Purpose
To determine classification criteria for tubulointerstitial nephritis with uveitis (TINU).
Design
Machine learning of cases with TINU and 8 other anterior uveitides.
Methods
Cases of anterior uveitides were collected in an informatics-designed preliminary database, and a final database was constructed of cases achieving supermajority agreement on the diagnosis, using formal consensus techniques. Cases were split into a training set and a validation set. Machine learning using multinomial logistic regression was used on the training set to determine a parsimonious set of criteria that minimized the misclassification rate among the anterior uveitides. The resulting criteria were evaluated on the validation set.
Results
One thousand eighty-three cases of anterior uveitides, including 94 cases of TINU, were evaluated by machine learning. The overall accuracy for anterior uveitides was 97.5% in the training set and 96.7% in the validation set (95% confidence interval 92.4, 98.6). Key criteria for TINU included anterior chamber inflammation and evidence of tubulointerstitial nephritis with either (1) a positive renal biopsy or (2) evidence of nephritis (elevated serum creatinine and/or abnormal urine analysis) and an elevated urine β-2 microglobulin. The misclassification rates for TINU were 1.2% in the training set and 0% in the validation set.
Conclusions
The criteria for TINU had a low misclassification rate and seemed to perform well enough for use in clinical and translational research.
T he syndrome of tubulointerstitial nephritis with uveitis (TINU) was first described as a distinct entity in 1975. It is considered a rare condition, with approximately 200 cases described in the literature through 2018. Tubulointerstitial nephritis with uveitis accounts for 0.2% to 2% of case series of uveitis, but it accounts for ∼10% to 20% of cases presenting with bilateral simultaneous acute anterior uveitis. , , Over 80% of cases present as an anterior uveitis, and 77% are bilateral at presentation. Retinal (eg, macular edema) and optic nerve (eg, disc edema) structural complications of the uveitis in TINU may occur, but in addition an anterior/intermediate uveitis and a panuveitis with either small choroidal lesions or retinal vascular findings (eg, cotton-wool spots, vascular sheathing, intraretinal hemorrhages) have been described. , , Although the review by Mandeville and associates described posterior findings in 17% of cases, 100% of cases had evidence of an anterior segment inflammation (anterior chamber cells and flare). Although typically presenting as an acute-onset anterior uveitis, chronic disease requiring long-term therapy, including immunosuppression, may occur. , ,
The syndrome of TINU is one of many diseases with tubulointerstitial nephritis (TIN) as the renal disease manifestation. The most commonly reported etiology for TIN is drug reaction, with antibiotics, nonsteroidal anti-inflammatory drugs, and proton pump inhibitors most often implicated. Other rheumatic diseases, such as systemic lupus erythematosus, Sjögren syndrome, systemic vasculitis, and IgG4 disease, also may have TIN as their renal manifestation. Despite the implication of drug reaction with TIN in general, none of the cases of TINU reported by Mackensen and associates seemed to be drug-related, suggesting that TINU may be distinct from drug-induced TIN.
Definitive diagnosis of TIN is made on renal biopsy. , , , However, renal biopsy is not always performed, especially when the renal disease is mild. Other renal laboratory findings reported in TINU include elevated serum creatinine in ∼90%, abnormal urine analysis, and elevated urine β2-microglobulin. Urinary abnormalities include proteinuria in ∼78% to 86%, microscopic hematuria in ∼42%, and aseptic leukocyturia in ∼55 to 70%. , Elevated urine β2-microglobulin has been reported to be present in nearly all patients tested at presentation and may correlate with the activity of the disease. , , Signs and symptoms of a systemic illness are reported in slightly over one-half of cases, including fever, fatigue and malaise, and weight loss, but are nonspecific. ,
The Standardization of Uveitis Nomenclature (SUN) Working Group is an international collaboration that has developed classification criteria for 25 of the most common uveitides using a formal approach to development and classification. Among the anterior uveitides studied was TINU.
Methods
The SUN Developing Classification Criteria for the Uveitides project proceeded in 4 phases, as previously described: (1) informatics, (2) case collection, (3) case selection, and (4) machine learning. , ,
Informatics
As previously described, the consensus-based informatics phase permitted the development of a standardized vocabulary and the development of a standardized, menu-driven hierarchical case collection instrument.
Case Collection and Case Selection
De-identified information was entered into the SUN preliminary database by the 76 contributing investigators for each disease, as previously described. , Cases in the preliminary database were reviewed by committees of 9 investigators for selection into the final database, using formal consensus techniques described in the accompanying article. , Because the goal was to develop classification criteria, only cases with a supermajority agreement (>75%) that the case was the disease in question were retained in the final database (ie, were “selected”).
Machine Learning
The final database then was randomly separated into a training set (∼85% of cases) and a validation set (∼15% of cases) for each disease, as described in the accompanying article. Machine learning was used on the training set to determine criteria that minimized misclassification. The criteria then were tested on the validation set; for both the training set
and the validation set, the misclassification rate was calculated for each disease. The misclassification rate was the proportion of cases classified incorrectly by the machine learning algorithm when compared to the consensus diagnosis. For TINU, the diseases against which it was evaluated were cytomegalovirus anterior uveitis, herpes simplex virus anterior uveitis, varicella zoster virus anterior uveitis, juvenile idiopathic arthritis–associated anterior uveitis, spondylitis/HLA-B27-associated anterior uveitis, Fuchs uveitis syndrome, sarcoidosis-associated anterior uveitis, and syphilitic anterior uveitis.
Comparison of Cases With and Without a Renal Biopsy Result Reported
Comparison of the characteristics of cases with and without renal biopsy results reported was performed with the χ 2 test for categorical variables or the Fisher exact test when the count of a variable was less than 5. Continuous variables were summarized as medians and compared with the Wilcoxon rank sum test.
The study adhered to the principles of the Declaration of Helsinki. Institutional review boards at each participating center reviewed and approved the study: the study typically was considered either minimal risk or exempt by the individual institutional review boards.
Results
One hundred twenty-five cases of TINU were collected, and 94 (75%) achieved supermajority agreement on the diagnosis during the “selection” phase and were used in the machine learning phase. These cases of TINU uveitis were compared to 989 cases of other anterior uveitides, including 89 cases of cytomegalovirus anterior uveitis, 101 cases of herpes simplex virus anterior uveitis, 146 cases of Fuchs uveitis syndrome, 202 cases of juvenile idiopathic arthritis–associated anterior uveitis, 184 cases of spondylitis/HLA-B27-associated anterior uveitis, 123 cases of varicella zoster virus anterior uveitis, 112 cases of sarcoidosis-associated anterior uveitis, and 32 cases of syphilitic anterior uveitis. The characteristics of cases with TINU at presentation to a SUN Working Group investigator are listed in Table 1 . A comparison of cases with and without renal biopsy data reported is provided in Table 2 . There were no significant differences between the 2 groups in the clinical characteristics of the uveitis. However, patients without a biopsy were younger, particularly <16 years of age. Patients without a biopsy were significantly more likely to have an elevated urine β-2-microglobulin reported, suggesting that it may be substituting for a renal biopsy in some patients or that when a positive biopsy is obtained, the test was deemed unnecessary or not reported.
| Characteristic | Result |
|---|---|
| Number of cases | 94 |
| Demographics | |
| Age, median, years (25th, 75th percentile) | 17 (13, 42) |
| Age category, years (%) | |
| ≤16 | 46 |
| 17-50 | 33 |
| 51-59 | 7 |
| ≥60 | 12 |
| Missing | 2 |
| Sex (%) | |
| Male | 36 |
| Female | 64 |
| Race/ethnicity (%) | |
| White, non-Hispanic | 70 |
| Black, non-Hispanic | 5 |
| Hispanic | 7 |
| Asian, Pacific Islander | 4 |
| Other | 4 |
| Missing/unknown | 8 |
| Uveitis history | |
| Uveitis course (%) | |
| Acute, monophasic | 14 |
| Acute, recurrent | 6 |
| Chronic | 60 |
| Indeterminate | 20 |
| Laterality (%) | |
| Unilateral | 14 |
| Unilateral, alternating | 0 |
| Bilateral | 86 |
| Ophthalmic examination | |
| Cornea | |
| Normal | 100 |
| Keratitis | 0 |
| Keratic precipitates (%) | |
| None | 49 |
| Fine | 40 |
| Round | 4 |
| Stellate | 2 |
| Mutton fat | 4 |
| Other | 0 |
| Anterior chamber cells, grade (%) | |
| ½+ | 16 |
| 1+ | 30 |
| 2+ | 31 |
| 3+ | 16 |
| 4+ | 7 |
| Hypopyon (%) | 0 |
| Anterior chamber flare, grade (%) | |
| 0 | 55 |
| 1+ | 28 |
| 2+ | 14 |
| 3+ | 2 |
| 4+ | 1 |
| Iris (%) | |
| Normal | 68 |
| Posterior synechiae | 32 |
| Sectoral iris atrophy | 0 |
| Patchy iris atrophy | 0 |
| Diffuse iris atrophy | 0 |
| Heterochromia | 0 |
| IOP, involved eyes | |
| Median, mm Hg (25th, 75th percentile) | 14 (12, 17) |
| Proportion of patients with IOP > 24 mm Hg either eye (%) | 1 |
| Vitreous cells, grade (%) | |
| 0 | 30 |
| ½+ | 27 |
| 1+ | 32 |
| 2+ | 5 |
| 3+ | 6 |
| 4+ | 0 |
| Vitreous haze, grade (%) | |
| 0 | 81 |
| ½+ | 7 |
| 1+ | 4 |
| 2+ | 6 |
| 3+ | 1 |
| 4+ | 1 |
| Vitreous snowballs | 0 |
| Choroidal lesions | 2 |
| Laboratory (%) | |
| Elevated serum creatinine | 58 |
| Elevated serum creatinine among cases with results reported | 89 |
| Elevated urine β-2 microglobulin | 23 |
| Elevated urine β-2 microglobulin among cases with results reported | 88 |
| Abnormal urine analysis | 58 |
| Abnormal urine analysis among cases with results reported | 89 |
| Positive renal biopsy | 31 |
| Positive renal biopsy a among cases with biopsy results reported | 100 |
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