Results from the Boston Kidney Biopsy Cohort Study - JASN

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The Prognostic Value of Histopathologic Lesions inNative Kidney Biopsy Specimens: Results from theBoston Kidney Biopsy Cohort Study

Anand Srivastava,1,2 Ragnar Palsson,1 Arnaud D. Kaze,1 Margaret E. Chen,1 Polly Palacios,1

Venkata Sabbisetti,1 Rebecca A. Betensky,3 Theodore I. Steinman,4 Ravi I. Thadhani,5,6,7

Gearoid M. McMahon,1 Isaac E. Stillman,8 Helmut G. Rennke,9 and Sushrut S. Waikar1

1Renal Division and 9Pathology Department, Brigham and Women’s Hospital, Boston, Massachusetts; 2Division ofNephrology and Hypertension, Center for Translational Metabolism and Health, Institute for Public Health and Medicine,Northwestern University Feinberg School of Medicine, Chicago, Illinois; 3Department of Biostatistics, Harvard T.H. ChanSchool of Public Health, Boston, Massachusetts; 4Renal Division and 8Department of Pathology, Beth Israel DeaconessMedical Center, Boston, Massachusetts; 5Division of Nephrology, Massachusetts General Hospital, Boston, Massachusetts;and 6Departments of Biomedical Sciences and 7Medicine, Cedars-Sinai Medical Center, Los Angeles, California

ABSTRACTBackground Few studies have evaluated whether histopathologic lesions on kidney biopsy provide prog-nostic information beyond clinical and laboratory data.

Methods We enrolled 676 individuals undergoing native kidney biopsy at three tertiary care hospitalsinto a prospective, observational cohort study. Biopsy specimens were adjudicated for semiquantitativescores in 13 categories of histopathology by two experienced renal pathologists. Proportional hazardsmodels tested the association between histopathologic lesions and risk of kidney disease progression($40% eGFR decline or RRT).

ResultsMean baseline eGFR was 57.5636.0 ml/min per 1.73 m2. During follow-up (median, 34.3 months),199 individuals suffered kidney disease progression. After adjustment for demographics, clinicopatho-logic diagnosis, and laboratory values, the following lesions (hazard ratio; 95% confidence interval) wereindependently associated with progression: inflammation in nonfibrosed interstitium (0.52; 0.32 to 0.83),moderate and severe versus minimal interstitial fibrosis/tubular atrophy (2.14; 1.24 to 3.69 and 3.42; 1.99to 5.87, respectively), moderate and severe versus minimal global glomerulosclerosis (2.17; 1.36 to 3.45and 3.31; 2.04 to 5.38, respectively), moderate and severe versus minimal arterial sclerosis (1.78; 1.15 to2.74 and 1.64; 1.04 to 2.60, respectively), and moderate and severe versus minimal arteriolar sclerosis(1.63; 1.08 to 2.46 and 2.33; 1.42 to 3.83, respectively). An 11-point chronicity score derived from semi-quantitative assessments of chronic lesions independently associated with higher risk of kidney diseaseprogression (hazard ratio per one-point increase, 1.19; 95% confidence interval, 1.12 to 1.27).

Conclusions Across a diverse group of kidney diseases, histopathologic lesions on kidney biopsy provideprognostic information, even after adjustment for proteinuria and eGFR.

J Am Soc Nephrol 29: 2213–2224, 2018. doi: https://doi.org/10.1681/ASN.2017121260

Tens of thousands of native kidney biopsies areperformed annually across the world for the evalua-tion and management of a variety of forms of kidneydisease.1,2 Information from pathologic examinationof biopsy tissue is used for diagnosis as well as prog-nosis.3–5 Despite the importance of the kidney biopsyin the care of patients with acute kidney diseases and

Received December 7, 2017. Accepted April 18, 2018.

Published online ahead of print. Publication date available atwww.jasn.org.

Correspondence: Dr. Sushrut S. Waikar, Renal Division, Brighamand Women’s Hospital, MRB-4, 75 Francis Street, Boston, MA02115. Email: [email protected]

Copyright © 2018 by the American Society of Nephrology

J Am Soc Nephrol 29: 2213–2224, 2018 ISSN : 1046-6673/2908-2213 2213

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CKDs,6 there are no widely used standardized guidelines forstructuring and reporting the results of kidney biopsy patho-logic examination. Standardized scoring systems have been de-veloped for specific kidney diseases but not as a global scoringor reporting system.7–15 A recent expert opinion–based pro-posal to score and grade chronic changes on the kidney biopsyspecimen included four lesions and a global chronicity scoreand highlighted the need for studies to examine the prognosticsignificance of each variable.16

It is often claimed that chronic tubulointerstitial lesions are themost important prognostic indicators from kidney biopsies.17–21

Despite this widespread belief, the underlying evidence base isrelatively thin and derives from small numbers of patients withspecific forms of kidney diseases without adequate adjustment forconfounding variables. Few studies have tested the prognosticvalue of histopathologic findings across a diverse set of kidneydiseases with adjustment for clinical variables, such asdemographics, clinicopathologic diagnosis, and laboratoryvariables.22,23 To address this gap in our understanding ofthe prognostic significance of kidney histopathology, weconducted a prospective cohort study, in which biopsieswere re-read by two study pathologists who were unawareof the original clinical or pathologic diagnosis. Each biopsywas reviewed under lightmicroscopy jointly and graded semi-quantitatively for acute and chronic lesions in the glomerular,tubulointerstitial, and vascular compartments. We followedpatients prospectively and tested whether individual histo-pathologic lesions predicted the subsequent development ofkidney disease progression ($40% decline in eGFR or theneed for RRT).

METHODS

Study PopulationThe Boston Kidney Biopsy Cohort (BKBC) is a prospective,observational cohort study of patients undergoing native kid-ney biopsy at three tertiary care hospitals in Boston, Mas-sachusetts. This study includes adult patients ($18 years ofage) who underwent a clinically indicated native kidney biopsybetween September 2006 and June 2016. Patients providedblood and urine samples on the day of kidney biopsy. Exclu-sion criteria included the inability to provide consent, enroll-ment in competing studies, severe anemia, and pregnancy. Allparticipants provided written consent. The study protocol wasapproved by the Partners Human Research Committee (theBrigham and Women’s Hospital Institutional Review Board),and is in accordance with the principles of the Declaration ofHelsinki.

Evaluation of HistopathologyAll biopsies were adjudicated under light microscopy by tworenal pathologists, who provided semiquantitative scores ofkidney inflammation, fibrosis, vascular sclerosis, and tubularinjury. The scoring system for individual histopathologic

lesions was developed by the pathologists for use in this studyon the basis of their review of the literature and clinical expe-rience.12,14,24–30 Formal criteria were not used for individuallesions. In joint pathology review sessions, the pathologistsreviewed the light microscopy slides alongside one anotherand verbally suggested their score for individual histopatho-logic lesion severity in the presence of A.S. and/or S.S.W. Ifthey did not initially agree, the case was discussed in moredetail to obtain consensus on individual histopathologic le-sion severity. Of the 13 categories used, all were scored duringstudy sessions except for the grades of segmental and globalglomerulosclerosis, which were taken from the biopsy report,because they were each calculated as a percentage of the totalnumber of glomeruli. Global glomerulosclerosis was furthergraded as “age related” or “pathologic” on the basis of thenumber of globally sclerosed glomeruli divided by the totalnumber of glomeruli as done by Hommos et al.31 The studypathologists reviewed the slides without knowledge of theoriginal biopsy diagnosis or biopsy report, typically severalmonths after the biopsy procedure and original pathology re-port. Not all lesions were able to be evaluated on all biopsies,but this amounted to ,5% missing data. We reviewed all pa-tients’ charts alongside the final histopathologic diagnosisto identify the primary and any secondary clinicopathologicdiagnoses.

Exposure and OutcomesThe primary exposures were semiquantitative measures of 13separate histopathologic lesions: mesangial expansion, globalglomerulosclerosis, segmental glomerulosclerosis, endocapillaryglomerular inflammation, extracapillary cellular crescents, fi-brinoid necrosis, fibrocellular crescents, interstitial fibrosisand tubular atrophy (IFTA), inflammation in the nonfibrosedinterstitium, inflammation in the fibrosed interstitium, acutetubular injury (ATI), arterial sclerosis, and arteriolar sclerosis.We calculated a kidney biopsy chronicity score on the basis ofthe proposal by Sethi et al.16 for standardized semiquantita-tive grading of chronic changes of glomerulosclerosis (zero tothree), interstitial fibrosis (zero to three), tubular atrophy

Significance Statement

Kidney biopsy remains an important tool in the diagnosis andmanagement of acute kidney disease and CKD. Kidney histopa-thology may provide both diagnostic and prognostic information.Whether histopathologic lesions provide prognostic informationindependent of clinical information has not beenevaluated in detail.In this study of 676 individuals undergoing native kidney biopsy, theauthors found that greater severity of interstitial fibrosis and tubularatrophy, arterial and arteriolar sclerosis, and global glomerulo-sclerosis were independent predictors of future kidney failure, evenafter adjusting for confounders, including eGFR and proteinuria. Achronicity score derived from the sum of semiquantitative assess-ments of chronic histopathologic lesions was also independentlyassociated with kidney failure, and could be incorporated intokidney pathology reports to provide clinicians useful prognosticinformation.

2214 Journal of the American Society of Nephrology J Am Soc Nephrol 29: 2213–2224, 2018


(zero to three), and arteriolosclerosis (zero or one). Because thetotal renal chronicity score by Sethi et al.16 adds the score forinterstitial fibrosis and the score for tubular atrophy separately,we weighted our IFTA scores by a factor of two.We also convertedour semiquantitative arterial sclerosis score to a binary score inkeeping with the proposal by Sethi et al.16

The primary outcome was kidney disease progression de-fined as $40% eGFR decline from baseline or the need forRRT (dialysis or kidney transplantation). eGFR during followup was obtained from the electronic medical record (EMR).The secondary outcome was the need for RRT. RRTstatus wasconfirmed by reviewing the EMR and linkage with the USRenal Data System database. Mortality status was confirmedwith the Social Security Death Index. Participants were followedup until the occurrence of death, voluntary study withdrawal,loss to follow-up, or June 30, 2017.

CovariatesWe collected patient information at the biopsy visit, includingdemographics, detailed medical history, medication lists, andpertinent laboratory data. Study data were collected and man-aged using REDCap electronic data capture tools hosted atPartners HealthCare.32 We obtained serum creatinine (SCr)from the EMR on the day of biopsy. In participants for whomthis was unavailable (n=117), we measured SCr in individualswith available blood samples collected on the day of biopsy(n=82). If no samples were available (n=35), we used the mostrecent SCr values available in the EMR from the date of kidneybiopsy up to 3 months before biopsy. We obtained spot urineprotein-to-creatinine ratio or urine albumin-to-creatinine ra-tio from the date of kidney biopsy to 3 months before biopsyfrom the EMR. If a participant did not have any of these values,we measured urine albumin-to-creatinine ratio from urinecollected on the day of the kidney biopsy (n=54). SCr andurinary creatinine were measured using a Jaffe-based method,and urine albumin was measured by an immunoturbidometricmethod. We used the creatinine-based Chronic Kidney DiseaseEpidemiology Collaboration equation to calculate the eGFR.33

Statistical AnalysesDescriptive statistics were summarized as mean6SD ormedian (interquartile range) for continuous variables, andfrequency distribution is presented with percentages for cate-gorical variables. For skewed data distributions, we performednatural logarithmic transformation as appropriate. Weassessed for associations between categorical variables andtwo-group comparisons using chi-squared tests. For evalua-tions between continuous variables and multiple group com-parisons, we used ANOVA (for normally distributed variables)and Kruskal–Wallis tests (for non-normally distributed vari-ables). We used Spearman correlation coefficients to deter-mine the associations between continuous variables andhistopathologic lesion scores. We calculated the weightedk-statistic to evaluate the reproducibility of histopathologicscores.

For the primary outcome (time to either $40% decline ineGFR or starting RRT), we treated the data as interval censored,because the exact date of the event may not be known (e.g., theexact time to $40% decline in eGFR could have occurred anytime in the interval between two successive laboratory mea-surements). We evaluated the association between individualhistopathologic lesions and subsequent kidney disease

Table 1. Baseline characteristics of the Boston KidneyBiopsy Cohort

Characteristics n=676

Age, yr 52.2616.5Women, % 52.5Race, %White 63.8Black 20.6Other 15.7

eGFR, ml/min per 1.73 m2 57.5636.0Serum creatinine, mg/dl 1.41 [0.94–2.24]Proteinuria, g/g creatinine 1.74 [0.43–4.38]No. of glomeruli on biopsy 31 [20–43]Reason for biopsy,a %Proteinuria 59.2Hematuria 27.4Nephrotic syndrome 14.5Nephritic syndrome 2.5Abnormal eGFR 53.5

Primary clinicopathologic diagnosis, %Proliferative GN 30.2Nonproliferative glomerulopathies 18.2Advanced glomerulosclerosis 11.5Diabetic nephropathy 11.1Vascular 8.0Tubulointerstitial 7.3Paraprotein 7.3Other 6.5

Comorbid conditions, %Diabetes mellitus 22.6Hypertension 49.3SLE 14.8Hepatitis C 2.5Malignancy 13.0

Medications, %ACEi/ARB 45.9Mineralocorticoid receptor antagonists 1.9Calcium channel blockers 23.4b-Blockers 29.4Immunosuppression 17.8Corticosteroids 17.6

Clinical site, %Site 1 57.8Site 2 32.0Site 3 10.2

Data presented as percentages,mean6SD, andmedian [interquartile range].ACEi, angiotensin-converting enzyme inhibitor; ARB, angiotensin receptorblocker.aPercentages do not add to 100, because there may have been multiplereasons for biopsy.

J Am Soc Nephrol 29: 2213–2224, 2018 Prognostic Value of Histopathology 2215

www.jasn.org CLINICAL RESEARCH

progression using a nonparametric survival function for inter-val-censored datawith differences assessed by the generalized logrank test.34,35Wemodeled the data using Cox proportional haz-ards (PH) regression models that accommodated interval-censored times to event.36,37 Cox PH models were used for thesecondary outcome of time to RRT. All PH models were fit firstwithout adjustment and then stratified by site withmultivariableadjustment for covariates, including age, sex, race, baselineeGFR, natural log-transformed proteinuria, angiotensin-converting enzyme inhibitor or angiotensin receptor blockeruse, and primary clinicopathologic diagnostic category of kidneydisease.

To test the predictive models, we calculated c statistics forthe outcome of RRT using a base model (including age, sex,log-transformed proteinuria, and baseline eGFR) and themodel further including the chronicity score.38,39 Resultsfrom subdistribution hazards models that acknowledged thecompeting risk of death were performed as a sensitivity anal-ysis for the outcome of RRT, but they were qualitatively

unchanged; therefore, they are not reported.40 We confirmedno violations of the PH assumption using the Kolmogorov-type supremum test, and the functional forms of the covariateswere assessed by checking martingale residuals. All statisticaltests were two sided, and P values ,0.05 were consideredsignificant. Statistical analyses were performed using SAS soft-ware version 9.4 (SAS Institute Inc., Cary, NC).

RESULTS

Study Population CharacteristicsPatient characteristics in the BKBC at the time of kidney biopsyare presented in Table 1. The mean age was 52.2616.5 yearsold, 52.5% were women, and 63.8% were white. The meaneGFR was 57.5636.0 ml/min per 1.73 m2, and median pro-teinuria was 1.74 g/g creatinine [interquartile range, 0.43–4.38 g/g creatinine]. The most common reasons for kidneybiopsy were proteinuria, abnormal eGFR, and hematuria.

Figure 1. Distribution of semiquantitative severity scores for each of the adjudicated 13 histopathological lesions in the BostonKidney Biopsy Cohort. The histopathologic categories were graded by percentage of renal cortical volume or affected glomeruli:none, #10%; mild, 11%–25%; moderate, 26%–50%; and severe, .50%. ATI, acute tubular injury; IFTA, interstitial fibrosis andtubular atrophy.



Table

2.Prim

aryclinicop

atho

logic

diagno

ses

ProliferativeGN,

n=20

4

Nonp

roliferative

Glomerulopathies

,n=12

3

Parap

rotein,

n=49

DN,

n=75

Vascu

lar,

n=54

Tubulointerstitial,

n=49

Adva

nced

,n=78

Other,

n=44

IgAne

phrop

athy

(73)

Mem

brano

usne

phrop

athy

(47)

ALam

yloid(21)

DN

(75)

Vascu

lar

sclerosis(37)

AIN

(14)

Seco

ndary

TBM

(15)

Lupus

nephritis

Minim

alch

ange

disea

se(24)

MIDD

(15)

TMA(12)

ATN

(14)

FSGS(40)

Normal

(15)

Class

2(8)

IdiopathicFS

GS(15)

AAam

yloid(5)

APL

S(2)

Chron

ic/active

IN(6)

Adva

nced

chronic

chan

ges

(37)

Lympho

ma

infiltration(7)

Class

3(A

orA/C

)(14

)Lu

pus

nephritis

Cast

nephrop

athy

(4)

Scleroderma

(1)

Oxalate

nephrop

athy

(6)

Aden

oviru

s(1)

Mild

IFTA

(7)

Class

3+5

(Aor

A/C

)(11

)Class

2+5(1)

Immun

otac

toid

GN

(1)

CNItox

icity

(1)

CIN

(3)

Class

4(A

orA/C

)(23

)Class

3(C)(1)

Light-cha

incrystal

tubulop

athy

(1)

Cho

lesterol

emboli(1)

Granu

lomatou

sIN

(3)

Class

4+5

(Aor

A/C

)(9)

Class

4(C)(5)

Light-cha

inproteinuria

(1)

Phos

pha

tene

phrop

athy

(2)

Class

4+6

(Aor

A/C

)(1)

Class

3(C)+

5(1)

Multip

lemye

loma(1)

Teno

fovir

nephrotoxicity

(1)

ANCA(27)

Class

4(C)+

5(1)

Immun

eco

mplex

GN

(14)

Class

5(23)

Postinfectious

GN

(3)

Class

6(1)

Cryog

lobulinem

ia(4)

Collapsing

glomerulop

athy

(3)

PGNMID

(2)

C1q

nephrop

athy

(1)

C3GN

(4)

Idiopathicno

dular

glomerulosclerosis(1)

HIV

immun

eco

mplex

GN

(1)

Fibrillary

GN

(3)

Hered

itary

nephritis(1)

Mem

brano

proliferative

GN

(2)

Crescen

ticGN

(3)

Actua

lnum

ber

ofpatients(n)inea

chcategory.D

N,d

iabeticne

phrop

athy

;AL,am

yloidlig

htch

ain;

AIN

,acu

teinterstitialn

ephritis;TB

M,thinbasem

entm

embrane

;MID

D,m

ono

clon

alim

mun

oglobulindep

osition

disea

se;T

MA,throm

boticmicroan

giopathy

;ATN

,acu

tetubular

necros

is;A

A,serum

amyloidAprotein;A

PLS,

antip

hosp

holip

idsynd

rome;

IN,interstitialne

phritis;IFTA

,interstitialfibrosisa

ndtubular

atrophy

;CNI,

calcineu

rininhibito

rtox

icity

;CIN

,chron

icinterstitialn

ephritis;PG

NMID

,proliferativeGN

with

mon

oclona

limmun

oglobulin

dep

osits

.



Supplemental Figure 1 shows a flow diagram for individualsenrolled in the BKBC.

Histopathologic and Clinicopathologic ClassificationAll biopsies were reviewed under light microscopy duringstudy sessions with two experienced renal pathologists whojointly adjudicated each biopsy semiquantitatively for acuteand chronic lesions as shown in Supplemental Table 1. Figure1 shows the breakdown of the semiquantitative scores for his-topathologic lesions. To test the reproducibility of the adjudi-cated scores, we had study pathologists rescore 26 selectedkidney biopsies several months after their initial review.Weighted k-statistics (95% CI) were 0.92 (0.77–1.00) forendocapillary glomerular inflammation, 1.00 (1.00–1.00) forcellular crescents, 0.72 (0.56–0.89) for fibrinoid necrosis, 0.65(0.02–1.00) for fibrocellular crescents, 0.54 (0.12–0.69) formesangial expansion, 0.67 (0.45–0.89) for ATI, 0.46 (0.16–0.76) for inflammation in the nonfibrosed interstitium, 0.52(0.27–0.78) for inflammation in the fibrosed interstitium, 0.72

(0.52–0.93) for IFTA, 0.64 (0.41–0.87) for arterial sclerosis,and 0.66 (0.44–0.87) for arteriolar sclerosis. Weightedk-statistics for global and segmental glomerulosclerosis werenot performed, because these lesions were not readjudicatedbut rather, were abstracted from the biopsy report.

Patients were classified into eight primary clinicopatho-logic diagnostic categories using histopathologic informationand review of the medical record. All primary clinicopatho-logic diagnoses included within each category are presented inTable 2.

Correlations with HistopathologySupplemental Figure 2 shows the distribution of eGFR andproteinuria categories in all patients with biopsies. The histo-pathologic lesions that most strongly correlated with eGFRwere IFTA (Rs=20.62, P,0.001), arteriolar sclerosis(Rs=20.48, P,0.001), inflammation in the fibrosed interstitium(Rs=20.47, P,0.001), global glomerulosclerosis (Rs=20.46,P,0.001), arterial sclerosis (Rs=20.44, P,0.001), and ATI

Figure 2. Histopathologic lesions are significantly associated with eGFR and proteinuria. Boxplots show significant differences be-tween grades of adjudicated histopathologic lesions and (A) eGFR or (B) proteinuria.



http://jasn.asnjournals.org/lookup/suppl/doi:10.1681/ASN.2017121260/-/DCSupplemental



Table 3. Individual histopathologic lesions and the risk of kidney disease progression

Histopathologic Lesion N Events per 100 person-yra Model 1 HR [95% CI] Model 2 HR [95% CI] Model 3 HR [95% CI]

Glomerular compartmentEndocapillary glomerular

inflammationAbsent 569 13.0 — — —

Present 101 10.6 0.91 [0.61 to 1.35] 1.22 [0.74 to 2.02] 1.33 [0.81 to 2.20]Cellular crescentsAbsent 586 13.1 — — —

Present 85 9.0 0.72 [0.45 to 1.15] 0.99 [0.56 to 1.78] 1.02 [0.54 to 1.95]Fibrinoid necrosisAbsent 611 13.3 — — —

Present 60 5.9 0.47 [0.24 to 0.92] 0.57 [0.28 to 1.16] 0.61 [0.29 to 1.27]Fibrocellular crescentsAbsent 602 12.9 — — —

Present 68 9.8 0.84 [0.52 to 1.36] 1.18 [0.68 to 2.06] 1.08 [0.59 to 1.96]Mesangial expansionNone or mild 438 8.9 — — —

Moderate 155 15.1 1.59 [1.13 to 2.23] 1.35 [0.92 to 1.98] 1.25 [0.85 to 1.83]Severe 69 38.1 3.64 [2.52 to 5.25] 1.56 [0.92 to 2.64] 1.21 [0.71 to 2.07]

Segmental sclerosisAbsent 532 12.0 — — —

Present 138 14.8 1.19 [0.85 to 1.66] 1.17 [0.82 to 1.67] 1.09 [0.71 to 1.69]Global glomerulosclerosisMinimal (#10%) 255 5.1 — — —

Mild (11%–25%) 164 9.8 1.76 [1.11 to 2.79] 1.62 [1.00 to 2.61] 1.54 [0.95 to 2.48]Moderate (26%–50%) 149 18.1 3.31 [2.18 to 5.02] 2.63 [1.66 to 4.14] 2.17 [1.36 to 3.45]Severe (.50%) 104 39.1 6.30 [4.18 to 9.48] 4.61 [2.91 to 7.32] 3.31 [2.04 to 5.38]

Tubulointerstitial compartmentAcute tubular injuryAbsent 412 10.4 — — —

Present 254 16.8 1.47 [1.11 to 1.95] 1.25 [0.92 to 1.70] 0.95 [0.68 to 1.33]Inflammation, nonfibrosedinterstitiumAbsent 560 13.1 — — —

Present 104 10.0 0.79 [0.53 to 1.20] 0.68 [0.43 to 1.08] 0.52 [0.32 to 0.83]Inflammation, fibrosed interstitiumNone or mild 436 9.5 — — —


Interstitial fibrosis/tubular atrophyMinimal (#10%) 249 4.3 — — —

Mild (11%–25%) 142 8.6 1.85 [1.13 to 3.05] 1.63 [0.96 to 2.75] 1.34 [0.78 to 2.31]Moderate (26%–50%) 118 18.2 3.71 [2.34 to 5.88] 2.99 [1.83 to 4.90] 2.14 [1.24 to 3.69]Severe (.50%) 158 38.3 7.15 [4.73 to 10.8] 5.07 [3.17 to 8.09] 3.42 [1.99 to 5.87]

Vascular compartmentArterial sclerosisNone or mild 287 6.3 — — —


Arteriolar sclerosisNone or mild 331 6.0 — — —


Model 1 is unadjusted. Model 2 is stratified by site and adjusted for age, sex, race, log-transformed proteinuria, primary clinicopathologic diagnosis, andangiotensin-converting enzyme inhibitor or angiotensin receptor blocker medication use. Model 3 includes Model 2 and further adjusts for eGFR. HR, hazardratio; 95% CI, 95% confidence interval; —, reference group.aApproximate events per 100 person-years. If an event occurred, the time used is one half of the interval width plus all of the time before the interval as theapproximate exposure time (the exact time an event occurred is not known if a $40% decline in eGFR occurred).



(Rs=20.40, P,0.001) (Supplemental Table 2). The histo-pathologic lesions that most strongly correlated with protein-uria were mesangial expansion (Rs=0.29, P,0.001), IFTA(Rs=0.13, P,0.001), endocapillary glomerular inflamma-tion (Rs=0.11, P=0.004), segmental sclerosis (Rs=0.11,P,0.01), arteriolar sclerosis (Rs=0.09, P=0.02), inflamma-tion in the fibrosed interstitium (Rs=0.09, P=0.03), andATI (Rs=0.08, P=0.03) (Supplemental Table 2). Figure 2shows boxplots between grades of histopathologic lesionsthat were most significantly associated with eGFR and pro-teinuria.

We found a number of significant correlations among his-topathologic lesions of glomerular, tubulointerstitial, andvascular injury (Supplemental Table 3). IFTA moderatelycorrelated with global glomerulosclerosis (Rs=0.64,P,0.001), inflammation in the fibrosed interstitium(Rs=0.61, P,0.001), arteriolar sclerosis (Rs=0.59,P,0.001), and arterial sclerosis (Rs=0.52, P,0.001). Crescentscorrelated with necrosis (Rs=0.69, P,0.001) and fibrocellularcrescents (Rs=0.60, P,0.001).

Prognostic Significance of Histopathologic LesionsDuring a median follow-up time of 34.3 months, 199 individualsexperienced subsequent kidney disease progression, and 111 in-dividuals were started on RRT. Table 3 shows the unadjusted andmultivariable-adjusted associations between each individual his-topathologic lesion and kidney disease progression. Results forprogression to RRTwere similar (Supplemental Table 4).

Glomerular LesionsHigherdegrees of global glomerulosclerosiswere associated with an increased risk ofkidney disease progression (Figure 3A)(generalized log rank P,0.001). The asso-ciation between global glomerulosclerosisand kidney disease progression was con-founded by eGFR. In a fully multivari-able-adjusted clinical model includinglog-transformed proteinuria and eGFR,26%–50% and .50% versus #10% globalglomerulosclerosis were associated withmore than two- and more than threefoldincreased risks of kidney function loss, re-spectively (Table 3). After accounting forage-related or no global glomerulosclerosisas previously described,31,41 global glomer-ulosclerosis deemed pathologic (abnormalfor age) was associated with a higher risk ofkidney disease progression after multivari-able adjustment (hazard ratio, 1.87; 95%confidence interval, 1.29 to 2.73). Age-related global glomerulosclerosis was notassociated with an increased risk of kidneydisease progression compared with noglobal glomerulosclerosis after multivari-able adjustment (hazard ratio, 0.97; 95%

confidence interval, 0.51 to 1.81). In multivariable-adjustedmodels, pathologic global glomerulosclerosis with involve-ment of 26%–50% and .50% glomeruli, compared with noor age-related global glomerulosclerosis, remained associatedwith an increased risk of kidney disease progression (Supple-mental Table 5).

Tubulointerstitial LesionsIncreasing severity of IFTAwas associatedwith subsequent lossof kidney function (Figure 3B) (generalized log rankP,0.001). The association was strongly confounded byeGFR. In a fully multivariable-adjusted model including log-transformed proteinuria and eGFR, 26%–50% and .50%IFTAversus#10% IFTAwere associated with a 2.1- and nearly3.5-fold increased risks of kidney disease progression, respec-tively (Table 3). Severe inflammation in the fibrosed intersti-tium was associated with 1.7-fold increased risk of kidneydisease progression that did not reach statistical significanceafter multivariable adjustment, but it was significant for theoutcome of RRT (Supplemental Table 4). Inflammation in thenonfibrosed interstitium (present versus absent) was associ-ated with a lower rather than a higher risk of kidney diseaseprogression in the fully adjusted model (Table 3).

Vascular LesionsBecause of the low number of scores of “none” for both arterialand arteriolar lesions, “none” and “mild”were collapsed into asingle category for analyses. The severity of arterial sclerosis

Figure 3. Chronic histopathologic lesions are associated with kidney disease progression.(A) Global glomerulosclerosis. (B) Interstitial fibrosis/tubular atrophy. (C) Arterial sclerosis. (D)Arteriolar sclerosis. Generalized log rank P,0.001 for all lesions.










and arteriolar sclerosis were both associated with future kidneydisease progression (Figure 3, C and D) (generalized log rankP,0.001). The association of arterial and arteriolar sclerosiswith subsequent kidney disease progression was confounded byeGFR.Moderate arterial sclerosis and severe arterial sclerosis (ver-sus none/mild) remained associated with nearly 1.8- and 1.7-foldincreased risks of kidney disease progression after multivariableadjustment, respectively (Table 3). Moderate arteriolar sclerosisand severe arteriolar sclerosis (versus none/mild) were associatedwith 1.6- and 2.3-fold increased risks of kidney disease progres-sion after multivariable adjustment, respectively (Table 3).

Kidney Biopsy Chronicity ScoreSethi et al.16 proposed a standardized grading of chronic changes innative kidney biopsy specimens on the basis of the following fourvariables: interstitial fibrosis, tubular atrophy, arteriosclerosis(without mention of arterioles), and glomerulosclerosis—all ofwhich were found in our study to be independently associatedwith kidneydisease progression. Results on the associationbetweenthe chronicity score and kidney disease progression are shown inTable 4.Results for the outcomeofRRTwere similar and are shownin Supplemental Table 6.We calculated total renal chronicity scoresfor each individual in this studyon thebasis of theproposal by Sethiet al.16 and tested the performance of the score for predicting 5-yearrisk of RRT; we compared the score with the Kidney Failure RiskEquation (KFRE), which includes age, race, sex, proteinuria, andeGFR.42,43The c statistic of themodelwithonly the chronicity scorewas 0.84 (95% confidence interval, 0.80 to 0.88). The c statistic ofthemodel with KFRE variables was 0.85 (95% confidence interval,0.81 to 0.89). The c statistic of the model with both the chronicityscore and the KFRE variables increased to 0.87 (95% confidenceinterval, 0.83 to 0.90; P=0.13 for comparison with the c statistic ofthe KFRE model).

DISCUSSION

In this prospective studyof adjudicated histopathologic lesionsacross a diverse set of kidney diseases, we found that severalhistopathologic lesions were independent predictors of kidneydisease progression. Themain findings were that IFTA, arterial

and arteriolar sclerosis, and global glomerulosclerosis were eachassociated with kidney disease progression even after adjustingfor a number of clinical predictors, including eGFR, proteinuria,and clinicopathologic diagnosis. Apreviously proposed chronicityscore from the sum of semiquantitative grading of chronic lesionswas also independently associatedwith kidneydisease progressionbut did not change risk prediction appreciably as judged by thechange in c statistic. The final findings were that the presence ofinflammation in the fibrosed interstitium and the presence ofinflammation in nonfibrosed interstitium were associated withhigher and lower risk of subsequent kidney disease progression,respectively; the latter was presumably due to the treatable natureof such lesions.

Kidney biopsies provide diagnostic and also prognostic in-formation.3–6 A key strength of our study is the inclusion ofdiverse forms of kidney disease and multivariable adjustmentfor clinicopathologic diagnosis as well as demographics andlaboratory values. Our findings extend and validate findingsfrom the published literature dating back to the 1960s.17,44,45

It is commonly stated that interstitial fibrosis is the histo-pathologic lesionmost strongly associated with a higher risk ofkidney failure.18,19,22,46 The evidence base for this assertion,however, derives from a number of studies restricted to spe-cific etiologies47–50 and studies that did not adjust compre-hensively for known confounders, such as clinicopathologicdiagnosis, eGFR, and proteinuria.20,51,52 Our findings confirmthe importance of IFTA and expand on the importance ofinterstitial inflammation,53 global glomerulosclerosis, arterialsclerosis, and arteriolar sclerosis. Our finding that kidneydisease progression is more common in those with global glo-merulosclerosis exceeding the expected degree on the basis ofage is consistent with the findings of Hommos et al.31 andsupport the need to take into account age-related pathologicchanges.

A number of studies have developed scoring systems forrenal pathology. Examples include activity and chronicity in-dices in lupus nephritis,50 the Oxford classification in IgAnephropathy,13,14 the Nephrotic Syndrome Study Networkdigital pathology scoring system,54 and prior suggestions forglobal chronicity scores.20,49,55 More recently, Sethi et al.16

suggested that biopsies should include semiquantitative scores

Table 4. Risk of kidney disease progression using the kidney biopsy chronicity score

Chronicity Scorea N Events per 100 person-yr Model 1 HR [95% CI] Model 2 HR [95% CI] Model 3 HR [95% CI]

Per one-point change 654 12.1 1.28 [1.22 to 1.33] 1.23 [1.17 to 1.30] 1.19 [1.12 to 1.27]Minimal chronic changes (0–1) 199 3.6 — — —

Mild chronic changes (2–4) 168 8.1 2.02 [1.17 to 3.48] 1.72 [0.97 to 3.06] 1.53 [0.85 to 2.75]Moderate chronic changes (5–7) 146 17.3 4.24 [2.55 to 7.04] 3.81 [2.20 to 6.59] 2.92 [1.61 to 5.31]Severe chronic changes ($8) 141 39.6 8.67 [5.35 to 14.1] 6.09 [3.51 to 10.6] 4.42 [2.37 to 8.22]

Shown are HRs (95% CIs) per one-point increase in the score (range from zero to ten) or compared to the reference group of minimal chronic changes. Model 1 isunadjusted.Model 2 isModel 1 stratified by site and adjusted for age, sex, race, log-transformed proteinuria, primary clinicopathologic diagnosis, and angiotensin-converting enzyme inhibitor or angiotensin receptor blocker medication use. Model 3 includes Model 2 and adjusts for eGFR. HR, hazard ratio; 95% CI, 95%confidence interval; —, reference group.aChronicity score is calculated by adding scores of global glomerulosclerosis (zero to three), interstitial fibrosis and tubular atrophy (zero to three), and arterialsclerosis (zero to one). Interstitial fibrosis and tubular atrophy are counted twice, because interstitial fibrosis and tubular atrophy are scored separately in theproposal by Sethi et al.16 Arterial sclerosis is given a score of zero for none/mild and one for moderate/severe lesions.




for the degree of glomerulosclerosis, interstitial fibrosis, tubularatrophy, and arteriosclerosis alongwith an overall chronicity scoreequal to the sum of the individual scores. Our findings provideempirical evidence in support of such a scoring system. The pro-posed scoring system by Sethi et al.16 did not include arteriolarsclerosis, but our study provides evidence for the prognostic im-portance of arteriolar sclerosis for kidney disease progression. Thedegrees of arterial and arteriolar lesions, although correlated, candiverge from one another on the basis of our finding of a modestcorrelation between the two scores (R=0.68). These findings sug-gest that nephropathologists should score arterial and arteriolarlesions separately because they both associate with kidney diseaseprogression and may represent different pathologic processes.Given the importance of arterial and arteriolar lesions, greaterstandardization by pathologists—in both terminology and grad-ing criteria—would be desirable.

eGFR and proteinuria are used by clinicians for prognosticassessment, but they do not capture the full extent of kidneypathology. Our results of independent associations betweenhistopathology and kidney disease progression reflect the in-adequacy of SCr and proteinuria as risk markers and pointtoward well described hypotheses on the causal associationsbetween histopathologic lesions and progression of kidneydisease. Global glomerulosclerosis and IFTA, for example,may denote focal nephron loss and adaptive responses of sur-viving nephrons that ultimately prove to be detrimental tokidney function.56,57 Arterial and arteriolar lesions couldbe a reflection (or cause) of systemic hypertension and failureof glomerular autoregulation.58–60 Whether chronic lesionsfrom kidney biopsy findings can direct specific treatments tomodify disease progression (for example, antifibrotic agentsfor those with excessive IFTA) is an area in need of more re-search and clinical trials. It is tempting to speculate that kidneybiopsies could provide value in patients who do not currentlyundergo kidney biopsy, such as individuals with presumedhypertension-associated CKD and presumed diabetic ne-phropathy. Indeed, the Kidney Precision Medicine Projectlaunched by the National Institute of Diabetes, Digestive andKidney Diseases is conducting multicenter studies to expandthe role for kidney biopsies and their molecular interrogationin individuals with common forms of CKD and AKI.

Several limitations should be noted in our study.We did notinclude readjudication of electron microscopy or immunoflu-orescence results primarily due to logistic constraints. We alsodid not perform quantitative morphometry or quantify fea-tures, such as podocyte number or peritubular capillary den-sity, which are important in the pathogenesis and progressionof variouskidneydiseases.Wedidnot take into account therapyadministered after the biopsy, which could alter an individual’strajectory to the outcome, particularly in individuals requiringimmunosuppressive therapy. The two renal pathologists didnot use formalized definitions and criteria for each gradingcategory; this is not a source of bias for our findings, however,because they were completely blinded to clinical variables,reason for biopsy, and original diagnosis. The relatively low

k-statistics for certain lesions could have biased results towardthe null hypothesis of no association between a given lesionand the outcomes tested. Although our cohort was diverse(from three separate academic medical centers) and large rel-ative to other biopsy cohorts with adjudicated histopathologicscores, it includes only individuals who underwent biopsiesfor specific clinical indications with diseases that are not nec-essarily reflective of the majority of patients with CKD andpatients with AKI. The number of biopsies from individualdisease categories was also small, particularly for rare forms ofkidney disease. Our readjudication process provided inter-nally consistent scoring for biopsies; however, it is not neces-sarily generalizable, because we relied on two expert renalpathologists who convened to score biopsies together in studysessions. Further development of standardized criteria forscoring lesions, as has been done by the Banff group for trans-plant biopsies, would be important to allow adoption by othercenters and enhance generalizability. The development of im-age analysis algorithms using digital pathology could also befocused on lesions that provide prognostic information, suchas we have described.

In conclusion, greater severity of lesions on native kidneybiopsies—independent of clinical factors, including clinico-pathologic diagnosis, eGFR, and proteinuria—associateswith a greater risk of kidney disease progression across a va-riety of kidney disease etiologies. A kidney biopsy chronicityscore also provides additional prognostic value above routineclinical variables. Our findings highlight the prognostic valueof careful review and semiquantitative scoring of the kidneybiopsy specimen.

ACKNOWLEDGMENTS

We thank themembers of the laboratory of S.S.W. for their invaluable

assistance in the Boston Kidney Biopsy Cohort.

This study is supported by National Institutes of Health (NIH)

grant R01DK093574 (to S.S.W.). A.S. was supported by NIH grant

F32DK11106. S.S.W. is also supported by NIH grants U01DK085660,

U01DK104308, and UG3DK114915.

This work was conducted with support from Harvard Catalyst. The

Harvard Clinical and Translational Science Center (National Center for

Advancing Translational Sciences, National Institutes of Health Award

UL1 TR001102) and financial contributions from Harvard University

and its affiliated academic healthcare centers. The content is solely the

responsibility of the authors and does not necessarily represent the of-

ficial views of Harvard Catalyst, Harvard University and its affiliated

academic healthcare centers, or the National Institutes of Health.

Part of this work was presented as a poster at the 2016 American

Society of Nephrology Scientific Session on November 19 in Chicago,

Illinois.

DISCLOSURESNone.



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