Nephrol Dial Transplant (2022) 37: 876–886

doi: 10.1093/ndt/gfab030
Advance Access publication 9 February 2021

Tubulointerstitial nephritis and uveitis syndrome: a systematic

ORIGINAL ARTICLE

review

Alessia Regusci1, Sebastiano A.G. Lava2, Gregorio P. Milani3,4, Mario G. Bianchetti5, Giacomo D.
Simonetti1,5 and Federica Vanoni 1

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1
Pediatric Institute of Southern Switzerland, Ente Ospedaliero Cantonale, Bellinzona, Switzerland, 2Pediatric Cardiology Unit, Department of
Pediatrics, Centre Hospitalier Universitaire Vaudois, University of Lausanne, Lausanne, Switzerland, 3Pediatric Unit, Fondazione IRCCS Ca‘
Granda Ospedale Maggiore Policlinico Milan, Italy, 4Department of Clinical Sciences and Community Health, Università degli Studi di Milano,
Milan, Italy, 5Faculty of Biomedical Sciences, University of Southern Switzerland, Lugano, Switzerland

Correspondence to: Federica Vanoni; E-mail: federica.vanoni@eoc.ch

ABSTRACT occurrence of tubulointerstitial nephritis (TIN) and uveitis in

Background. Tubulointerstitial nephritis and uveitis (TINU)
syndrome is defined as the occurrence of tubulointerstitial ne-
phritis (TIN) and uveitis in the absence of other systemic dis-
eases. The most comprehensive review on this condition was
published in 2001.
Methods. We conducted a systematic review of the literature
for cases of TINU syndrome. MEDLINE and Embase databases
were screened. Full-length articles or letters reporting cases with
both TIN and uveitis were selected. We investigated differences
between males and females and paediatric and adult cases.
Multivariate analysis was performed to identify potential risk
factors for chronic kidney disease (CKD) development.
Results. A total of 233 articles reporting 592 TINU cases were
retained for the analysis. The median age of the included sub-
jects was 17 years (interquartile range 13–46) with a female pre-
dominance (65%). Uveitis most frequently (52%) followed renal
disease and was mostly anterior (65%) and bilateral (88%).
Children tended to have more ocular relapses, while they were
slightly less likely than adults to suffer from acute kidney injury
and to develop CKD. Adult age as well as posterior or panuveitis
were associated with an increased risk of developing CKD.
Conclusions. TINU affects both children and adults, with some
differences between these two categories. Adult age and the
presence of a posterior uveitis or panuveitis appear to be associ-
ated with the development of CKD.
Keywords: systematic review, TINU, tubulointerstitial nephri-
tis, uveitis
INTRODUCTION
As first described in 1975 by Dobrin et al. [1], tubulointerstitial
nephritis and uveitis (TINU) syndrome is defined as the
the absence of other systemic diseases. It is therefore a diagnosis
of exclusion [1, 2].
The most comprehensive review to date, published almost
20 years ago, identified 133 cases [2]. In recent years there has
been an increased awareness of this disease and several case
reports and case series have been published. In an effort to bet-
ter characterize this disease, we performed a systematic review.
MATERIALS AND METHODS
Search strategy
A computer-based search of MEDLINE and Embase was
performed. Pertinent secondary references were also screened.
The principles advised by the Economic and Social Research
Council guidance on the conduct of narrative synthesis and on
the Preferred Reporting Items for Systematic Reviews and
Meta-Analyses (PRISMA) were applied [3]. Articles published
from inception to 31 March 2020 were considered. The search
terms were ‘TINU’ OR ‘TINU syndrome’ OR
(‘Tubulointerstitial nephritis’ AND ‘uveitis syndrome’) OR
(‘Tubulointerstitial nephritis’ AND ‘uveitis’) and ‘Dobrin
syndrome’. Reports published in languages other than Dutch,
English, French, German, Italian, Portuguese or Spanish were
excluded.
Criteria for study selection
For the final analysis, full-length articles or letters reporting
cases with both TIN and uveitis were selected. Cases of TINU
were defined according to the authors’ diagnosis. The criteria
proposed by the Kidney Disease: Improving Global Outcomes
(KDIGO) Work Group were applied to define acute kidney

C The Author(s) 2021. Published by Oxford University Press on behalf of the ERA-EDTA. All rights reserved.
V
KEY LEARNING POINTS

What is already known about this subject?

• Tubulointerstitial nephritis and uveitis (TINU) syndrome is a multisystemic autoimmune disorder that may occur in
response to various environmental triggers, including drugs and microbial pathogens.
• It is assumed that this condition typically affects adolescents and young adults with a female predominance.
• The renal prognosis is often good, whereas ocular involvement tends to recur and can lead to visual impairment.
What this study adds?
• This is the largest systematic review of TINU syndrome, including >500 cases.
• This condition affects both children and adults, with a female predominance in adults.
• Ocular relapses are more frequent in children, while acute kidney injury and chronic kidney disease (CKD) are more
frequent in adults.

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• Posterior or panuveitis as well as adult age are associated with an increased risk of developing CKD.
What impact this may have on practice or policy?
• TINU patients may have a different risk of poor renal outcome and complicated evolution on the basis of their age
and pattern of ocular involvement.
• Prospective studies are needed to better define risk factors and propose personalized care.

injury and chronic renal failure was defined according to
KDIGO guidelines [4, 5]. We excluded those cases in which
uveitis or interstitial nephritis was secondary to other condi-
tions and cases in which demographic data (age and sex) were
missing. If two reports described the same case, we considered
only the more detailed publication. The literature search and ar-
ticle selection were conducted independently by two authors
(A.R. and F.V.) who separately evaluated each article for eligi-
bility. Incongruent results were resolved by consensus. When
consensus could not be reached, a third senior researcher
(S.A.G.L.) adjudicated the decision.
Data extraction and analysis
Data were extracted independently by two authors (A.R. and
F.V.) using standardized, piloted forms prepared in advance
and collected into a dedicated database. The following data
were retained: age at diagnosis, sex, type and localization of uve-
itis, triggering factors, ocular symptoms (visual loss, blurred vi-
sion, ocular pain or redness, photophobia), onset of uveitis with
respect to TIN development, systemic symptoms or complica-
tions (including fever, weight loss, fatigue and arterial hyperten-
sion), treatment(s), length of follow-up and clinical outcome. In
addition, the following laboratory values were considered: cre-
atinine, urea, C-reactive protein, erythrocyte sedimentation
rate, white blood cell count, haemoglobin, urinalysis, b2-micro-
globin, gammaglobulin, C3, C4, antinuclear antibodies (ANAs),
anti-neutrophil cytoplasmic antibodies (ANCAs) and renal
biopsy.
The development of TIN and uveitis was considered con-
comitant if the interval between their respective onset was
<3 weeks. If this information was not given, we retained the
author’s definition as provided in the text.
Statistics
The Cohen’s j coefficient was used to assess the agreement
between investigators for study inclusion and exclusion. The
results are summarized either as the median and interquartile
range (IQR) or absolute number and frequency, as appropriate.
To investigate differences between paediatric and adult
cases, we separately considered subjects who were <18 and
18 years of age.
Fisher’s exact test and the Kruskal–Wallis test (with the
Bonferroni test adjustment for multiple comparisons) were
used to compare categorical and continuous data, respectively.
To identify potential risk factors for chronic kidney disease
(CKD) development, we exclusively considered cases with a
follow-up of at least 6 months and reported data on circulating
creatinine levels both at baseline and follow-up. Odds ratios
(ORs) of CKD and corresponding 95% confidence intervals
(CIs) from multiple logistic regression models were calculated
for the following variables: age at onset (continuous variable),
sex (female versus male), detection of ANA/ANCA (presence
versus absence), uveitis localization (anterior versus other local-
izations), occurrence of monolateral uveitis (versus bilateral
uveitis), temporal relationship between uveitis and renal in-
volvement (concurrent versus ocular involvement as the first
manifestation versus renal involvement as the first

TINU syndrome: systematic review 877

manifestation), presence of hypergammaglobulinaemia (yes/
Records identified Records identified
no), ocular relapse (yes/no) and renal relapse (yes/no). The through search in the through search in the
Akaike information criterion was used to select the best multi- Medline database EMBASE database
ple model. Missing data were managed by pairwise deletion. (N=308) (N=473)

Statistical significance was assumed for P-values <0.05.

RESULTS
Records screened after
Search results duplicates removed (N=567)

The literature search process is depicted in Figure 1. The full

Records excluded (N=311)
text of 256 articles was obtained and assessed in detail and 233 • Not pertaining (n=151)
articles [1, 6–238] were retained for final analysis, including 108 • Review (n=42)
from Europe, 70 from Asia, 33 from North America, 8 from • Language (n=62)
• Comments/letters (n=29)
Central and South America, 8 from Africa and 6 from Oceania. • Supplementary duplicates (n=18)

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The reports were published in English (n ¼ 187), French • No abstract available (n=9)
(n ¼ 19), Spanish (n ¼ 15) and German (n ¼ 12). The Cohen’s
j coefficient between investigators on the application of inclu- Full-text assessed in detail
sion and exclusion criteria was 0.87. for eligibility (N=256)

Demographic, clinical and laboratory data

Records excluded (N=26)
We identified 592 patients (female:male ratio 1.8) with a me- • Not sufficiently well
dian age of 17 years (IQR 13–46). In total, 384 (65%) were described (n=11)
• Lack of demographic
females and 301 (51%) were <18 years of age. Uveitis was ante- data (n=15)
rior in 382 (65%) cases and bilateral in 440 (88%) cases. The on-
set of uveitis occurred more frequently after renal disease
Secondary references (N=3)
(Table 1). The following systemic symptoms or complications
were reported: fatigue (n ¼ 291/314), weight loss (n ¼ 219/251),
Full-text articles included (N=233)
fever (n ¼ 212/301) and arterial hypertension (n ¼ 45/188).
Ocular symptoms were detailed in 339 cases (57%), including
FIGURE 1: PRISMA flowchart for study selection.
ocular pain (n ¼ 168), conjunctival injection (n ¼ 155), blurred
vision (n ¼ 87), visual loss (n ¼ 83) and photophobia (n ¼ 82).
Clinical and laboratory characteristics are reported in Table 1.

Treatments
A total of 522 patients received steroids as first-line therapy:
topical in 356 cases and systemic in 448 cases. A second-line
therapy was reported in 108 patients. Of these, 90 patients were
prescribed single or multiple immunosuppressive agents, in-
cluding methotrexate (n ¼ 32), mycophenolate (n ¼ 30), cyclo-
sporine (n ¼ 19), azathioprine (n ¼ 16), cyclophosphamide
(n ¼ 6), chlorambucil (n ¼ 5) and other drugs (n ¼ 17).
Eighteen (n ¼ 18) patients required haemodialysis. Eleven
(n ¼ 11) patients did not receive any therapy (Supplementary
data, Table S2). The need for second-line therapy did not ap-
pear to be associated with the development of CKD at follow-
up. In fact, of the 108 patients receiving second-line treatment,
only 13 (12%) developed CKD. Similarly, among 409 patients
not receiving second-line treatments, 82 (20%) further devel-
oped CKD (P ¼ 0.0686 versus patients not developing CKD).

Univariate analysis
TIN preceded uveitis more often in children (52%) com-
pared with adults (37%; P < 0.001) (Table 2). Ocular relapse oc-
curred more frequently in children (56%) compared with adults
(45%; P ¼ 0.03). On the other hand, CKD (P < 0.001) was more
frequent among adults (37%) than children (11%). Acute kid-
ney injury (P < 0.001) was slightly less frequent among children
FIGURE 2: (A) Fundus examination of the left eye in a 13-year-old
boy affected by TINU. The picture shows papilloedema and venous
turgor. (B) Optical coherence tomography shows oedema of the
nerve fibre with extension towards the fovea of the left eye of a
13-year-old boy with detachment of the sensorineural retina at the
subfoveal site.

878 A. Regusci et al.

Table 1. Demographic, clinical and laboratory data

Characteristics N Values
Gender (male:female), n (%) 592 208 (35):384 (65)
Age (years), median (IQR) 592 17 (13–46)
Trigger(s) for TINUa, n (%) 352
None 223 (63)
Drugs 72 (21)
Infection 22 (6)
Toxic agent 23 (7)
More than one possible trigger 12 (3)
Uveitis, n (%) 592
Anterior 382 (65)
Posterior 13 (2.2)
Intermediate 29 (4.9)
Panuveitis 62 (10)
Not specified 106 (18)

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Uveitis (unilateral:bilateral), n (%) 500 60 (12):440 (88)
Uveitis onset, n (%) 480
Before renal involvement 90 (19)
Concurrent renal involvement 142 (29)
After renal involvement 248 (52)
Acute renal failure, n (%) 421 392 (93)
Urinary abnormalities, n (%)
Proteinuria 402 349(93)
Leucocituria 250 210 (59)
Microscopic haematuria 201 138 (84)
Glycosuria 280 229 (82)
Hypergammaglobulinaemia, n (%) 204 112 (55)
Autoantibodiesb, n (%) 314 46 (15)
Renal biopsy, n (%)
Consistent with tubulointerstitial nephritis 485 485 (100)
Length of follow-up 413
Months, median (IQR) 18 (10–28)
Ocular relapse(s), n (%) 207 (50)
Renal relapse(s), n (%) 54 (15)
CKD, n (%) 102 (25)
a
Full details and references in Supplementary Table 1.
b
ANAs and/or ANCAs.

(87%) than adults (98%). Children [n ¼ 4 (1.3%)] were less fre-
quently (P ¼ 0.02) treated with dialysis than adults [n ¼ 14
(7.0%)]. No significant differences were detected with respect to
uveitis characteristics, rate of renal relapse or triggering factors.
Sex comparisons revealed that females (median 26, IQR ¼
14–49 years) were older than males (median 15, IQR ¼ 12.6–
30 years) at the age of diagnosis (Table 3). No differences in the
characteristics of uveitis, time onset of nephritis with respect to
uveitis, rate of acute and chronic renal failure or rate of
ocular and renal relapses were detected when comparing males
and females.
Multiple logistic regression analysis
Data from 254 subjects (138 studies) met the criteria for
multiple logistic regression analysis. In the final selected model,
age at onset [OR 1.07 (95% CI 1.04–1.10)] was associated with
an increased risk of CKD development, whereas the develop-
ment of (only) anterior uveitis [OR 0.06 (95% CI 0.01–0.31)]
was associated with a decreased risk (Table 4).
DISCUSSION
According to the most recent systematic review on TINU syn-
drome, including ~600 cases, TINU syndrome is both a paedi-
atric and an adult disease. Children tend to have more ocular
relapses and are slightly less likely to develop acute kidney in-
jury than adults. Adults more frequently develop CKD. Finally,
adult age and uveitis not being anterior (i.e. posterior uveitis or
panuveitis) (Figure 3) are associated with an increased risk of
developing CKD.
This review confirms the known female predominance,
which appears to be more striking in adult ages (55% females in
the paediatric age, 76% among adults). This finding is not sur-
prising. In fact, TINU syndrome is a multisystemic, presumably
autoimmune disorder. It is well known that autoimmune dis-
eases occur more frequently in females. Oestrogens act as
enhancers of humoral immunity and testosterone and proges-
terone act as natural immunosuppressants [239]. Women have
increased immune reactivity with higher immunoglobulin lev-
els and higher antibody production. This feature may also ex-
plain the increased frequency of autoantibodies (ANAs/
ANCAs) in females.

TINU syndrome: systematic review 879

Table 2. Univariate analysis by age

Characteristics <18 years 18 years P-value

n 301 291
Gender (female), n (%) 164 (55) 220 (76) <0.001
Trigger for TINU, n (%) 0.35
None 143 (66) 80 (58)
Drugs 43 (20) 29 (21)
Infection 12 (6) 10 (7)
Toxic agent 10 (5) 13 (10)
More than one possible trigger 7 (3) 5 (4)
Uveitis, n (%) 0.12
Anterior 205 (68) 177 (61)
Posterior 3 (1) 10 (3)
Intermediate 11 (4) 18 (6)
Panuveitis 31 (10) 31 (11)
Not specified 51 (17) 55 (19)

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Uveitis (unilateral:bilateral), n (%) 21 (9):226 (91) 39 (15):214 (85) 0.04
Urinary abnormalities, n (%)
Proteinuria 166 (88) 183 (86) 0.46
Leucocituria 77 (80) 133 (86) 0.22
Microscopic haematuria 63 (63) 75 (74) 0.09
Glycosuria 127 (85) 102 (78) 0.12
Hypergammaglobulinaemia, n (%) 57 (68) 55 (46) 0.003
Autoantibodiesa, n (%) 24 (15) 21 (13) 0.63
Uveitis onset, n (%) 301 291 0.001
Before renal involvement 33 (11) 57 (20)
Concurrent with renal 69 (23) 73 (25)
involvement
After renal involvement 143 (47) 105 (36)
Not specified 56 (19) 56 (19)
Acute kidney injury 174 (87) 218 (98) <0.001
Length of follow-up (months), 18 (7.0–32) 19 (12–24) 0.81
median (IQR)
CKD, n (%) 22 (11) 80 (37) <0.001
Ocular relapse(s), n (%) 103 (56) 104 (45) 0.03
Renal relapse(s), n (%) 22 (15) 32 (14.7) 0.8
Statistically significant values in bold.
a
ANAs and/or ANCAs.

This analysis shows that adults develop kidney injury and
CKD more frequently than children. These findings are consis-
tent with data reported by Legendre et al. [120] and Mackensen
et al. [131]. Some authors suggest a high-risk correlation between
changes in the first renal biopsy (such as tubular atrophy) and
permanent renal dysfunction [91]. We hypothesize that in adults
the kidneys are partially premorbid, depending on the lifestyle
and comorbidities (i.e. hypertension, hypercholesterolemia, over-
weight) with reduced functional reserve. Therefore, when a fur-
ther insult occurs (such as TIN), kidneys are more severely
affected than in otherwise healthy children. However, at present
we do not have sufficient data to confirm this hypothesis.
This review confirmed that TIN often precedes uveitis, as
noted in previous studies [2, 131, 181]. Interestingly, subgroup
analysis revealed that in children, uveitis is diagnosed more fre-
quently after TIN (Figure 3). This may be because uveitis is of-
ten asymptomatic [91, 181] and children often do not complain
about ocular symptoms, such as decreased vision. It is therefore
not surprising that in children, ophthalmological investigations
are only performed after diagnosing nephritis, thereby unravel-
ling uveitis.
Children seem to have a more severe course of uveitis with
more frequent relapses. There is no clear pathophysiological ex-
planation for the increased relapse and possibly chronic course
of ocular disease in children. It is recognized that difficult and
not optimal compliance with topical treatment in ocular dis-
eases, especially in adolescents, is frequent [240, 241]. On the
other hand, as previously discussed, children may not complain
about ocular symptoms, which could lead to a delay in diagno-
sis [242] and therapy, eventually resulting in a more severe
course.
Adult age is a potential risk factor for CKD development.
On the other hand, the presence of anterior uveitis alone was
less frequently associated with CKD. In contrast, Legendre et al.
[120] and Mackensen et al. [131] reported that the courses of
uveitis and nephritis were not related. This discrepancy might
be explained by the small number of patients included in those
studies. The present findings indeed suggest the need for the
closest follow-up for patients developing uveitis beyond the an-
terior chamber who might also require a more aggressive treat-
ment. This hypothesis should be confirmed in well-designed
prospective studies.

880 A. Regusci et al.

Table 3. Univariate analysis by sex

Characteristics Male Female P-value

n 208 384
Age (years), median (IQR) 15 (13–30) 26 (14–49) <0.001
Trigger for TINU, n (%) 0.12
None 80 (67) 143 (61)
Drugs 22 (18) 50 (22)
Infection 3 (3) 19 (8)
Toxic agent 11 (9) 12 (5)
More than one possible trigger 3 (3) 9 (4)
Uveitis, n (%) 0.22
Anterior 128 (63) 254 (65)
Posterior 3 (1) 10 (3)
Intermediate 11 (5) 18 (5)
Panuveitis 28 (14) 34 (9)
Not specified 34 (17) 72 (18)

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Uveitis (unilateral:bilateral), n (%) 17 (10):155 (90) 43 (13):285 (87) 0.46
Urinary abnormalities, n (%)
Proteinuria 109 (87) 240 (87) 1.00
Leucocituria 51 (77) 159 (86) 0.12
Microscopic haematuria 40 (69) 98 (69) 1.00
Glicosuria 69 (79) 160 (83) 0.51
Hypergammaglobulinaemia, n (%)
Autoantibodiesa, n (%) 10 (8.5) 35 (17) 0.045
Uveitis onset, n (%) 184 384 0.21
Before renal involvement 29 (16) 61 (16)
Concurrent with renal 56 (30) 86 (23)
involvement
After renal involvement 78 (42) 170 (44)
Not specified 21 (12) 67(17)
Acute kidney injury, n (%) 124 (95) 268 (92) 0.53
Length of follow-up (months), 18 (7.5–29.5) 18 (12–28) 0.77
median (IQR)
CKD, n (%) 29 (23) 73 (26) 0.54
Ocular relapse(s), n (%) 67 (50) 140 (50) 1.00
Renal relapse(s), n (%) 14 (13) 40 (16) 0.52
Statistically significant values in bold.
a
ANAs and/or ANCAs.

Table 4. Selected model for the multivariate analysis

Model OR (95% CI) P-value

Age (years) 1.07 (1.04–1.10) <0.00001
Anterior uveitis 0.06 (0.01–0.31) 0.0007
Hypergammaglobulinaemia 3.46 (1.38–13.00) 0.06
Statistically significant values in bold.

The current work has some strengths and limitations.

The large number of identified cases allowed us to perform
some subgroup analyses and to identify possible risk factors
for the development of long-term complications, in particu-
lar CKD.
However, this analysis is based on data reported by different,
partially heterogeneous studies. Furthermore, the identification
of risk factors was attempted by a retrospective analysis, which
represents a preliminary, explorative approach that needs to be
confirmed in prospective, well-designed studies. Finally, consid-
ering that most papers were case reports or small case series, it
was not possible to perform a meta-analysis.
In conclusion, this study notes that TINU affects both
children and adults, with some differences between these two
FIGURE 3: TIN with interstitial lymphocytes and occasional plasma
cells (haematoxylin and eosin stain).
categories. Adult age and the presence of uveitis involving the
posterior segments appear to be the risk factors for the devel-
opment of CKD. Future prospective studies are needed to
better investigate risk factors and potentially personalized
care.
SUPPLEMENTARY DATA
Supplementary data are available at ndt online.

TINU syndrome: systematic review 881

FUNDING
Not applicable.
AUTHORS’ CONTRIBUTIONS
S.A.G.L., G.D.S. and M.G.B. conceptualized and designed the
study. A.R. and F.V. collected the data, carried out the initial
analyses, drafted the initial manuscript and revised the manu-
script. G.P.M. was responsible for statistical analysis. G.P.M.,
S.A.G.L., F.V. and G.D.S. contributed to data analysis and inter-
pretation, drafted the initial manuscript and revised the manu-
script. All authors approved the final manuscript as submitted
and agree to be accountable for all aspects of the work.
CONFLICT OF INTEREST STATEMENT
The authors declare that they have no conflicts of interest.
DATA AVAILABILITY STATEMENT
A database of the included studies is available upon reasonable
request from the corresponding author.
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Received: 23.9.2020; Editorial decision: 22.1.2021
A. Regusci et al.