 dominant or immuno-
classification, diagnosis, and reporting of GN. J Am Soc globulin (either monoclonal or polyclonal).
Nephrol. 2016;27:1278-1287. MPGN pattern can be due to, for example,

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immune complexes (see MPGN and Focal and years; 325 vs 375 nm average in female vs male
Diffuse Lupus Nephritis (ISN/RPS Class III and adults).
IV)), other deposits (fibrillary GN) or clonal Note: More specific morphologic diagnosis of type of
deposits (proliferative GN with monoclonal abnormality causing thin GBM may be made by
immunoglobulin deposits), or C3 glomerul- special immunostaining for subtypes of type IV
opathy (including C3 GN and dense deposit collagen. Total absence of collagen IV α5 chain in-
disease [DDD]). dicates male with X-linked Alport. Mosaic GBM
c. Polyclonal IgG with full house staining (ie, all staining pattern for collagen IV α5 indicates female
immunoglobulins [IgG, IgA, IgM], C3, and X-linked heterozygote. Preserved collagen IV α5
C1q) suggests lupus nephritis class III focal or staining in Bowman capsule but not in GBM indicates
IV diffuse, depending on whether <50% autosomal form of Alport due to mutation in α3 or
or ≥50% of glomeruli involved. α4 chain.
d. Polyclonal IgG and strong IgM component, C. Mesangial hypercellularity
often with clonal shift (ie, 1 light chain i. Variable mesangial hypercellularity with nodules:
significantly dominant); may have strong PAS- nodular sclerosis may be seen in the following
positive deposits in capillary lumens (cry- conditions. Correlation with IF and/or EM allows
oplugs) and short fibrillary substructure by distinction of these possibilities:
EM: cryoglobulinemic GN. a. Diabetic nephropathy: nodular sclerosis, with
e. Polyclonal IgG with lesser C3; GBM variable increased matrix more than cells, thick GBM,
double contours by silver stain, randomly ar- arteriolar hyalinosis (afferent and efferent), no
ranged fibrils by EM, negative Congo Red, deposits.
positive DNAJB9 staining by IHC: fibrillary GN. b. Monoclonal immunoglobulin deposition dis-
Note: Rarely, fibrillary GN has been described ease: most common type is light chain depo-
with apparent clonal deposits. Studies with sition disease (see Light Chain Deposition
newer antibodies against combined heavy and Disease, Light and Heavy Chain Deposition
light chain regions and mass spectrometry Disease, and Heavy Chain Deposition Disease).
support the deposits are polyclonal in nearly all Nodular sclerosis with monoclonal light chain
cases. staining of GBM and tubular basement mem-
iii. Thickened appearance of GBMs by LM with brane (TBM) with corresponding amorphous
variable IF. powdery deposits by EM.
Amyloid deposits can result in thickened GBM c. Idiopathic nodular glomerulosclerosis: appears
with long feathery spikes on silver stain, Congo morphologically like diabetic glomerulo-
red positive (see AL Amyloidosis). sclerosis but patients do not have diabetes.
AL amyloid shows positive IF for 1 light chain, d. Amyloid (see AL Amyloidosis and Hereditary
with smudgy mesangial and capillary wall and Other Non-AL Amyloidoses): relatively
pattern, often also in vessels (most often λ but κ acellular expansion of mesangial areas, may be
can also form amyloid; rare cases of heavy chain nodular, may have feathery spikes of GBM by
amyloid exist). LM, has randomly arranged 9-11 nm fibrils by
Note: IF is negative or shows only nonspecific EM, Congo Red positive.
trapping in other types of amyloid, with specific e. MPGN pattern: can be nodular—various cau-
type defined by IHC and/or mass spectrometry ses (see below), diagnosed by IF, EM, IHC
(see Hereditary and Other Non-AL Amyloidoses). (see MPGN).
B. Thin GBM by EM ii. Mesangial hypercellularity with positive IF
Collagen IV abnormalities, such as Alport syndrome, without nodules—distinction of cause relies
have thin GBM as an early lesion in X-linked affected heavily on IF findings:
male, male or female autosomal recessive heterozy- a. Mesangial lupus nephritis (see Minimal
gotes, or female X-linked heterozygotes (see Thin Mesangial and Mesangial Proliferative
Glomerular Basement Membrane Lesion and Alport Lupus Nephritis (ISN/RPS Class I and
Syndrome). II)): IF and EM, and clinical history
Note: Thin GBMs cannot reliably be detected by LM. distinguish mesangial lupus nephritis from
GBM should be extensively thin to diagnose thin other causes of mesangial immune com-
GBM lesion, as very segmental thinning may occur in plexes. Lupus nephritis is characterized by
healthy individuals. IF positivity often with all 3 immuno-
Note: GBM thickness increases normally with age, so globulins and both complements (full
thickness must be compared with age-matched house), reticular aggregates in endothelial
control (w100 vs 200 nm in age 1 year vs age 8 cells by EM (footprints of high interferon

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levels, found in endothelial cells found in endothelial cells throughout the

throughout the body). body).
b. IgA nephropathy (IgAN): diagnosis made by iii. Cryoglobulinemic GN: may have predominant
IF. Dominant or co-dominant (with other IgM, substructure of deposits by EM, and
immunoglobulins) IgA mesangial deposits, sometimes strongly positive PAS plugs (cry-
with mesangial deposits most often detected oplugs) in capillary lumens.
by EM, are typical. Deposits may extend to iv. Postinfectious GN: most commonly has promi-
subendothelial areas of adjacent GBMs, often nent PMN (polymorphonuclear leukocyte)
eliciting a focal endocapillary hypercellular infiltrate in the glomerular tuft, with starry sky
reaction. appearance of IgG and strong C3 deposits by IF,
c. Chronic infection-related GN: deposits may be and hump-shaped subepithelial deposits by EM.
IgG or IgM predominant. The presence of any In the chronic phase, seen more often in adults,
subepithelial hump-shaped deposits, seen by the term “infection-related GN” should be used
EM, in addition to the mesangial deposits, as the infection often is ongoing. The active
strongly suggests an infection-related etiology lesions seen in classic poststreptococcal GN may
(see Post-Infectious Glomerulonephritis). C3- not be present, with only mild hypercellularity,
dominant GN due to complement dysregula- few if any neutrophils in the glomerular capil-
tion can also have hump-shaped deposits. laries, and rare hump-typed deposits, often in
iii. Mesangial hypercellularity without immune the hinge region where the GBM reflects over
complexes—the differential diagnosis includes: the mesangium.
a. Variant of minimal change disease (MCD)/ v. Fibrillary GN: has IgG polyclonal predomi-
FSGS (EM shows extensive foot process nance, randomly arranged deposits with fibril-
effacement in untreated MCD or primary FSGS lary substructure 11-24 nm by EM, Congo
(due to initial podocyte injury). red–negative, DNAJB9 positive by IHC.
b. Early diabetic nephropathy (GBM thickening vi. Immunotactoid glomerulopathy: has IgG pre-
by EM). dominance, deposits are often clonal, with
c. A nonspecific finding. microtubular and/or parallel array substructure
D. Endocapillary hypercellularity by EM and is usually associated with a para-
The MPGN pattern is characterized by mesangial and protein. Similar morphology may be caused by
endocapillary hypercellularity, a term denoting a cryoglobulin deposits, particularly monoclonal
combination of both endothelial cell prominence and cryoglobulin.
influx of leukocytes in glomerular capillaries, with vii. DDD: has C3 only or C3 dominant staining, at
double contours of the GBM by LM. Glomeruli may least 2 intensity steps greater than IgG, with
show a nodular pattern. IF, EM, and/or IHC are limited immunoglobulin, dense transformation
needed for specific diagnosis. If the MPGN pattern is of GBM, with dense mesangial nodules by EM.
caused by deposits, IF or IHC will show the causative viii. C3-dominant GN: has C3 only or dominant
deposits along capillary loop and in mesangial areas, staining, at least 2 intensity steps greater than
with subendothelial and mesangial deposits by EM. IgG, limited or no immunoglobulin, with de-
This pattern can be caused by immune complexes posits of varying density, which may be sub-
(ie, with immunoglobulin[s] and complement [see endothelial, mesangial, and often
Membranoproliferative Glomerulonephritis]), C3- intramembranous permeating the GBM, and can
dominant deposits in C3 glomerulopathies, mono- also have hump-type subepithelial deposits by
clonal proteins (see Light Chain Deposition Disease, EM.
Light and Heavy Chain Deposition Disease, and E. Sclerosis
Heavy Chain Deposition Disease), and other deposits Glomerulosclerosis must be assessed in terms of its
or chronic microangiopathies, with or without location within the glomerular tuft and its quality.
thrombosis (see Thrombotic Microangiopathy): Glomerulomegaly may be present in cases of FSGS
i. MPGN pattern due to immune complex de- even before sclerosis is evident. Comparisons of
posits: has predominant IgG, double contours of glomerular size must be age matched.
GBM by LM, and subendothelial and mesangial i. Usual type sclerosis: localized anywhere within
deposits. the glomerular tuft, defined by obliteration of
ii. Lupus nephritis class III focal or IV diffuse: is capillary lumens by increased matrix and/or
characterized by IF positivity, often with all 3 hyalin, extensive foot process effacement by EM,
immunoglobulins and both complement typical of FSGS (see FSGS, NOS).
components C3 and either C4 or C1q (full ii. Collapsing glomerulosclerosis (see Collapsing
house), reticular aggregates in endothelial Glomerulopathy and HIV-Associated
cells (footprints of high interferon levels, Nephropathy): defined by collapse and

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retraction of glomerular tuft that can be a. Linear IgG stain along capillary wall, polyclonal,
segmental (involving part of the tuft) or global with discontinuous or even granular C3, of
(involving all of the tuft), with proliferation of GBM in anti-GBM antibody-mediated GN. No
overlying visceral epithelial cells, may be idio- deposits are visualized by EM. No extra-
pathic (most often seen in patients with high-risk glomerular kidney lesions are present, unless
alleles of APOL1) or linked to a variety of etiol- the patient also has microscopic polyangiitis
ogies, such as viral infections (eg, HIV, parvo- (see Pauci-immune Necrotizing Crescentic
virus, SARS-CoV-2), medications (eg, Glomerulonephritis).
bisphosphonates, tumor necrosis factor α ago- b. Immune complex disease (eg, lupus nephritis
nists, anabolic steroids) or severe ischemia class III focal or IV diffuse, postinfectious GN,
(nephroxicity due to calcineurin inhibitor or IgAN).
cocaine) and rarely in combination with diffuse c. Pauci-immune necrotizing crescentic GN:
lupus nephritis. minimal or no deposits by IF and/or EM.
Note: This lesion has worse prognosis than other d. Granulomatosis with polyangiitis (GPA),
types of FSGS. Collapsing glomerulopathy due to microscopic polyangiitis (MPA), or eosino-
HIV or SARS-CoV-2 can show reticular aggre- philic polyangiitis (EPA).
gates by EM. Note: GPA, MPA, and EPA cannot be distin-
iii. Tip lesion variant of FSGS: defined by sclerosis guished from each other in a kidney biopsy.
involving the proximal tubular pole of the They all can have glomerular necrotizing le-
glomerulus, with adhesion to the proximal tu- sions with crescents and may also involve small
bule, often with intracapillary foam cells, exten- vessels with vasculitis.
sive foot process effacement by EM, may have G. Unusual Lesions—Rare Diseases
better prognosis than usual FSGS. This lesion is Note: EM and/or LM may reveal abnormal accu-
not specific for primary FSGS. mulations that are diagnostic of specific diseases.
Note: Absence of segmental sclerosis in an i. Foamy podocytes: most common cause is Fabry
adequate sample (>25 glomeruli, including jux- disease. Myelin-body type inclusions seen by EM
tamedullary area), no immune complexes, and in various cells, especially podocytes. Other
complete foot process effacement is consistent storage diseases can also cause this lesion (see
with MCD in a nephrotic patient. Fabry Nephropathy).
iv. Hilar variant of FSGS: the sclerosis is at the ii. Intraglomerular foamy macrophages, often with
vascular pole, often with hyalinosis, and typically secondary sclerosis: consider lipid storage disease
is associated with a maladaptive reaction to (eg, LCAT deficiency). This lesion can also be
nephron loss or low nephron number or other seen in diabetic nephropathy and with sclerosis
overload (as, eg, with obesity-related and marked proteinuria.
glomerulopathy). iii. Abundant type III banded collagen in glomeruli
v. Secondary sclerosis: can occur with any injury. In in mesangial, subendothelial areas by EM:
diseases due to immune deposits, sclerosis can consider type III collagen glomerulopathy.
occur. Sclerosis due to healing of past aggressive
necrotizing injuries, whether immune complex-
related or pauci-immune, will often show broad- Additional Readings
based adhesion, fibrous crescent, and/or peri- ➢ Bridoux F, Hugue V, Coldefy O, et al. Fibrillary
glomerular fibrosis (see Pauci-immune Necrotizing glomerulonephritis and immunotactoid (microtu-
Crescentic GN, Arterionephrosclerosis, and Chronic bular) glomerulopathy are associated with distinct
Pyelonephritis). Globally sclerosed glomeruli due immunologic features. Kidney Int. 2002;62:1764-
to such aggressive injury show a fractionated 1775.
appearance of the tuft, surrounded by fibrous ➢ D’Agati VD, Fogo AB, Bruijn JA, Jennette JC. Pathologic
matrix. classification of focal segmental glomerulosclerosis: a
F. Crescents working proposal. Am J Kidney Dis. 2004;43(2):368-
Crescents are classified as cellular, fibrocellular, or 382. +ESSENTIAL READING
fibrous, depending on degree of fibrous tissue, with ➢ D’Agati VD, Kaskel FD, Falk RJ. Focal segmental glo-
less responsiveness to therapy corresponding to greater merulosclerosis. N Engl J Med. 2011;365:2398-2411.
degrees of fibrosis. Crescents are composed of prolif- ➢ Fogo AB. Causes and pathogenesis of focal segmental
erating parietal epithelial cells and variable inflamma- glomerulosclerosis. Nat Rev Nephrol. 2015;11(2):76-
tory cells and matrix and occur with any injury that 87.
breaks the capillary wall. Injury may be categorized as ➢ Geetha D, Jefferson JA. ANCA-associated vasculitis: core
in the following. curriculum 2020. Am J Kidney Dis. 2020;75(1):
i. Immune etiology: 124-137.

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 Najafian et al

➢ Glassock RJ, Alvarado A, Prosek J, et al. Staphylococcus- ➢ Trimarchi H, Barratt J, Cattran DC, et al. IgAN Classi-
related glomerulonephritis and poststreptococcal fication Working Group of the International IgA Ne-
glomerulonephritis: why defining “post” is important in phropathy Network and the Renal Pathology Society;
understanding and treating infection-related glomeru- Conference Participants. Oxford classification of IgA
lonephritis. Am J Kidney Dis. 2015;65(6):826-832. nephropathy 2016: an update from the IgA Nephrop-
➢ Goodship TH, Cook HT, Fakhouri F, et al. Atypical athy Classification Working Group. Kidney Int.
hemolytic uremic syndrome and C3 glomerulopathy: 2017;91(5):1014-1021.
conclusions from a “Kidney Disease: Improving Global
Outcomes” (KDIGO) Controversies Conference. Kidney II. Vascular Lesions
Int. 2017;91(3):539-551. +ESSENTIAL READING A. SclerosisIntimal fibrosis/medial hypertrophy repre-
➢ Haas M. Alport syndrome and thin glomerular base- sent common hypertension-associated changes (see
ment membrane nephropathy: a practical approach Arterionephrosclerosis).
to diagnosis. Arch Pathol Lab Med. 2009;133(2): B. Thrombotic lesions
224-232. +ESSENTIAL READING i. Arteriolar/glomerular predominance: typical of
➢ Lusco MA, Fogo AB. Hereditary nephritis and thin TMA due to hemolytic uremic syndrome.
basement membrane lesion. Glomerular Dis. 2021;1:135- Microangiopathy lesions without thrombosis
144. include necrosis within the wall, red blood cell
➢ Markowitz GS, Lin J, Valeri AM, et al. Idiopathic fragments within the vascular wall, and mucoid
nodular glomerulosclerosis is a distinct clinicopatho- expansion of the intima.
logic entity linked to hypertension and smoking. Hum ii. Arteriolar/interlobular artery predominance of
Pathol. 2002;33(8):826-835. microangiopathy lesions: more typical of
➢ Najafian B, Alpers CE, Fogo AB. Pathology of human systemic sclerosis. This may overlap morpho-
diabetic nephropathy. Contrib Nephrol. 2011;170:36-47. logically completely with lesions seen with se-
➢ Nasr S, Fogo AB. New developments in the diagnosis of vere hypertension (see Arterionephrosclerosis).
fibrillary glomerulonephritis. Kidney Int. 2019;96:581- C. Necrosis
592. “Fibrinoid” necrosis (lesion in, eg, systemic
➢ Nasr SH, Fidler ME, Said SM, et al. Immunofluorescence sclerosis and severe hypertension [see
staining for immunoglobulin heavy chain/light chain Arterionephrosclerosis]): term used to describe
on kidney biopsies is a valuable ancillary technique for necrosis of wall with chunky, eosinophilic appear-
the diagnosis of monoclonal gammopathy-associated ance, often containing fibrin and karyorrhectic
kidney diseases. Kidney Int. 2021;100(1):155-170. debris.
➢ Picken MM. Diagnosis of amyloid beyond Congo red. D. Vasculitis
Curr Opin Nephrol Hypertens. 2021;30(3):303-309. Defined as vascular inflammation with lympho-
➢ Renwick N, Nasr SH, Chung WK, et al. Foamy podo- cytes/PMNs and may be transmural or just intimal.
cytes. Am J Kidney Dis. 2003;41(4):891-896. Positive IF may be seen in lupus vasculitis or cry-
➢ Rossini M, Fogo AB. Interpreting segmental glomerular oglobulinemic vasculitis. Pauci-immune conditions
sclerosis. Curr Diag Pathol. 2004;10:1-10. may also have vasculitis lesions (see Focal or Diffuse
➢ Said SM, Leung N, Alexander MP, et al. DNAJB9- Lupus Nephritis, ISN/RPS Class III and IV, and
positive monotypic fibrillary glomerulonephritis is Cryoglobulinemic GN).
not associated with monoclonal gammopathy in E. Embolic lesions
the vast majority of patients. Kidney Int. 2020;98:498- Cholesterol emboli lodge in interlobular arteries,
504. and sometimes also in smaller vessels downstream
➢ Sethi S. New ‘antigens’ in membranous nephropathy. J (rarely in glomeruli) and appear as clear cleft-
Am Soc Nephrol. 2021;32(2):268-278. shaped space with surrounding mononuclear cell
➢ Sethi S, Rajkumar SV, D’Agati VD. The complexity and reaction (cholesterol per se is extracted during
heterogeneity of monoclonal immunoglobulin- processing for LM).
associated renal diseases. J Am Soc Nephrol. 2018; F. Endothelial lesion
29(7):1810-1823. Swollen endothelial cells are a feature of the endo-
➢ Smith RJH, Appel GB, Blom AM, et al. C3 glo- theliosis lesion of pre-eclampsia/eclampsia (see
merulopathy—understanding a rare complement- Thrombotic Microangiopathy).
driven renal disease. Nat Rev Nephrol.
2019;15(3):129-143.
➢ Swanepoel CR, Atta MG, D’Agati VD, et al. Kidney Additional Readings
disease in the setting of HIV infection: conclusions ➢ Butler EA, Baron M, Fogo AB, et al. Generation of a
from a Kidney Disease: Improving Global Outcomes core set of items to develop classification criteria for
(KDIGO) Controversies Conference. Kidney Int. scleroderma renal crisis using consensus methodology.
2018;93(3):545-559. Arthritis Rheumatol. 2019;71(6):964-971.

126 AJKD Vol 80 | Iss 1 | July 2022

Najafian et al

➢ Freedman BI, Cohen AH. Hypertension-attributed ne- neoplasms can manifest by infiltration of the
phropathy: what’s in a name? Nat Rev Nephrol. malignant cells, which may be lymphocytes,
2016;12:27-36. +ESSENTIAL READING blasts, or other cells. Monomorphic sheets of
such cells, infiltration into surrounding fat,
III. Tubulointerstitial Lesions blast appearance, cytologic atypia, and clinical
A. Necrosis vs acute tubular injury (ATI) history of such neoplasms can then lead to
i. Frank necrosis: sloughing off of cells (see Toxic diagnosis with additional IHC studies to define
Acute Tubular Injury). clonality of the process.
ii. ATI: shows flattened, regenerating epithelium, v. Eosinophils clustered in the interstitium:
often with vacuolization, may see sloughing of consider hypersensitivity reaction (see Acute
cells, without thickened tubular basement Interstitial Nephritis).
membranes. Note: In diabetic nephropathy, eosinophils
Note: Acute tubular necrosis can occur in may be seen in areas of scarring and non-
isolation or with associated glomerular necrosis scarred areas and do not imply a hypersensi-
(the combination is called cortical necrosis and tivity reaction.
can involve broad regions of the cortex). vi. Granulomas: the most common cause for
Note: Ischemic etiology often results in zones of non-necrotizing granulomas is a hypersen-
injury; toxic etiology often results in individual sitivity reaction. Confluent granulomas
cell injury/blebbing/degeneration/apoptosis. suggest possible sarcoidosis (see Acute
B. Edema Interstitial Nephritis and Sarcoidosis).
Increased interstitial space with loose appearance vii. Necrotizing granulomas are indicative of
and normal thickness TBMs is generally due to infection, particularly TB, fungus, or
edema. This is in contrast to interstitial fibrosis (see adenovirus.
below), where tubules are widely spaced and TBMs viii. Interstitial inflammation with positive TBM IF
are thickened, with intervening dense, fibrotic tis- staining:
sue with increased collagenous matrix (see Acute a. Linear staining for IgG is diagnostic of anti-
Interstitial Nephritis, Chronic Interstitial Nephritis, TBM antibody disease.
and Tubular Atrophy). b. Granular, discrete, immune complex de-
C. Interstitial inflammation posits along TBM by IF and EM: staining
i. Intratubular PMNs forming plugs are diag- pattern is most often associated with lupus
nostic of acute pyelonephritis. nephritis but can also be seen w25% of
ii. Interstitial or peritubular capillary PMNs may polyoma virus nephropathy cases and in
be nonspecific, due to renal vein thrombosis, most cases of IgG4-related disease.
or acute antibody-mediated rejection (see D. Intratubular casts
Transplant section). Medullary angiitis with i. Pigmented:
increased PMNs in vasa recta can be due to a. Bilirubin casts (eg, in acute liver failure
ANCA-associated vasculitis or drug hypersen- [positive with Hall stain])(see Bile
sitivity reaction (see Acute Interstitial Nephritis Nephrosis).
and Pauciimmune Necrotizing Crescentic b. Myoglobin casts in rhabdomyolysis (positive
Glomerulonephritis). with antimyoglobin IHC) and characteristic
iii. Lymphocytes in the interstitium with edema appearance by EM.
are diagnostic of acute interstitial nephritis, a c. Numerous tubules with iron pigment:
lesion with varying etiology (see consider sickle cell nephropathy; hemolysis,
Tubulointerstitial Nephritis With Uveitis and consider anticoagulant nephropathy if mostly
Kidney Disease in Primary Sj€ ogren Syndrome). intact RBCs and extending to Bowman spaces
Note: There is often associated tubulitis, even and peritubular capillaries.
in native kidneys. Note: Iron in degraded hemoglobin (eg, in
iv. Lymphocytes and interstitial fibrosis are more interstitium or tubules) can be detected by
characteristic of chronic interstitial nephritis. Prussian blue stain; hemoglobin is best
Note: This is a nonspecific diagnosis, and an detected by antihemoglobin IHC.
underlying cause should be diligently sought, ii. Other casts:
such as light chain cast nephropathy (see a. Tamm-Horsfall protein stains pink and may
“Intratubular casts” section and Chronic elicit a local granulomatous reaction when
Interstitial Nephritis, Light Cast Nephropathy, leaked into the interstitium.
Tubulointerstitial Nephritis with Uveitis, and b. Fractured, brittle appearing with surrounding
Kidney Disease in Primary Sj€ ogren Syndrome). syncytial giant cell reaction: highly indicative
Note: Kidney involvement by hematopoietic of light chain cast nephropathy (also known

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 Najafian et al

as myeloma cast nephropathy). Additional Readings

Note: Not all cases of light chain cast ne- ➢ Bracamonte E, Leca N, Smith KD, et al. Tubular base-
phropathy show monoclonal staining of casts ment membrane immune deposits in association with
with light chain. Consider IF after pronase BK polyomavirus nephropathy. Am J Transplant.
digestion on paraffin-embedded tissue. 2007;7(6):1552-1560.
E. Crystals ➢ Brodsky SV, Satoskar A, Hemminger J, et al.
i. Polarizable: Anticoagulant-related nephropathy in kidney biopsy: a
a. Calcium oxalate are the most commonly single-center report of 41 cases. Kidney Med.
detected polarizable crystals, appearing rela- 2019;1(2):51-56.
tively clear on LM and with birefringent fan- ➢ Cornell LD. IgG4-related kidney disease. Semin Diagn
shaped morphology when polarized. Pathol. 2012;29(4):245-250.
Note: Oxalosis can be secondary (eg, enteric ➢ Dai DF, Sasaki K, Lin MY, et al. Interstitial eosinophilic
hyperoxaluria) or primary due to genetic aggregates in diabetic nephropathy: allergy or not?
defects in key enzymes of oxalate meta- Nephrol Dial Transplant. 2015;30(8):1370-1376.
bolism; scattered calcium oxalate crystals ➢ Drummond K, Mauer M. The early natural history of
commonly occur secondary to scarring and nephropathy in type 1 diabetes: II. Early renal structural
low glomerular filtration rate. In primary changes in type I diabetes. Diabetes. 2002;51:1580-
oxalosis or oxalosis due to ethylene glycol 1587.
ingestion or secondary to jejunal intestinal ➢ Dvanajscak Z, Cossey LN, Larsen CP. A practical
bypass, the crystals are extremely numerous approach to the pathology of renal intratubular
and associated with tubular injury. casts. Semin Diagn Pathol. 2020;37(3):127-134.
b. 2,8-Dihydroxyadenine (2,8-DHA) crystals +ESSENTIAL READING
appear similar to calcium oxalate when ➢ Markowitz GS, Perazella MA. Acute phosphate ne-
polarized but are muddy brown (vs clear and phropathy. Kidney Int. 2009;76(10):1027-1034.
colorless) on H&E stain (see 2,8- ➢ Nasr SH, Sethi S, Cornell LD et al. Crystalline ne-
Dihydroxyadeninuria). phropathy due to 2,8-dihydroxyadeninuria: an under-
ii. Nonpolarizable: recognized cause of irreversible renal failure. Nephrol
a. Calcium phosphate crystals: nonpolarizable, Dial Transplant. 2010;25(6):1909-1915.
bluish purple on H&E stain (see ➢ Stokes MB, Valeri AM, Herlitz L, et al. Light chain
Nephrocalcinosis and Acute Phosphate proximal tubulopathy: clinical and pathologic charac-
Nephropathy). teristics in the modern treatment era. J Am Soc Nephrol.
b. Indinavir: rectangular intratubular crystalline 2016;27(5):1555-1565. +ESSENTIAL READING
material with surrounding granulomatous
reaction (see Indinavir Nephropathy). Outline of Transplant Kidney Lesions
c. Urate: feathery crystals with surrounding
Many diseases can recur in the transplant, including
tophus reaction (see Gouty Nephropathy).
immune complex and complement related (eg, IgAN,
F. Interstitial fibrosis and tubular atrophy (IFTA)
lupus nephritis, MPGN, DDD) and nonimmune disease
IFTA generally correlates better with kidney function
(eg, diabetic nephropathy, FSGS). IF should be done for
than extent of glomerular lesions, which often are
complete evaluation on the first biopsy of a transplant,
focal and segmental, with the notable exception of
with EM done as needed to evaluate the findings,
early diabetic nephropathy where diffuse lesions are
depending on the clinical setting (see “Outline of Native
common with mild glomerulomegaly and mesangial
Kidney–Specific Lesions” section).
expansion. The pattern gives hints to the etiology:
i. Diffuse pattern: nonspecific. I. Glomerular Lesions
ii. Striped, along medullary rays: related to A. Glomerulitis with increased mononuclear cells/
ischemia along medullary rays; cyclosporine PMNs
toxicity is an example (see Calcineurin Inhibitor Consider antibody-mediated rejection, virus, or
Nephrotoxicity). recurrent or de novo GN (see Acute Antibody-
iii. Patchy/geographic, “jigsaw puzzle” pattern: Mediated Rejection and Chronic Antibody-
suggestive of chronic pyelonephritis, often with Mediated Rejection and various glomerular dis-
thyroidization appearance of the intratubular eases discussed under “Endocapillary hyper-
casts (resembling thyroid colloid). cellularity” section).
iv. Endocrine change of tubules: seen with pro- B. Enlarged cells with smudgy nuclei
longed ischemia, with less surrounding inter- Possible virus, particularly cytomegalovirus (CMV);
stitial matrix (see Ischemic Acute Tubular rarely polyoma virus can infect glomerular epithe-
Injury). lial cells.

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C. Intraglomerular fibrin thrombi ii. Concentric pattern, extending to media: more

This lesion can be due to antibody-mediated suggestive of cyclosporine toxicity (see
rejection, a drug-induced toxicity causing TMA, Calcineurin Inhibitor Nephrotoxicity).
disseminated intravascular coagulation (DIC) that is B. Endothelialitis
donor-derived, or any of the causes that affect Defined as intimal infiltration by mononuclear cells
native kidneys: underneath the endothelium of arteries or arteri-
i. Antibody-mediated rejection: most often with oles. Endothelialitis is indicative of acute vascular
glomerulitis and peritubular capillaritis (see Acute rejection, Cooperative Clinical Trials in Trans-
Antibody-Mediated Rejection). plantation (CCTT) type 2; Banff T-cell mediated
ii. Recurrence of atypical hemolytic uremic syn- rejection type II (see Acute T-Cell-Mediated Cellular
drome (HUS) (see Thrombotic Rejection).
Microangiopathy). C. Peritubular capillaritis
iii. Drug-induced (eg, calcineurin inhibitor Leukocytes within peritubular capillaries may be
toxicity) (see Thrombotic Microangiopathy). indicative of acute antibody-mediated rejection or
iv. Shiga toxin (see Thrombotic Microangiopathy). may be present within areas with acute T-cell
D. GBM double contours mediated rejection.
i. Transplant glomerulopathy (expansion of the Note: C4d positivity by IF in peritubular capil-
lamina rara interna by lucent material, seen by laries >10% on frozen tissue correlates with
EM, no immune deposits): usually chronic donor-specific antibody, and along with signifi-
sequela of acute antibody-mediated rejection cant glomerulitis and peritubular capillaritis is
(see Chronic Antibody-Mediated Rejection). diagnostic of acute antibody-mediated rejection.
ii. Chronic, organizing phase of TMA. D. Transmural vascular inflammation
iii. Recurrent or de novo MPGN type disease (eg, This lesion is suspicious for acute antibody-
cryoglobulin-related GN, C3 glomer- mediated rejection.
ulopathies): IF and EM differentiate immune E. Thrombi
complex etiology from other causes of double i. Glomeruli/smaller arteries: consider hyperacute
contour GBM (see section above on MPGN rejection or TMA due to antibody-mediated
pattern). rejection, drug, or other (see above and Acute
Note: Chronic TMA has the same appearance as Antibody-Mediated Rejection).
transplant glomerulopathy by EM; one can ii. Larger arteries: consider, for example, surgical
differentiate by clinical correlation. technical difficulties, antiphospholipid antibody
E. Segmental sclerosis (see Thrombotic Microangiopathy).
i. Recurrent FSGS: no GBM double contour in F. Necrosis
nonsclerotic areas, foot processes extensively Fibrinoid necrosis is most consistent with active
effaced by EM (see FSGS, NOS). antibody-mediated rejection (type 3 CCTT, acute
ii. Transplant glomerulopathy: GBM double vascular rejection, or Banff grade III T-cell medi-
contour in nonsclerotic areas, increased lam- ated rejection, the latter with concomitant tubu-
ina rara interna by EM, less foot processes lointerstitial lymphocytic inflammation), often
effacement than in recurrent FSGS (see associated with C4d positivity in peritubular
Chronic Antibody-Mediated Rejection). capillaries by IF (see Acute Antibody-Mediated
iii. Sclerosis with collapsing features: Rejection).
a. Cyclosporin toxicity (see Calcineurin Inhibitor Note: Necrotic vessels in the middle of an area of
Nephrotoxicity). cortical necrosis do not have specific diagnostic
b. Pamidronate-associated (see FSGS, Collapsing sensitivity for etiology of this lesion.
Variant). III. Tubulointerstitial lesions
c. Parvovirus (see FSGS, Collapsing Variant). A. Edema
d. Possible recurrence of collapsing FSGS (see i. Without any leukocyte infiltrate: renal vein
also FSGS, NOS). thrombosis, obstruction, nonspecific injury.
e. Severe ischemia (see FSGS, Collapsing ii. With leukocyte infiltrate: consider acute T-cell-
Variant). mediated rejection, viral infection, other infec-
II. Vascular lesions tion, or reaction to tissue necrosis (see Polyoma
A. Hyaline Virus Nephropathy, Acute Pyelonephritis, and
i. Eccentric: Cortical Necrosis).
a. Pre-existing in the donor. B. PMNs
b. Hypertension-associated (see Arterionephros- i. In tubular lumen: if forming plug of PMNs in
clerosis). tubules, diagnostic of acute pyelonephritis.
c. Diabetic nephropathy-associated. ii. In peritubular capillaries:

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 Najafian et al

a. Numerous: suspect antibody-mediated ii. In nonscarred areas: can be part of acute T-cell-
rejection. mediated rejection (plasma cell-rich acute
b. Less numerous: consider possible renal vein rejection, possibly worse prognosis).
thrombosis. iii. Expansile/dysplastic: consider posttransplant
C. Interstitial lymphocytes lymphoproliferative disease (PTLD).
i. In scarred areas: nonspecific. If associated with Note: Features suggesting PTLD are expansile
significant tubulitis in nonseverely atrophic mass, dysplastic cells, monomorphism, serpig-
tubules, consider chronic active T-cell-medi- inous necrosis.
ated rejection (see Acute T-Cell-Mediated Note: Staining for Epstein-Barr (EB) virus is
Cellular Rejection). a useful adjunct for diagnosis of PTLD.
ii. In nonscarred areas: consider acute T-cell- Most PTLD, but not all, are EB virus posi-
mediated rejection, look for tubulitis. tive and clonal. Additional staining studies
iii. Tubulitis: and clinical investigation can confirm the
a. Lymphocytes invading severely atrophic tu- diagnosis.
bules: nonspecific. F. Mixed interstitial infiltrate
b. Lymphocytes invading nonseverely atrophic Pleomorphic infiltrate with lymphocytes, plasma
tubules: see above. Consider chronic active cells, and PMNs raises suspicion of viral infection,
T-cell-mediated rejection (see Acute T-Cell- particularly polyoma virus. CMV infection is much
Mediated Cellular Rejection). more rare in transplant biopsies but also can cause
c. Lymphocytes invading intact tubules: lesion interstitial inflammation and viral cytopathic
of acute T-cell-mediated rejection; not change.
pathognomonic for rejection, can also be Note: Look for viral changes (eg, inclusions,
seen with viral infection, hypersensitivity smudgy, enlarged tubular nuclei). Diagnosis of
reaction (see Polyoma Virus Nephropathy polyoma virus nephropathy is made by immu-
and Acute Interstitial Nephritis). nostaining for SV40 (detects all 3 polyoma vi-
Note: The Banff classification system is ruses: BK, JC, and SV). In situ hybridization can
widely used for diagnosis of transplant le- be done with probes specific for BK versus JC to
sions. The CCTT classification (see below) distinguish these 2 viruses. Tissue-based poly-
may also be useful, with lower threshold merase chain reaction has also been used to di-
specifically for diagnosis of T-cell-mediated agnose rare cases of SV40 infection. CMV
rejection. infection and adenovirus infection can be diag-
CCTT types: type 1, acute T-cell rejection nosed by IHC. EM appearances are also charac-
with tubulitis; type 2, acute vascular rejec- teristic and differ for these viruses versus polyoma
tion with endothelialitis (lymphocytes un- viruses.
derneath endothelium of arteries or G. IFTA
arterioles); type 3, acute vascular rejection Tubular atrophy is characterized by flattened
with fibrinoid necrosis, indicative of tubular epithelium and thick TBM, widely
antibody-mediated mechanisms. spaced tubules with intervening fibrosis
The thresholds for minimum criteria for (chronic allograft nephropathy, also designated
extent of tubulitis and lymphocytic infiltrate as IFTA).
for diagnosing type 1 T-cell-mediated i. Diffuse IFTA: nonspecific.
rejection differ by CCTT and Banff criteria. ii. Striped pattern IFTA, along medullary rays:
Current evidence-based studies by Banff consider possible calcineurin inhibitor toxicity
working groups likely will lead to lowering with ischemia along medullary rays.
of the Bannf threshold (now >25% of iii. Patchy, geographic IFTA: possible chronic
cortex with inflammation required, with pyelonephritis.
extensive tubulitis). H. Enlarged tubular nuclei
D. Interstitial eosinophils i. May be reactive after injury (see Toxic Acute
i. Possible hypersensitivity reaction due to, for Tubular Injury and Ischemic Acute Tubular
example, a drug (see Acute Interstitial Injury).
Nephritis). ii. Virus: enlarged, smudgy cells, may have
ii. Can be part of acute T-cell-mediated rejection. inclusions.
Note: No evidence that eosinophils per se in a. Polyoma virus infection.
rejection impacts prognosis. b. CMV infection.
E. Interstitial plasma cells c. Adenovirus infection.
i. In scarred areas: nonspecific. I. Acute tubular necrosis

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Najafian et al

i. Frank necrosis, sloughing off of cells (see Toxic ➢ Nickeleit V, Singh HK, Randhawa P, et al. The Banff
Acute Tubular Injury and Ischemic Acute Working Group classification of definitive poly-
Tubular Injury). omavirus nephropathy: morphologic definitions and
ii. Flattened, regenerating epithelium: typical of clinical correlations. J Am Soc Nephrol. 2018;29(2):680-
ischemic tubular injury. 693.
Note: Tubular necrosis can occur in isolation or ➢ Roufosse C, Simmonds N, Clahsen-van Groningen M,
with associated glomerular necrosis (the com- et al. A 2018 reference guide to the Banff Classification
bination is called cortical necrosis). of Renal Allograft Pathology. Transplantation.
J. ATI 2018;102(11):1795-1814. +ESSENTIAL READING
Flattened simplified tubular epithelium.
Note: Ischemic etiology often results in zones of
injury; toxic etiology often results in individual cell Article Information
injury/blebbing/degeneration/apoptosis. Authors’ Full Names and Academic Degrees: Behzad Najafian,
Mark A. Lusco, Charles E. Alpers, and Agnes B. Fogo.
Authors’ Affiliations: Department of Pathology, Microbiology, and
Additional Readings Immunology, Vanderbilt University Medical Center, Nashville,
➢ Cosio FG, Cattran DC. Recent advances in our under- Tennessee (MAL, ABF); and Department of Laboratory Medicine and
standing of recurrent primary glomerulonephritis after Pathology, University of Washington, Seattle, Washington (BN, CEA).
kidney transplantation. Kidney Int. 2017;91(2):304-314. Address for Correspondence: Agnes B. Fogo, MD, Department of
➢ Gaut JP, Liapis H. Acute kidney injury pathology and Pathology, Microbiology and Immunology, MCN C3310, Vanderbilt
University Medical Center, Nashville, TN 37232. Email: agnes.
pathophysiology: a retrospective review. Clin Kidney J. [email protected]
2020;14(2):526-536. +ESSENTIAL READING
Support: None.
➢ Farouk SS, Rein JL. The many faces of calcineurin inhibitor
Financial Disclosure: The authors declare that they have no
toxicity-what the FK? Adv Chronic Kidney Dis. 2020;27(1):56-66. relevant financial interests.
➢ Loupy A, Haas M, Roufosse C, et al. The Banff 2019
Peer Review: Received June 17, 2021 in response to an invitation
Kidney Meeting Report (I): updates on and clarifi- from the journal. Evaluated by 2 external peer reviewers, the
cation of criteria for T cell- and antibody-mediated Pathology Editor, and a member of the Feature Advisory Board,
rejection. Am J Transplant. 2020;20(9):2318-2331. with direct editorial input from the Feature Editor and a Deputy
+ESSENTIAL READING Editor. Accepted in revised form August 21, 2021.

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