Tubulointerstitial nephritis and uveitis syndrome: a systematic review

Abstract

Background

Tubulointerstitial nephritis and uveitis (TINU) syndrome is defined as the occurrence of tubulointerstitial nephritis (TIN) and uveitis in the absence of other systemic diseases. 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 subjects was 17 years (interquartile range 13–46) with a female predominance (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 associated with the development of CKD.

systematic review, TINU, tubulointerstitial nephritis, uveitis

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.

• 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.

INTRODUCTION

As first described in 1975 by Dobrin et al. [1], tubulointerstitial nephritis and uveitis (TINU) syndrome is defined as the occurrence of tubulointerstitial nephritis (TIN) and uveitis in 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 better 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 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 conditions 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 article selection were conducted independently by two authors (A.R. and F.V.) who separately evaluated each article for eligibility. 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 uveitis, triggering factors, ocular symptoms (visual loss, blurred vision, ocular pain or redness, photophobia), onset of uveitis with respect to TIN development, systemic symptoms or complications (including fever, weight loss, fatigue and arterial hypertension), treatment(s), length of follow-up and clinical outcome. In addition, the following laboratory values were considered: creatinine, urea, C-reactive protein, erythrocyte sedimentation rate, white blood cell count, haemoglobin, urinalysis, β2-microglobin, gammaglobulin, C3, C4, antinuclear antibodies (ANAs), anti-neutrophil cytoplasmic antibodies (ANCAs) and renal biopsy.

The development of TIN and uveitis was considered concomitant 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 κ 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 localizations), occurrence of monolateral uveitis (versus bilateral uveitis), temporal relationship between uveitis and renal involvement (concurrent versus ocular involvement as the first manifestation versus renal involvement as the first manifestation), presence of hypergammaglobulinaemia (yes/no), ocular relapse (yes/no) and renal relapse (yes/no). The Akaike information criterion was used to select the best multiple model. Missing data were managed by pairwise deletion. Statistical significance was assumed for P-values <0.05.

RESULTS

Search results

The literature search process is depicted in Figure 1. The full text of 256 articles was obtained and assessed in detail and 233 articles [1, 6–238] were retained for final analysis, including 108 from Europe, 70 from Asia, 33 from North America, 8 from Central and South America, 8 from Africa and 6 from Oceania. The reports were published in English (n = 187), French (n = 19), Spanish (n = 15) and German (n = 12). The Cohen’s κ coefficient between investigators on the application of inclusion and exclusion criteria was 0.87.

FIGURE 1

PRISMA flowchart for study selection.

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.

Demographic, clinical and laboratory data

We identified 592 patients (female:male ratio 1.8) with a median age of 17 years (IQR 13–46). In total, 384 (65%) were females and 301 (51%) were <18 years of age. Uveitis was anterior in 382 (65%) cases and bilateral in 440 (88%) cases. The onset of uveitis occurred more frequently after renal disease (Table 1). The following systemic symptoms or complications were reported: fatigue (n = 291/314), weight loss (n = 219/251), fever (n = 212/301) and arterial hypertension (n = 45/188). Ocular symptoms were detailed in 339 cases (57%), including ocular pain (n = 168), conjunctival injection (n = 155), blurred vision (n = 87), visual loss (n = 83) and photophobia (n = 82). Clinical and laboratory characteristics are reported in Table 1.

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)
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. ^bANAs and/or ANCAs.

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, including methotrexate (n = 32), mycophenolate (n = 30), cyclosporine (n = 19), azathioprine (n = 16), cyclophosphamide (n = 6), chlorambucil (n = 5) and other drugs (n = 17). Eighteen (n = 18) patients required haemodialysis. Eleven (n = 11) patients did not receive any therapy (Supplementary data, Table S2). The need for second-line therapy did not appear 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 developed CKD (P = 0.0686 versus patients not developing CKD).

Univariate analysis

TIN preceded uveitis more often in children (52%) compared with adults (37%; P < 0.001) (Table 2). Ocular relapse occurred more frequently in children (56%) compared with adults (45%; P = 0.03). On the other hand, CKD (P < 0.001) was more frequent among adults (37%) than children (11%). Acute kidney injury (P < 0.001) was slightly less frequent among children (87%) than adults (98%). Children [n = 4 (1.3%)] were less frequently (P = 0.02) treated with dialysis than adults [n = 14 (7.0%)]. No significant differences were detected with respect to uveitis characteristics, rate of renal relapse or triggering factors.

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)
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 involvement	69 (23)	73 (25)
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), median (IQR)	18 (7.0–32)	19 (12–24)	0.81
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.

Sex comparisons revealed that females (median 26, IQR = 14–49 years) were older than males (median 15, IQR = 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.

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)
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 involvement	56 (30)	86 (23)
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), median (IQR)	18 (7.5–29.5)	18 (12–28)	0.77
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.

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 development of (only) anterior uveitis [OR 0.06 (95% CI 0.01–0.31)] was associated with a decreased risk (Table 4).

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.

DISCUSSION

According to the most recent systematic review on TINU syndrome, including ~600 cases, TINU syndrome is both a paediatric and an adult disease. Children tend to have more ocular relapses and are slightly less likely to develop acute kidney injury 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.

FIGURE 3

TIN with interstitial lymphocytes and occasional plasma cells (haematoxylin and eosin stain).

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 surprising. In fact, TINU syndrome is a multisystemic, presumably autoimmune disorder. It is well known that autoimmune diseases occur more frequently in females. Oestrogens act as enhancers of humoral immunity and testosterone and progesterone act as natural immunosuppressants [239]. Women have increased immune reactivity with higher immunoglobulin levels and higher antibody production. This feature may also explain the increased frequency of autoantibodies (ANAs/ANCAs) in females.

This analysis shows that adults develop kidney injury and CKD more frequently than children. These findings are consistent 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, overweight) with reduced functional reserve. Therefore, when a further 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 frequently after TIN (Figure 3). This may be because uveitis is often 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 unravelling uveitis.

Children seem to have a more severe course of uveitis with more frequent relapses. There is no clear pathophysiological explanation 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 diseases, 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 diagnosis [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 anterior chamber who might also require a more aggressive treatment. This hypothesis should be confirmed in well-designed prospective studies.

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 particular 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, considering 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 categories. Adult age and the presence of uveitis involving the posterior segments appear to be the risk factors for the development 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.

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 manuscript. 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 interpretation, drafted the initial manuscript and revised the manuscript. 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.