Paper

Lupus
2023, Vol. 32(3) 411–423
Predicting kidney outcomes among Latin © The Author(s) 2023
Article reuse guidelines:
American patients with lupus nephritis: The sagepub.com/journals-permissions
DOI: 10.1177/09612033231151597

prognostic value of interstitial fibrosis and journals.sagepub.com/home/lup

tubular atrophy and tubulointerstitial

inflammation

Joaquı́n Rodelo1, Lina Aguirre1, Katherine Ortegón1, José Ustáriz1, Ligia Calderon1,
Alejandra Taborda2, Luis Fernando Arias2 and Luis Alonso González3 

Abstract
Objective: To assess the effect of tubulointerstitial inflammation (TII) and interstitial fibrosis and tubular atrophy (IFTA)
on kidney survival in lupus nephritis (LN).
Methods: Two hundred eighty five patients with biopsy-proven LN were retrospectively studied. Kidney survival was
defined as the time from initial biopsy to end-stage kidney disease (ESKD), dialysis, or transplant. Kidney survival analysis
was performed by the Kaplan–Meier method and the statistical difference between survival curves compared by the log-
rank test. Cumulative incidence functions with competing risk of death for kidney survival were also graphed. Multivariable
Cox proportional hazards regression and competing-risk analyses were performed to identify independent predictors of
ESKD.
Results: Fifty-seven patients (20%) progressed to ESKD during a median time of 4.2 (2.0–55.2) months after biopsy. TII was
present in 206 (72.3%) biopsies, while IFTA in 99 (34.7%) biopsies. Patients with moderate-to-severe IFTA had worse
kidney survival than those with none or mild IFTA in both the Kaplan–Meier (p = 0.018) and the competing-risk analyses
(p = 0.017). Patients with class IV ± V LN had worse kidney survival than those with non-class IV LN by the Kaplan–Meier
method (p = 0.050), but not in the competing-risk analysis (p = 0.154). Worse kidney survival was also found among those
with fibrous crescents than those without, in both the Kaplan–Meier (p = 0.010) and the competing-risk (p = 0.011)
analyses. By multivariable Cox regression analysis, older age (HR 1.04, 95% CI 1.01–1.07) and class IV ± V LN (HR 5.06, 95%
CI 1.82–14.09) were associated with higher risk of ESKD after adjusting for sex, ethnicity, TII, and IFTA. By competing-risk
analyses, class IV ± V LN (SHR 3.32, 95% CI 1.25–8.83) and no response to immunosuppressive therapy (SHR 4.55, 95% CI
1.54–13.41) were associated with a higher risk of ESKD, while eGFR >90 mL/min/1.73 m2 (SHR 0.98 for each ml/min/
1.73 m2, 95% 0.97–0.99) with a lower risk.
Conclusions: Patients with moderate-to-severe IFTA had worse kidney survival than those with none or mild IFTA.
Worse kidney survival was also found among those with class IV LN and fibrous crescents versus those without IV LN and
fibrous crescents, respectively.

Keywords
lupus nephritis, interstitial inflammation, interstitial fibrosis, tubular atrophy, kidney survival

1
Division of Nephrolology, Department of Internal Medicine, School of Medicine, Hospital Universitario de San Vicente Fundación, Universidad de
Antioquia, Medellı́n, Colombia
2
Department of Pathology, School of Medicine, Universidad de Antioquia, Medellı́n, Colombia
3
Division of Rheumatology, Department of Internal Medicine, School of Medicine, Hospital Universitario de San Vicente Fundación, Universidad de
Antioquia, Medellı́n, Colombia

Corresponding author:
Luis Alonso González, Division of Rheumatology, Department of Internal Medicine, School of Medicine, Universidad de Antioquia, calle 10E # 25-165, apto
402, Medellı́n 050021, Colombia.
Email: alonso.gonzalez@udea.edu.co
412
Introduction
Lupus nephritis (LN), an important cause of morbidity and
mortality in patients with systemic lupus erythematosus
(SLE), affects nearly 50% of them during the course of their
disease.1 Despite intense immunosuppressive treatment,
19%–25% of patients with LN will progress to end-stage
kidney disease (ESKD) within 15 years of diagnosis.2,3
Although multiple efforts have been made in the search
for diagnostic tests, we still do not have reliable non-
invasive biomarkers for LN, since those currently avail-
able lack sensitivity and specificity for differentiating renal
activity from renal damage.4 Therefore, kidney biopsy re-
mains the gold standard for diagnosing, classifying, and
determining the degree of activity and chronicity of LN,
despite the limitations of the histological classifications.5
The 2003 International Society of Nephrology/Renal
Pathology Society (ISN/RPS) classification focus pre-
dominantly on glomerular lesions. One of the drawbacks of
this classification is the non-inclusion of tubulointerstitial
injury or vascular lesions, which are risk factors for ESKD.6
Taking these drawbacks into consideration, the 2018 revised
ISN/RPS classification for LN proposes a sub-classification
of different vascular and tubulointerstitial lesions according
to their pathogenic mechanism.7
Tubulointerstitial inflammation (TII) and interstitial fi-
brosis and tubular atrophy (IFTA) are associated with worse
kidney survival in patients with LN.8–13 However, despite
these data, their presence or absence is not usually used to
guide therapeutic decisions. Given the influence of tubu-
lointerstitial lesions on renal outcomes, we aimed to in-
vestigate the effect of TII and IFTA on kidney survival of
those patients with biopsy-proven LN.
Materials and methods
Design and patients
We performed a retrospective cohort study of 285 SLE
patients with biopsy-proven LN, older than 18 years and
diagnosed and followed-up at Hospital Universitario San
Vicente Fundación (HUSVF), Medellı́n, Colombia, be-
tween January 2011 and December 2019. All patients
fulfilled the 1997 American College of Rheumatology
(ACR) criteria and the 2012 Systemic Lupus International
Collaborating Clinics (SLICC) criteria for SLE
classification.14,15 Kidney transplant recipients and those
with renal malignancy were excluded.
Renal pathology
All biopsies were read and reclassified according to the
revised ISN/RPS 2018 classification by two independent
nephropathologists.7 Disagreements were resolved by
Lupus 32(3)
consensus. Biopsy samples had at least 10 glomeruli for
evaluation and were examined using light and immuno-
fluorescence microscopy for the primary diagnosis.
Acute tubulointerstitial lesions were defined as TII in the
absence of interstitial fibrosis, whereas chronic lesions were
defined as IFTA. These lesions were assessed using he-
matoxylin and eosin, periodic acid-Schiff, Masson’s Tri-
chrome, and methenamine silver stains. IFTA scores were
classified according to the estimated percentage seen in the
cortical area of the biopsy sample as follows: absent (grade
0) as 0%; mild (grade 1) <25%; moderate (grade 2) 25%–
50%, and severe (grade 3) >50% of the total area. For the
primary analysis, we created the dichotomous variable any
(mild, moderate and severe IFTA) versus no IFTA. We also
examined none or mild versus moderate-to-severe IFTA.7
The extent of TII was semiquantitative scored as 0 or
absence of inflammation, mild (grade 1) if the extension
was <25%, moderate (grade 2) if it was 25%–50%, and
severe (grade 3) if >50% of the sample.7 Activity (0–24) and
chronicity (0–12) indices for each biopsy sample were
calculated according to the modified National Institutes of
Health (NIH) LN activity and chronicity scoring system.7
For the primary analysis, we also created the dichotomous
variable any (mild, moderate, and severe TII) versus no TII.
Variables
Sociodemographic, clinical, immunological, laboratory, and
therapeutic data were obtained from HUSVF electronic
medical records and supplemented with data from the pa-
thology database of HUSVF and the University of Anti-
oquia. Sociodemographic variables included age at kidney
biopsy, sex, ethnicity (White, Mestizo, and African-Latin
American), duration of SLE at the time of kidney biopsy,
and duration of LN at the time of kidney biopsy. Clinical
variables included hypertension (systolic blood
pressure ≥140 mm Hg or diastolic blood pressure ≥90 mm
Hg on at least two different days within 1 month of kidney
biopsy and/or patient self-reported intake of antihyperten-
sive medications regardless of cause), disease activity [SLE
Disease activity Index SLEDAI)] at the time of kidney
biopsy,16 renal flares (present or absent), time from biopsy
to death, time from biopsy to renal replacement therapy
(RRT), and time from biopsy to last follow-up. Immuno-
logical variables at any time before the kidney biopsy date
included antinuclear antibodies (ANA), anti-Sm, and an-
tiphospholipid antibodies (aPL). Immunological and labo-
ratory variables collected within 1 week prior to kidney
biopsy included anti-double stranded DNA (anti-dsDNA),
serum complement concentrations (C3 and C4), hemo-
globin level, platelet count, white blood cell (WBC) count,
serum creatinine, estimated glomerular filtration rate
(eGFR) by the CKD-EPI equation,17 24-h urine protein
measurement within 1 week prior to the biopsy date,
Rodelo et al.
hematuria [>3 red blood cells (RBCs)/high-power field
(hpf)], and leukocyturia (>5 WBCs/hpf in the absence of
infection). Outcome variables included RRT and mortality.
Therapeutic variables included (1) glucocorticoids: intra-
venous methylprednisolone pulses (500 mg/day for three
doses), followed by oral prednisolone [0.5–1 mg/kg/day],
with tapering by 20% at 2-week intervals to ≤10 mg/day by
3 months if remission is achieved; (2) induction therapy for
6 months with mycophenolate mofetil (MMF), intravenous
cyclophosphamide (CyC) monthly pulses, calcineurin in-
hibitors [cyclosporine or tacrolimus), or rituximab; (3)
maintenance therapy with MMF or azathioprine for at least
3 years or quarterly intravenous CyC for up to 2 years.
Kidney and patient survival
Kidney survival was defined as the time interval from the
date of initial kidney biopsy to the occurrence of any of the
following conditions: ESKD (eGFR <15 mL per minute per
1.73 m2 for at least 3 months)18 or RRT (dialysis
for >3 months or kidney transplant). Patient survival was
defined as the time interval from the date of kidney biopsy
until death, defined as all-cause mortality. To develop
kidney survival analyses, the following variables were also
included serum creatinine and eGFR by the CKD-EPI
equation at discharge, 1 month, and 1 year after the kid-
ney biopsy, and the last available measurement during
follow-up; follow-up duration; complete, partial remission
and non-response to immunosuppressive treatment as de-
fined by the KDIGO 2012 clinical practice guideline for
glomerulonephritis19; and the time to remission. The
HUSVF ethics committee approved this study.
Statistical analyses
Continuous variables were presented as mean ± SD or
median (interquartile range, IQR), depending on whether
they followed a normal or non-normal distribution, while
categorical variables were presented as absolute (number)
and relative frequencies (percentage). To compare demo-
graphic, clinical, laboratory variables, and histological
findings of IFTA and TII among the different ISN/RPS
classes of LN, descriptive statistics were calculated using
the Chi-square test for categorical variables, the Student’s t
test for continuous variables with normal distribution, and
the Mann–Whitney U test for continuous variables with
non-normal distribution.
We performed survival analyses to assess progression
from the date of kidney biopsy to ESKD among patients
with different LN classes, IFTA, and TII. Survival rates
were generated using the Kaplan–Meier method and
compared by the log-rank (Mantel–Cox) test.
Competing risk survival analyses were used to estimate
the cumulative incidence functions for ESKD and mortality.
413
These cumulative incidence curves were plotted and
stratified by LN class and the presence or absence of IFTA
or TII on kidney biopsy and compared using the Gray’s
test.20 Cumulative incidence functions were censored if
patients died or were loss to follow-up, at the last clinic visit
or phone call. Logistic regression analyses were used to
examine the association between characteristics and IFTA,
and the results were expressed as odds ratios (OR) and their
respective 95% confidence intervals.
To determine the predictive factors of ESKD, we per-
formed univariable and multivariable Cox regression ana-
lyses. Variables with a p ≤ 0.25 in these univariable Cox
regressions were entered into Cox proportional hazards
multivariable regression analysis using a computer-driven
forward selection procedure. Multivariable regression an-
alyses using the competing risk of death in models of ESKD
were also performed. These multivariable analyses were
adjusted for age, sex, ethnicity, eGFR, and histological
findings (LN class, TII, and IFTA). Exploratory multivar-
iable Cox regression and competing-risk models, including
only patients with class III and IV ± V LN, were also
performed to determine predictors of ESK. Results of the
univariable and multivariable analyses are reported as
hazard ratios (HRs) for Cox regression analyses and as
subhazard ratios (SHRs) for competing risk analyses; a p ≤
0.05 was statistically significant.
All analyses were performed using STATA Statistical
Software, version 16 (College Station, TX: StataCorp LP).
Results
A total of 285 SLE patients with biopsy-proven LN were
included in this study. The mean (SD) patient age at kidney
biopsy was 32.7 (11.2) years, 86% were female, and
Mestizo was the largest ethnic group (77.5%). At the time of
kidney biopsy, the median (IQR) SLE duration was 8.0
(1.0–48.0) months, and the median (IQR) LN duration was
1.0 (0.5–10.0) month. LN was present at the onset of lupus
in 119 (41.8%) patients. Forty-one percent of the patients
were hypertensive. The median (IQR) SLEDAI score at the
time of the biopsy was 18 (14–22). The frequencies of the
clinical and immunological 2012 SLICC criteria are shown
in Table 1.
At the time of kidney biopsy, the median (IQR) serum
creatinine was 0.90 (0.68–1.50) mg/dL, the median (IQR)
eGFR was 90 (48–118) mL/min/1.73 m2, and the median
(IQR) proteinuria was 2.5 (1.2–5.1) gr/day; low serum C3
and C4 levels were documented in 78.9% and 63.9% of the
patients, respectively, and the median (IQR) serum C3 and
C4 levels, within 1 week prior to kidney biopsy, were 47
(32–67) mg/dL and 6 (3–11) mg/dL, respectively.
The frequencies of immunosuppressants used in in-
duction and maintenance treatment are shown in Table 1.
Maintenance therapy was unreported in 57 (20.0%) patients
414 Lupus 32(3)

Table 1. Sociodemographic, clinical, laboratory, and therapeutic characteristics of patients with lupus nephritis who underwent kidney
biopsy (n = 285).

Value

Sociodemographic variables
Age, years, mean±SD 32.7±11.2
Female sex, n (%) 245 (86.0)
Ethnic group, n (%)
Whites 31 (10.9)
Afro-Colombians 33 (11.6)
Mestizos 221 (77.5)
Duration of SLE at biopsy, months, median (IQR) 8 (1–48)
Duration of lupus nephritis at biopsy, months, median (IQR) 1 (0.5–10)
Follow-up time of the entire cohort, months, median (IQR) 27.5 (1.1–63.4)
Clinical variables
Hypertension, n (%) 117 (41.1)
SLEDAI, median (IQR) 18 (14–22)
Time from biopsy to last follow-up, years, median (IQR) 2.3 (0.25–5.2)
SLICC clinical criteria, n (%)
Acute cutaneous lupus 154 (54.0)
Chronic cutaneous lupus 37 (13.0)
Oral or nasal ulcers 95 (33.3)
Non-scarring alopecia 99 (34.7)
Arthritis 201 (70.5)
Serositis 82 (28.8)
Renal 285 (100%)
Neurologic 25 (8.8)
Hemolytic anemia 50 (17.5)
Leukopenia (<4000/mm3) 62 (21.7)
Lymphopenia (<1000/mm3) 161 (56.5)
Thrombocytopenia (<100,000/mm3) 27 (9.5)
SLICC immunologic criteria, n (%)
ANA ≥1:80 285 (100)
Anti-dsDNA 218 (76.5)
Anti-Sm positivity, n (%) 95 (33.3)
Lupus anticoagulant positivity, n (%) 37 (13,0)
IgG anticardiolipin antibodies, n (%) 81 (28.4)
IgM anticardiolipin antibodies, n (%) 42 (14.7)
Low serum C3 levels (<88 mg/dL), n (%) 225 (78.9)
Low serum C4 levels (<10 mg/dL), n (%) 182 (63.9)
Low serum C3 or C4 levels, n (%) 231 (81.1)
Laboratory variables
Serum creatinine, mg/dL, median (IQR) 0.90 (0.68–1.50)
eGFR (CKD-EPI equation), ml/min/1.73 m2, median (IQR) 90 (48–118)
Proteinuria gr/24-h, median (IQR) 2.53 (1.18–5.13)
Hematuria, n (%) 212 (74.4)
Induction therapy
Intravenous pulses of methylprednisolone, n (%) 199 (69.8)
Intravenous CyC and steroids (NIH protocol), n (%) 170 (59.6)
MMF and steroids, n (%) 57 (20.0)
Multitarget (TAC, MMF, and steroids) therapy, n (%) 2 (0.7)
Rituximab and steroids, n (%) 17 (6.0)
CNI (CsA or TAC) and steroids, n (%) 39 (13.7)
Maintenance therapy

(continued)
Rodelo et al.
Table 1. (continued)
MMF, n (%)
AZA, n (%)
Intravenous CyC
Unreported maintenance therapy
Outcomes during follow-up
Remission at 6 months
Complete, n (%)
Partial, n (%)
Renal flares, n (%)
RRT, n (%)
Hemodialysis, n
Peritoneal dialysis, n
kidney transplant, n
Mortality, n (%)
SD: Standard deviation; IQR: (75th percentile minus 25th percentile); SLEDAI: Systemic lupus erythematosus disease activity Index; ANA: Antinuclear
antibodies; eGFR: Estimated glomerular filtration rate; CKD-EPI = chronic kidney disease Epidemiology Collaboration; ISN/RPS: International Society of
Nephrology/Renal pathology Society; RRT: Renal replacement therapy; CyC: Cyclophosphamide; NIH: National Institutes of Health; CNI: Calcineurin
inhibitors; CsA: Cyclosporine A; TAC: Tacrolimus; MMF: mycophenolate mofetil; AZA: Azathioprine.
since 15 died and 42 started RRT during induction treat-
ment. Forty-one (14.4%) patients required hemodialysis at
SLE diagnosis due to rapidly progressive glomerulone-
phritis (n = 45), 57 (20.0%) progressed to ESKD at a median
(IQR) of 4.2 (2.0–55.2) months after biopsy and 63 (22.1%)
died at a median (IQR) of 19.6 (8.0–55.2) months after
biopsy. The main cause of death was infection (61.9%)
followed by cardiovascular disease (19.0%). These data are
summarized in Table 1.
Baseline characteristics according to the
histopathological class of lupus nephritis
Of the 285 patients, 2 (0.7%) had class I, 31 (10.9%) class II,
46 (16.2%) class III, 116 (40.7%) class IV, 34 (11.9%) class
V, 28 (9.8%) class III + V, and 28 (9.8%) class IV + V on
renal biopsy.
The mean age values for patients with class III, and class
III + V were significantly higher than those in the other
classes (37 ± 12 and 36 ± 11 years, respectively; p = 0.02).
Patients with class IV had higher systolic and diastolic
blood pressure, and higher serum creatinine than those
without class IV. The median (IQR) eGFR of patients with
class IV was significantly lower than that reported in the
other classes [65 (34–103) mL/min/1.73 m2; p < 0.001).
Nephrotic-range proteinuria (>3.5 g/24 h) was significantly
more frequent in patients with class V (alone or in com-
bination with class III or IV).
Patients with class IV ± V had significantly higher NIH
activity and chronicity indices than patients with non-class
IV LN (p < 0.001). Cellular and fibrous crescents were
415
Value
134 (47.0)
89 (31.2)
5 (1.8)
57 (20.0)
136 (47.5)
38 (13.3%)
63 (22.1%)
57 (20.0)
41
11
5
63 (22.1)
significantly more frequent in class IV than in the other
classes (56%; p < 0.001 and 27.6%; p = 0.007, respectively)
(Table 2). Regarding C3 and C4 complement levels, anti-
DNA antibody positivity, and the total glomeruli number
(≥10) on kidney biopsy, there were no statistically signif-
icant difference between LN classes.
Tubulointerstitial lesions
Interstitial inflammation. Overall, tubulointerstitial lesions
(TII and/or IFTA) were present in 215 (75.4%) biopsies. TII
lesions were identified in 206 (72.3%) kidney biopsies,
being significantly more common in class III (80.4%) and
class IV LN (88.8%); p < 0.001] than in the other classes.
Mild TII lesions were the most frequent, observed in 135
(47.4%) biopsies while moderate-to-severe in 71(24.9%)
patients (Table 2). TII lesions were associated with hy-
pertension, higher use of renin-angiotensin-system (RAS)-
acting agents, elevated serum creatinine, lower eGFR, lower
hemoglobin, and higher NIH activity and chronicity indices.
TII lesions were also associated with higher proteinuria in
24-h urine and more active urine sediment (Table 3).
Interstitial fibrosis and tubular atrophy. IFTA lesions were
detected in 99 (34.7%) kidney biopsies, being more frequent
in class IV LN [alone (44.8%) or in combination with class
V (50.0%); p = 0.004] than in the other classes. Moderate-
to-severe IFTA was only observed in 14 (4.9%) biopsies and
was more common in class IV (13 biopsies) compared with
non-class IV LN (only in one biopsy classified as class V)
(Table 2). Patients with IFTA were older, had a longer SLE
Table 2. Baseline characteristics of the study population by the 2003 International Society of Nephrology/Renal Pathology Society (ISN/RPS) classification.
416

Class I (n = 2) and Class III + V Class IV + V

Characteristics class II (n = 31) Class III (n = 46) Class IV (n = 116) Class V (n = 34) (n = 28) (n = 28) p Value

Age, years, mean±SD 33 ± 11 37 ± 12 31 ± 11 32 ± 10 36 ± 11 29 ± 10 0.020

Mestizo ethnicity 19 (57.6) 38 (82.6) 98 (84.5) 25 (73.5) 19 (67.9) 20 (71.4) 0.127
Female sex, n (%) 31 (93.9%) 39 (84.8%) 105 (90.5%) 27 (79.4%) 23 (82.1%) 20 (71.4%) 0.067a
Systolic blood pressure, mean±SD 120 ± 19 124 ± 20 139 ± 28 125 ± 16 128 ± 28 134 ± 23 <0.001
Diastolic blood pressure, mean±SD 76 ± 10 77 ± 12 84 ± 16 80 ± 11 76 ± 18 82 ± 14 0.013
Serum creatinine, mg/dL, median (IQR) 0.69 (0.60–0.80) 0.88 (0.68–1.50) 1.20 (0.79–2.11) 0.70 (0.60–0.90) 0.76 (0.66–1.17) 0.95 (0.80–1.39 <0.001
eGFR (CKD-EPI equation), ml/min/1.73 m2, median (IQR) 117 (102–125) 90 (45–115) 65 (34–103) 115 (87–127) 103 (59–120) 97 (57–115) <0.001
Proteinuria gr/24-h, median (IQR) 0.94 (0.34–1.77) 1.55 (1.01–2.85) 3.23(1.51–5.50) 4.08(2.21–8.10) 4.08(0.95–8.20) 4.23 (2.10–8.20) <0.001
NIH activity Index, median (IQR) 1 (0–1) 4 (2–5) 9 (6–11) 1 (0–1) 3 (2–4) 6 (5–9) <0.001
NIH chronicity Index, median (IQR) 0 (0–0) 0 (0–3) 2 (0–4) 0 (0–1) 2 (0–3) 2 (0–4) <0.001
TII, n (%)
Absent 19 (57.6) 9 (19.6) 13 (11.2) 18 (53.0) 13 (46.5) 7 (25.0) <0.001a
<25% 14 (42.4) 32 (69.6) 56 (48.3) 12 (35.3) 9 (32.1) 12 (42.9)
25%–50% 4 (8.7) 33 (28.4) 3 (8.8) 4 (14.3) 7 (25.0)
>50% 1 (2.1) 14 (12.1) 1 (2.9) 2 (7.1) 2 (7.1)
IFTA, n (%)
Absent 30 (90.9) 33 (71.7) 64 (55.2) 28 (82.4) 17 (60.7) 14 (50.0) 0.004a
<25% 3 (9.1) 13 (28.3) 40 (34.5) 5 (14.7) 11 (39.3) 13 (46.4)
25%–50% 7 (6.0) 1 (2.9) 1 (3.6)
>50% 5 (4.3)
Cellular crescents, n (%)
Absent 33 (100.0) 35 (76.1) 51 (44.0) 33 (97.1) 21 (75.0) 19 (67.9) <0.001a
<25% 11 (23.8) 26 (22.4) 6 (21.4) 6 (21.4)
25%–50% 21 (18.1) 1 (2.9) 1 (3.6) 3 (10.7)
>50% 18 (15.5)
Fibrous crescents, n (%)
Absent 33 (100.0) 41 (89.1) 84 (72.4) 34 (100.0) 26 (92.9) 25 (89.3) 0.007
<25% 5 (10.9) 25 (21.6) 2 (7.1) 3 (10.7)
25%–50% 6 (5.2)
>50% 1 (0.8)
Outcomes, n (%)
RRT 4 (8.7) 42 (36.2) 1 (2.9) 6 (21.4) 5 (17.9) 0.582
Hemodialysis 2 (4.3) 31 (26.7%) 1 (2.9 5 (17.9) 3 (10.7)
Peritoneal dialysis 2 (4.3) 6 (5.2%) 1 (3.6) 2 (7.1)
kidney transplant 5 (4.3%)
Death 4 (12.1%) 15 (32.6%) 31 (26.7%) 4 (11.8%) 2 (7.1%) 7 (25.0%) 0.030
SD: Standard deviation; IQR: (75th percentile minus 25th percentile); eGFR: Estimated glomerular filtration rate; NIH: National Institutes of Health; RRT: Renal replacement therapy TII: tubulointerstitial
Lupus 32(3)

inflammation; IFTA: Interstitial fibrosis and tubular atrophy

a
Fisher’s exact test
Rodelo et al. 417

duration at biopsy, a longer LN duration at biopsy, were
more frequently hypertensive, had higher serum creatinine,
lower eGFR, lower hemoglobin, and higher NIH activity
and chronicity indices than those without IFTA (Table 3).
Factors associated with IFTA
By multivariable logistic regression analysis, hypertension
(OR 2.77, 95% CI 1.57–4.88; p < 0.001) and longer disease
duration (OR 1.03, 95% CI 1.02–1.05; p < 0.001) were
associated with the occurrence of IFTA, while
eGFR >105 mL/min/1.73 m2 (OR 0.98, 95% CI 0.97–0.99;
p < 0.001) and hemoglobin >10.6 g/dL at the time of biopsy
(OR 0.84; 95% CI 0.73–0.96; p = 0.010) were negatively
associated with its occurrence (Supplementary Table 1).
Histopathological findings and kidney survival
Class IV ± V LN had worse kidney survival than non-class IV
LN by the Kaplan–Meier method (p = 0.050), but not in the
competing risk analysis (p = 0.154) (Figure 1(a) and (b)). When
comparing kidney survival in those with classes I, II, and V LN
(n = 67) with that of those with LN with intracapillary hy-
percellularity (n = 218; class III ± Vand class IV ± V) only one
(1.5%) patient with class V LN progressed to ESKD compared
to 57 (26.1%) patients with LN with intracapillary hyper-
cellularity who progressed to ESKD (p < 0.001).
Those with moderate-to-severe IFTA had worse kidney
survival than those with none or mild IFTA in both the
Kaplan–Meier method and the competing risk analyses (p =
0.018 and p = 0.017, respectively) (Figure 1(c) and (d)).
Kidney survival was also worse among those with glomerular
fibrous crescents than those without, in both the Kaplan–
Meier method and the competing risk analyses (p = 0.010
and p = 0.011, respectively) (Figure 1 (e) and (f)). In contrast,
in Kaplan–Meier survival analysis TII was not associated with
worse kidney survival (p = 0.500); furthermore, when the
severity of TII was categorized as absent, mild, and moderate/
severe, no differences were found between the groups in terms
of renal survival (p = 0.737). Also, the presence of glomerular

Table 3. Baseline demographic, clinical, and laboratory characteristics of the study population by interstitial fibrosis and tubular atrophy
(IF/TA) and tubulointerstitial inflammation (TII).

IFTA TII

Present n = 99 Absent n = 186 Present n = 206 Absent n = 79

(34.7%) (65.3%) p value (72.3%) (27.7%) p Value

Demographic and clinical variables

Age, years, mean±SD 34.3±12.2 31.9±10.5 0.092 33.2±11.5 31.6±10.2 0.272
Female sex, n (%) 89 (89.9%) 156 (83.9%) 0.163 177 (85.9%) 68 (86.1%) 0.973
Mestizo ethnicity 81 (81.8%) 138(74.2%) 0.198 163(79.1%) 56 (70.9%) 0.266
Duration of SLE at biopsy, months, 24 (2–60) 6 (1–36.5) 0.029 10 (1–48) 4 (1–48) 0.281
median (IQR)
Duration of lupus nephritis at biopsy, 2 (0.5–24) 1 (0.5–4) 0.019 1 (0.5–12) 1 (0.3–6) 0.204
months, median (IQR)
Hypertension 61 (61.6%) 56 (30.1%) <0.001 94 (45.6%) 23 (29.1%) 0.010
ACE-I or ARB 82 (82.8%) 129 (69.3%) 0.016 164 (79.6%) 47 (59.5%) 0.001
SLEDAI, median (IQR) 18 (14–24) 18 (14–22) 0.797 18 (14–22) 18 (14–22) 0.923
Laboratory variables
Serum creatinine, mg/dL, median (IQR) 1.33 (0.83–1.91) 0.79 (0.64–1.15) <0.001 1.04 (0.70–1.70) 0.71 (0.63–0.93) <0.001
eGFR (CKD-EPI equation), ml/min/1.73 56 (35–96) 105 (71–123) <0.001 79 (43–114) 111 (82–127) <0.001
m2, median (IQR)
Hemoglobin (g/dL), median (IQR) 9.9 (8.2–11.0) 10.6 (9.3–12.3) <0.001 10.2 (8.8–11.4) 11.0 (9.6–12.7) 0.002
Proteinuria gr/24-h, median (IQR) 3.20 (1.57–5.87) 2.04 (1.06–4.8) 0.089 2.98 (1.39–5.87) 1.81 (0.80–3.77) 0.004
Urine red blood cells per hfp, 10 (3–30) 6 (2–23) 0.066 10 (3–30) 5 (1–12) 0.027
median (IQR)
Urine leukocytes per hfp, 6 (0–12) 4 (1–10) 0.256 5 (1–12) 3 (0–10) 0.016
median (IQR)
NIH activity and chronicity indices
NIH Activity Index, median (IQR) 6 (3–9) 4 (1–7) 0.002 6 (3–9) 1 (0–4) <0.001
NIH Chronicity Index, median (IQR) 4 (3–5) 0 (0–1) <0.001 1 (0–3) 0 (0–1) <0.001

SD: Standard deviation; IQR: (75th percentile minus 25th percentile); ACE-I: angiotensin converting enzyme inhibitors; ARB: Angiotensin receptor
blocker; CKD-EPI = chronic kidney disease Epidemiology Collaboration; hfp: high-power field; SLEDAI: Systemic lupus erythematosus disease activity
Index; NIH: National Institutes of Health.
418 Lupus 32(3)

Figure 1. Prediction of renal survival by (1) International Society of Nephrology/Renal Pathology Society (ISN/RPS) (Class IV ± V LN and
non-class IV LN): (a) Kaplan–Meier curves and (b) competing-risk regression; (2) interstitial fibrosis and tubular atrophy severity
(IFTA) (moderate/severe IFTA and none/mild IFT): (c) Kaplan–Meier curves and (d) competing-risk regression; and (3) presence or
absence of fibrous crescents: (e) Kaplan–Meier curves and (f) competing-risk regression.

cellular crescents was not associated with worse kidney
survival neither in Kaplan–Meier method (p = 0.349) nor in
the competent risk analysis (p = 0.259).
Predictive factors of kidney survival in lupus nephritis
Cox proportional hazards regression analyses were per-
formed to identify independent predictors of ESKD in LN
patients (Table 4). Univariable analyses showed that
Mestizo ethnicity, eGFR, class IV ± V LN, and lack of
response to induction therapy were of borderline statistical
significance. By multivariable analysis, older age (HR 1.04,
95% CI 1.01–1.07; p = 0.032), and class IV ± V LN (HR
5.06, 95% CI 1.82–14.09, p = 0.002) were associated with
higher risk of ESKD after adjusting for sex, ethnicity, and
interstitial lesions (TII and IFTA).
After excluding those patients who died without having
developed ESKD, by multivariable competing-risk analysis,
class IV ± V LN (SHR 3.32, 95% CI 1.25–8.83, p = 0.016),
and lack of response to immunosuppressive therapy (SHR
4.55, 95% CI 1.54–13.41, p = 0.006) were associated with
higher risk of ESKD, while eGFR >90 mL/min/1.73 m2 (SHR
0.98 for each ml/min/1.73 m2, 95% 0.97–0.99; p < 0.001)
with a lower risk of ESKD (Table 4).
In additional exploratory multivariable Cox model in-
cluding only patients with LN class IV ± V (n = 144), neither
TII (HR 1.51; 95% CI 0.27–8.28; p = 0.638) nor IFTA (HR
1.25; 95% CI 0.56–2.83; p = 0.586) were found to be in-
dependent predictors of ESKD. By excluding IFTA from this
multivariate model, TII was not a predictor of ESKD either.
Risk categorization for kidney survival by
tubulointerstitial lesions
To see how TII and IFTA impact kidney survival, based on a
risk categorization model by Wilson et al.,11 patients were
Rodelo et al. 419

Table 4. Univariable and multivariable Cox proportional hazards regression and competing-risk analyses of predictive factors of end-
stage kidney disease in patients with lupus nephritis.

Cox proportional hazards regression model

Univariable analysis Multivariable analysis

Variable HR (95% CI) p Value HR (95% CI) p Value

Age at kidney biopsy 1.02 (0.99–1.05) 0.157 1.04 (1.01–1.07) 0.032

Male sex 1.36 (0.42–4.44) 0.610 3.39 (0.62–18.59) 0.160
Ethnicity
White Reference group
Afro-Colombian 0.48 (0.14–1.69) 0.253 0.85 (0.19–3.74) 0.833
Mestizo 0.37 (0.13–1.10) 0.074 0.31 (0.09–1.03) 0.055
eGFR > 90 mL/min/1.73 m2 0.99 (0.98–1.00) 0.080 1.00 (0.99–1.01) 0.502
SLEDAI at the time of biopsy 0.98 (0.95–1.02) 0.347
TII (present vs absent) 1.49 (0.46–4.83) 0.504 2.55 (0.71–9.14) 0.152
IFTA (present vs absent) 0.87 (0.49–1.53) 0.621 1.00 (0.49–2.06) 0.997
Class IV (±V) vs non-class IV LN 2.00 (0.97–4.14) 0.061 5.06 (1.82–14.09) 0.002
Immunosuppressive treatment
NIH high-dose regimen Reference group
MMF and steroids 0.85 (0.42–1.73) 0.663
CNI (CsA or TAC) and steroids 1.05 (0.46–2.38) 0.913
Treatment response
Complete remission Reference group
Partial remission 2.15 (0.59–7.75) 0.244 2.45(0.60–10.11) 0.214
No remission 2.98 (0.91–9.70) 0.070 2.82 (0.75–10.64) 0.127
Renal flare 1.04 (0.34–3.20) 0.942

Competing risk regression model

Univariable analysis Multivariable analysis

SHR (95% CI) p Value SHR (95% CI) p Value

Age at kidney biopsy 0.98 (0.96–1.00) 0.063 0.99 (0.96–1.02) 0.423

Male sex 0.42 (0.13–1.37) 0.149 0.37 (0.07–2.12) 0.267
Ethnicity
White Reference group
Afro-Colombian 1.39 (0.36–5.31) 0.633 2.11(0.71–6.29) 0.180
Mestizo 1.47 (0.48–4.50) 0.504 0.91 (0.39–2.11) 0.820
eGFR > 90 mL/min/1.73 m2 0.98 (0.97–0.99) <0.001 0.98 (0.97–0.99) <0.001
SLEDAI at the time of biopsy 0.98 (0.94–1.03) 0.469
TII (present vs absent) 0.43 (0.13–1.44) 0.170 0.61 (0.15–2.39) 0.477
IFTA (present vs absent) 0.46 (0.26–0.81) 0.007 0.72 (0.35–1.48) 0.368
Class IV (±V) vs non-class IV LN 3.51 (1.76–6.99) <0.001 3.32 (1.25–8.83) 0.016
Immunosuppressive treatment
NIH high-dose regimen Reference group
MMF and steroids 1.02 (0.52–1.98) 0.958 0.70 (0.30–1.60) 0.394
CNI (CsA or TAC) and steroids 2.17 (1.11–4.27) 0.024 1.25 (0.52–3.04) 0.619
Treatment response
Complete remission Reference group
Partial remission 3.76 (1.13–12.49) 0.031 2.61 (0.79–8.62) 0.116
No remission 3.75 (1.23–11.39) 0.020 4.55 (1.54–13.41) 0.006
Renal flare 1.53 (0.52–4.54) 0.440

eGFR: Estimated glomerular filtration rate; SLEDAI: Systemic lupus erythematosus disease activity Index; TII: tubulointerstitial inflammation; IFTA:
Interstitial fibrosis and tubular atrophy; NIH: National Institutes of Health; ISN/RPS: International Society of Nephrology/Renal pathology Society; MMF:
mycophenolate mofetil; CNI: Calcineurin inhibitors; CsA: Cyclosporine A; TAC: Tacrolimus.
420 Lupus 32(3)

Table 5. Risk categories for kidney survival and mortality according to the extent of tubulointerstitial inflammation and interstitial
fibrosis and tubular atrophy on kidney biopsy (n = 285); risk categorization model adapted from Wilson et al. (ref.11).

Green, low risk (n = 165, 10% RRT, 17% mortality); yellow, intermediate risk (n = 91, 26% RRT, 27% mortality); red, high risk (n = 29, 62% RRT, 34%
mortality). ESKD: end-stage kidney disease RRT: renal replacement therapy.

divided into three risk categories based on the histological
findings observed in renal biopsy: low risk (green):
TII <25% and IFTA <25%; intermediate risk (yellow):
TII ≥25–50% and IFTA ≥25–50%; and high risk
(red): TII ≥50% and IFTA ≥50%. Patients with less severe
tubulointerstitial lesions had the lowest risk of ESKD and
mortality (green category), while those with more severe
tubulointerstitial lesions had the highest risk of ESKD and
mortality (red category) (Table 5).
Discussion
Kidney biopsy is frequently used to evaluate the severity
and extent of renal involvement, to provide prognostic
information, and to guide the immunosuppressive therapy in
LN. However, its usefulness has been questioned since the
kidney prognosis is mainly based on the 2003 ISN/RPS
classification,6 which has a glomerulo-centric approach and
excludes tubulointerstitial lesions when these better predict
renal survival.8,11 In fact, discrepancies between the severity
of tubulointerstitial and vascular lesions and that of the
glomerular compartment have been observed in kidney
biopsies.21 Consistent with this observation, a negative
impact of tubulointerstitial involvement on kidney survival
has been reported in LN, regardless of the extent of glo-
merular damage.8–13,22,23 Both TII and IFTA independently
predict progression to ESKD, especially if these lesions are
more severe and extensive (≥50%).9,11,13 Therefore, grading
Rodelo et al.
these lesions is important, as it allows categorizing the risk
of ESKD as low, moderate, and high.11 We found that
patients with the most severe tubulointerstitial lesions,
particularly IFTA, are at the highest risk of progressing to
ESKD with 20.0% of the patients progressing to ESKD at a
median of 4.2 months after biopsy. This rapid progression to
ESKD could be explained because at the time of disease
diagnosis or admission to our nephrology unit, 41 (14.4%)
patients had rapidly progressive glomerulonephritis and
required hemodialysis.
In our study, tubulointerstitial lesions (TII and/or IFTA)
in LN were present in 215 (75.4%) biopsies, which is within
the range previously reported in other studies (39%–
100%).8,9,12,13,23–26 The 100% prevalence of TII (72.1%
severe and 27.9% mild TII) was reported by Hsieh et al. who
measured TII by CD45 staining, a more sensitive method,
but not readily available in clinical practice.8
Moderate-to-severe tubulointerstitial lesions were found
in 76 (26.7%) biopsies, with moderate-to-severe TII in 71
(24.9%) biopsies and moderate-to-severe IFTA in only 14
(4.9%). By Kaplan–Meier survival analysis, those with
moderate-to-severe IFTA, but not TII, had worse kidney
survival. Our findings are consistent with those reported by
Broder et al., who demonstrated by Kaplan–Meier survival
curves significantly different rates to ESKD progression
between moderate-to-severe tubulointerstitial damage,
compared to none or mild tubulointerstitial damage, while
no association between ESKD and moderate-to-severe TII
was found.13 In our study, 57.1% of patients with moderate-
to-severe IFTA also had moderate-to-severe TII, suggesting
that inflammation occurs early in the course of the disease
and subsequently leads to the development of fibrosis and
atrophy. As TII is potentially reversible, its early identification
can help identify high-risk patients who would benefit from
early immunosuppression before the development of irre-
versible scarring.8,12 When examining risk categories for renal
survival by tubulointerstitial lesions, patients with the highest
risk for ESKD had the most severe tubulointerstitial lesions. Of
the 29 patients in the high-risk group, 62% progressed to
ESKD, while of the 165 patients categorized as low risk, only
10% progressed to ESKD (Table 5). These findings are in line
with the observations reported by Wilson, et al.11 who found
that 53% of high-risk patients progressed to ESKD versus only
9% of low-risk patients.
We also observed worse kidney survival among patients
with glomerular fibrous crescents compared to those without,
in both the Kaplan–Meier survival and the competing risk
analyses. These findings highlight the role of chronicity, not
only in the glomerular compartment but also in the tubu-
lointerstitial compartment, as a critical factor in predicting
renal outcomes, as demonstrated by other authors.10,11,13,27
In logistic regression analyses, we found that IFTA was
associated with longer disease duration, hypertension, lower
eGFR, and lower hemoglobin levels. As expected, IFTA is
421
more likely to occur later in the course of the disease, while
TII occurs earlier. Similar to previous studies,9,10,28 IFTA
was associated with eGFR <56 mL/min/1.73 m2. Further-
more, we also confirmed the previously reported associa-
tions of IFTA with hypertension,9 and lower hemoglobin
concentrations.10 In our study, patients with IFTA had a
median hemoglobin of 9.9 g/dL, while a hemoglobin
value ≥10.6 g/dL was negatively associated with IFTA. A
decreased erythropoietin production as a result of tubu-
lointerstitial lesions is a major cause of anemia in these
patients, this being a risk factor for the progression of
kidney disease. In fact, in patients with biopsy-proven di-
abetic nephropathy, a higher IFTA score has been strongly
associated with lower hemoglobin levels.29
In this study we showed that older age and class IV ± V
LN were independently associated with higher risk of
ESKD. In addition, after excluding those patients who died
without having developed ESKD, lack of response to im-
munosuppressive therapy emerged as a predictor of ESKD
occurrence, while eGFR >90 mL/min/1.73 m2 was asso-
ciated with lower risk of ESKD and class IV ± V LN re-
mained independently associated with higher risk of ESKD.
These results confirm the worse renal prognosis often as-
sociated with LN with intracapillary hypercellularity.22,30,31
In fact, 26% of our patients with LN with intracapillary
hypercellularity progressed to ESKD and only 1 patient
with class V progressed to ESKD.
Contrary to expectations, neither IFTA nor TII were
associated with higher risk of ESKD in multivariate re-
gression analysis. The effect of IFTA on renal survival in
LN has been previously reported in several studies, in which
IFTA, particularly moderate or severe, was a strong pre-
dictor of ESKD.9–11,13,23 In our study, the low number of
biopsies [n = 14 (4.9%)] with moderate-to-severe IFTA, the
short duration of LN at the time of kidney biopsy [1.0
(0.5–10.0) month], and the short-term follow-up, a median
of 27.5 (1.1–63.4) months, after biopsy may explain the lack
of association of IFTA with higher risk of ESKD in the Cox
regression analyses. Furthermore, as moderate-to-severe
IFTA was found almost exclusively in patients with class
IV LN, its effect on renal survival may have been attenuated
by the effect of class IV LN, an independent predictor of
ESKD in our study. Therefore, we assessed collinearity
between IFTA and class IV LN obtaining a variance in-
flation factor (VIF) of 1.34 (default VIF cutoff value of 5),
which ruled out collinearity between these two variables.
However, as stated before, in the Kaplan–Meier survival
analysis those with moderate-to-severe IFTA had worse
kidney survival.
This study has several limitations. Due to its retrospective
design, some data could inevitably have been missing. In
addition, as this is a single-center cohort study of a mostly
Mestizo population, its findings are not generalizable to other
populations. The relative short-term follow-up after biopsy,
422
may have limited the identification of other predictors of
kidney outcome. Given that there was some heterogeneity in
the treatment, this may have influenced the associations be-
tween histological findings and kidney outcomes.
Despite these limitations, the current study has some
strengths. The large number of biopsies makes it the largest
single-center Latin American study addressing tubu-
lointerstitial lesions in LN. Cumulative incidence functions
for ESKD after biopsy were also estimated accounting for
competing risk of death. All the biopsies included in this
study were evaluated by two experienced nephropatholo-
gists who reported the degree of tubulointerstitial in-
volvement for every biopsy. To the best of our knowledge,
the prognostic value of tubulointerstitial lesions has not
been examined in Latin American patients with SLE.
In conclusion, we have shown that in a mostly Mestizo
Latin American population, patients with moderate-to-
severe IFTA had worse kidney survival than those with
none or mild IFTA. Patients with glomerular lesions (class
IV LN and fibrous crescents) also had worse kidney sur-
vival. Notably, the presence of chronic glomerular and
tubulointerstitial lesions early in the course of the disease
provides an essential window for potential early therapeutic
interventions. In view of this, a detailed renal biopsy
evaluation is always mandatory.
Declaration of conflicting interests
The author(s) declared no potential conflicts of interest with re-
spect to the research, authorship, and/or publication of this article.
Funding
The author(s) received no financial support for the research, au-
thorship, and/or publication of this article.
Data availability
Clinical data can be made available upon request.
ORCID iD
Luis Alonso González  https://orcid.org/0000-0002-6523-3919
Supplemental Material
Supplementary material for this article is available on the online.
References
1. Parikh SV, Almaani S, Brodsky S, et al. Update on lupus
nephritis: core curriculum 2020. Am J Kidney Dis 2020; 76:
265–281.
2. Mahajan A, Amelio J, Gairy K, et al. Systemic lupus er-
ythematosus, lupus nephritis and end-stage renal disease: a
Lupus 32(3)
pragmatic review mapping disease severity and progression.
Lupus 2020; 29: 1011–1020.
3. Tektonidou MG, Dasgupta A and Ward MM. Risk of end-
stage renal disease in patients with lupus nephritis, 1971-
2015: a systematic review and Bayesian meta-analysis.
Arthritis Rheumatol 2016; 68: 1432–1441.
4. González LA, Ugarte-Gil MF and Alarcón GS. Systemic
lupus erythematosus: the search for the ideal biomarker.
Lupus 2021; 30: 181–203.
5. Ayoub I, Cassol C, Almaani S, et al. The kidney biopsy in
systemic lupus erythematosus: a view of the past and a vision
of the future. Adv Chronic Kidney Dis 2019; 26: 360–368.
6. Weening JJ, D’Agati VD, Schwartz MM, et al. The classi-
fication of glomerulonephritis in systemic lupus eryth-
ematosus revisited. J Am Soc Nephrol 2004; 15: 241–250.
7. Bajema IM, Wilhelmus S, Alpers CE, et al. Revision of the
international society of nephrology/renal pathology society
classification for lupus nephritis: clarification of definitions,
and modified national institutes of health activity and chro-
nicity indices. Kidney Int 2018; 93: 789–796.
8. Hsieh C, Chang A, Brandt D, et al. Predicting outcomes of
lupus nephritis with tubulointerstitial inflammation and
scarring. Arthritis Care Res (Hoboken) 2011; 63: 865–874.
9. Gomes MF, Mardones C, Xipell M, et al. The extent of tu-
bulointerstitial inflammation is an independent predictor of
renal survival in lupus nephritis. J Nephrol 2021; 34:
1897–1905.
10. Leatherwood C, Speyer CB, Feldman CH, et al. Clinical
characteristics and renal prognosis associated with interstitial
fibrosis and tubular atrophy (IFTA) and vascular injury in
lupus nephritis biopsies. Semin Arthritis Rheum 2019; 49:
396–404.
11. Wilson PC, Kashgarian M and Moeckel G. Interstitial inflam-
mation and interstitial fibrosis and tubular atrophy predict renal
survival in lupus nephritis. Clin Kidney J 2018; 11: 207–218.
12. Alsuwaida AO. Interstitial inflammation and long-term renal
outcomes in lupus nephritis. Lupus 2013; 22: 1446–1454.
13. Broder A, Mowrey WB, Khan HN, et al. Tubulointerstitial
damage predicts end stage renal disease in lupus nephritis
with preserved to moderately impaired renal function: a
retrospective cohort study. Semin Arthritis Rheum 2018; 47:
545–551.
14. Hochberg MC. Updating the American College of Rheu-
matology revised criteria for the classification of systemic
lupus erythematosus. Arthritis Rheum 1997; 40: 1725.
15. Petri M, Orbai AM, Alarcón GS, et al. Derivation and val-
idation of the systemic lupus international collaborating
clinics classification criteria for systemic lupus eryth-
ematosus. Arthritis Rheum 2012; 64: 2677–2686.
16. Bombardier C, Gladman DD, Urowitz MB, et al. Derivation
of the SLEDAI. A disease activity index for lupus patients.
The committee on prognosis studies in SLE. Arthritis Rheum
1992; 35: 630–640.
Rodelo et al.
17. Levey AS, Stevens LA, Schmid CH, et al. CKD-EPI (chronic
kidney disease epidemiology collaboration). A new equation
to estimate glomerular filtration rate. Ann Intern Med 2009;
150: 604–612.
18. (KDIGO) CKD Work Group. KDIGO 2012 clinical practice
guideline for the evaluation and management of chronic
kidney disease. Kidney Int Suppl 2013; 3: 1–150.
19. Kidney Disease: Improving Global Outcomes (KDIGO) Glo-
merulonephritis Work Group. KDIGO clinical practice guideline
for glomerulonephritis. Kidney Int Suppl 2012; 2: 139–274.
20. Fine JP and Gray RJ. A proportional hazards model for the sub-
distribution of a competing risk. J Am Stat Assoc 1999; 94: 496–509.
21. Obrişcă B, Vornicu A, Procop A, et al. A histology-guided
approach to the management of patients with lupus nephritis:
are we there yet? Biomedicines 2022; 10(6): 1409.
22. Obrişcă B, Jurubiță R, Andronesi A, et al. Histological
predictors of renal outcome in lupus nephritis: the importance
of tubulointerstitial lesions and scoring of glomerular lesions.
Lupus 2018; 27: 1455–1463.
23. Yu F, Wu LH, Tan Y, et al. Tubulointerstitial lesions of pa-
tients with lupus nephritis classified by the 2003 international
society of nephrology and renal pathology society system.
Kidney Int 2010; 77: 820–829.
24. O’Dell JR, Hays RC, Guggenheim SJ, et al. Tubulointerstitial
renal disease in systemic lupus erythematosus. Arch Intern
Med 1985; 145: 1996–1999.
423
25. Alexopoulos E, Seron D, Hartley RB, et al. Lupus nephritis:
correlation of interstitial cells with glomerular function.
Kidney Int 1990; 37: 100–109.
26. Rijnink EC, Teng YKO, Wilhelmus S, et al. Clinical and
histopathologic characteristics associated with renal out-
comes in lupus nephritis. Clin J Am Soc Nephrol 2017; 12:
734–743.
27. Hiramatsu N, Kuroiwa T, Ikeuchi H, et al. Revised classi-
fication of lupus nephritis is valuable in predicting renal
outcome with an indication of the proportion of glomeruli
affected by chronic lesions. Rheumatology (Oxford) 2008;
47: 702–707.
28. Londoño Jimenez A, Mowrey WB, Putterman C, et al. Brief
report: tubulointerstitial damage in lupus nephritis: a com-
parison of the factors associated with tubulointerstitial in-
flammation and renal scarring. Arthritis Rheumatol 2018; 70:
1801–1806.
29. Mise K, Hoshino J, Ueno T, et al. Impact of tubulointerstitial
lesions on anaemia in patients with biopsy-proven diabetic
nephropathy. Diabet Med 2015; 32: 546–555.
30. Gasparotto M, Gatto M, Binda V, et al. Lupus nephritis:
clinical presentations and outcomes in the 21st century.
Rheumatology (Oxford) 2020; 59(Suppl5): v39–v51.
31. Wang H, Ren YL, Chang J, et al. A systematic review and
meta-analysis of prevalence of biopsy-proven lupus nephritis.
Arch Rheumatol 2017; 33: 17–25.