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Tubulointerstitial nephritis and uveitis syndrome (TINU). Treatment with immunosuppressive therapy
ARTICLE IN PRESS a r c h s o c e s p o f t a l m o l . 2 0 1 7;x x x(x x):xxx–xxx
ARCHIVOS DE LA SOCIEDAD ESPAÑOLA DE OFTALMOLOGÍA www.elsevier.es/oftalmologia
Short communication
Tubulointerstitial nephritis and uveitis syndrome (TINU). Treatment with immunosuppressive therapy夽,夽夽 T. Rueda-Rueda, J.L. Sánchez-Vicente, A. Moruno-Rodríguez ∗ , M. Castilla-Martino, F. López-Herrero, M. Contreras-Díaz, F. Molina-Socola, L. Sáez-Ortega, ˜ A. Munoz-Morales Departamento de Oftalmología, Hospital Universitario Virgen del Rocío, Sevilla, Spain
a r t i c l e
i n f o
a b s t r a c t
Article history:
Case report: Two cases of tubulointerstitial nephritis and uveitis are presented. Immuno-
Received 15 November 2016
suppressive therapy was required to control the uveitis. Contrary to that usually described,
Accepted 2 January 2017
uveitis became chronic, which made immunosuppressive therapy necessary. Nephritis was
Available online xxx
successfully treated with steroids.
Keywords:
and requires clinical suspicion due to there being no specific laboratory study available.
Discussion: Tubulointerstitial nephritis and uveitis syndrome is an under-diagnosed disorder Tubulointerstitial nephritis and uveitis syndrome Immunosuppressive therapy
Recurrences and relapses of ocular inflammation are common. Immunosuppressive therapy is not often needed. ˜ ˜ S.L.U. All rights © 2017 Sociedad Espanola de Oftalmolog´ıa. Published by Elsevier Espana, reserved.
Uveitis Nephritis
Síndrome de nefritis túbulo-intersticial y uveítis (TINU). Tratamiento con inmunosupresores r e s u m e n Palabras clave:
Caso clínico: Presentamos 2 casos de síndrome de nefritis túbulo-intersticial y uveítis que
Síndrome de nefritis
necesitaron tratamiento con inmunosupresores para lograr el control de la uveítis. Al con-
túbulo-intersticial y uveítis
trario de lo habitualmente descrito, la uveítis adquirió un carácter crónico, siendo necesario
Inmunosupresores
el tratamiento inmunosupresor. La nefritis sí respondió al tratamiento con corticoides.
Uveítis
Discusión: El síndrome de nefritis túbulo intersticial y uveítis constituye una condición infra-
Nefritis
˜ diagnosticada que requiere un alto índice de sospecha diagnóstica, ya que no se acompana
夽 Please cite this article as: Rueda-Rueda T, Sánchez-Vicente JL, Moruno-Rodríguez A, Castilla-Martino M, López-Herrero F, ContrerasDíaz M, et al. Síndrome de nefritis túbulo-intersticial y uveítis (TINU). Tratamiento con inmunosupresores. Arch Soc Esp Oftalmol. 2017. http://dx.doi.org/10.1016/j.oftal.2017.01.008 夽夽 ˜ de Uveítis This paper was partially presented at the Congress of the Uveitis and Ocular Inflammation Group of Spain [Grupo Espanol e Inflamation Ocular (GEMU)] held in Madrid on February 26, 2016. ∗ Corresponding author. E-mail address: antoniomoruno [email protected] (A. Moruno-Rodríguez). ˜ ˜ S.L.U. All rights reserved. 2173-5794/© 2017 Sociedad Espanola de Oftalmolog´ıa. Published by Elsevier Espana,
OFTALE-1157; No. of Pages 5
ARTICLE IN PRESS 2
a r c h s o c e s p o f t a l m o l . 2 0 1 7;x x x(x x):xxx–xxx
de alteraciones específicas. La inflamación ocular cursa con frecuentes recurrencias, siendo necesario, en raras ocasiones, el tratamiento inmunosupresor. ˜ ˜ S.L.U. Todos de Oftalmolog´ıa. Publicado por Elsevier Espana, © 2017 Sociedad Espanola los derechos reservados.
Introduction The tubulointerstitial nephritis and uveitis syndrome was described by Dobrin in 1975.1 It is characterized by the combination of acute tubulointerstitial nephritis (TIN) and uveitis, the latter generally being anterior, bilateral and nongranulomatous. It occurs more frequently in adults and young females, although it can also present unilaterally, granulomatous and as intermediate uveitis or panuveitis. It accounts for approximately 2% of uveitis cases in a third level hospital, and is probably an infradiagnosed entity.2 Diagnostic could be difficult because renal and ocular involvement may not
appear concurrently. Uveitis could appear up to one year after kidney disease and in some cases it could appear in the first place.3 In general, uveitis responds positively to treatment with topical corticoids and cycloplegic. In the absence of response, oral corticoid treatment should be established. Immunosuppressants such as cyclosporine, methotrexate or mycophenolate3 are required only exceptionally. Nephritis usually resolves spontaneously, with rapid recovery of kidney function parameters.2 Two cases of TINU with anterior and posterior pole involvement are presented, that required immunosuppressants for controlling ocular inflammation.
Fig. 1 – Posterior pole retinography and fluorescein angiography of patient 2 during the second anterior uveitis episode.
ARTICLE IN PRESS a r c h s o c e s p o f t a l m o l . 2 0 1 7;x x x(x x):xxx–xxx
3
Fig. 2 – Patient 2. Papillitis and vitritis that appeared in the course of the disease.
Clinic case Case 1 Female, 37, diagnosed at age 13 with TIN through biopsy. After being diagnosed with nephropathy, she exhibited a first episode of anterior uveitis, being diagnosed with TINU. For a number of years, the patient endured repeated episodes of bilateral anterior uveitis. Subsequently, several crises arose with posterior involvement and cystic macular edema that required systemic corticoids, cyclosporine and mycophenolate, achieving complete remission and preserving a visual acuity of 1.0 in both eyes (BE). In April 2014, the patient visited the authors’ practice due to a new episode of bilateral anterior uveitis with Tyndall, non-pigmented thin keratic precipitates, pupil synechiae and posterior nuclear and subcapsular cataract. Best corrected visual acuity (BCVA) was 0.4 in the right eye (RE) and 0.6 in the left eye (LE). At the posterior level, vitritis,
papillitis and lesions similar to Dalen-Fuchs nodules were ® observed. Optical coherence tomography (Topcon 3D OCT1000, Topcon Corporation, Tokyo, Japan) showed bilateral cystic macular edema. Due to posterior pole involvement, treatments with systemic corticoids was prescribed. In the absence of improvement, cyclosporine and mycophenolate were added at a dose of 1 g/12 h orally and, in the absence of response, of 3 g/day). Due to poor evolution, infliximab was added. Despite said treatment, evolution was poor, with the patient developing intense papillary paleness and macular atrophy with a final BCVA of 0.05 in BE.
Case 2 Female, 14, with anterior uveitis episode in the LE 3 years earlier who visited due to new non-granulomatous bilateral anterior uveitis (Fig. 1). Urine sediments identified data compatible with TIN (glycosuria, proteinuria, hypouricemia and potassium in urine).
ARTICLE IN PRESS 4
a r c h s o c e s p o f t a l m o l . 2 0 1 7;x x x(x x):xxx–xxx
Fig. 3 – Vasculitis in patient 2. Hyper-florescent lesions involving to atrophy. The depigmented chorioretinal nummular scars are reminiscent of Dalen-Fuchs nodules.
Fig. 4 – Depigmented chorioretinal nummular scars corresponding to the hyper-florescent lesions of Fig. 3.
Treatment was established with topical and systemic corticoids as well as cycloplegic, with diagnostic being confirmed through kidney biopsy. Despite said treatment, inflammation in anterior chamber persisted with appearance of vitritis, for which reason it was decided to add cyclosporine (200 mg/day) and mycophenolate (500 mg/12 h in the beginning and 1 g/12 h later on). Said treatment was not effective, with increased vitritis and retinal involvement in the form of vasculitis and papillitis (Figs. 2 and 3) as well as the development of Dalen-Fuchs nodule-like lesions (Figs. 3 and 4). When infliximab was added, inflammation was controlled. Final BCVA was 1.0 in BE.
Discussion TIN is an inflammatory disease of the kidneys, either idiopathic or due to infectious agents or numerous medicaments,
including nonsteroid anti-inflammatories.4 It can be accompanied by uveitis, generally anterior and bilateral. Posterior involvement can also arise in the form of vitritis, chorioretinitis, intraretinal hemorrhages, vasculitis and retinal edema. Diagnostic requires the presence of TIN and uveitis without other associated diseases that could account for renal and ocular involvement. The TIN confirmation diagnostic is based on kidney biopsy demonstrating the presence of edema and tubulointerstitial inflammation, respecting glomeruli and vascular structures.5 Even though TINU uveitis usually has a good and responds to topical or oral corticoids treatment,3,6 the present cases required immunosuppressants treatment. One evolved toward poor VA with papillary and macular atrophy, while the other preserved a final VA of 1.0 in BE. The presence of similar lesions at the clinic and angiographic level, such as Dalen-Fuchs nodules (Figs. 3 and 4) is
ARTICLE IN PRESS a r c h s o c e s p o f t a l m o l . 2 0 1 7;x x x(x x):xxx–xxx
worthy of note. The presence of these lesions in TINU has not been described previously. By way of conclusion, the TINU syndrome constitutes an underdiagnosed entity requiring a high level of clinical suspicion because on many occasions uveitis and TIN do not appear concurrently. In addition, even though in the majority of cases uveitis has a positive prognosis, responding to treatment with topical and oral corticoids, immunosuppressants are required in some cases and a poor end result could occur.
Conflict of interests No conflict of any type of interests was declared by the authors.
Acknowledgments The authors wish to acknowledge the Ophthalmology Society of Spain and the editors of this journal.
5
references
1. Dobrin RS, Vernier RL, Fish AL. Acute eosinophilic interstitial nephritis and renal failure with bone marrow-lymph node granulomas and anterior uveitis. A new syndrome. Am J Med. 1975;59:325–33. 2. Mackensen F, Billing H. Tubulointerstitial nephritis and uveitis syndrome. Curr Opin Ophthalmol. 2009;20:525–31. 3. Thomassen VH, Ring T, Thaarup J, Baggesen K. Tubulointerstitial nephritis and uveitis (TINU) syndrome: a case report and review of the literature. Acta Ophthalmol. 2009;87:676–9. 4. Saarela V, Nuutinen M, Ala-Houhala M, Arikoski P, Rönnholm K, Jahnukainen T. Tubulointerstitial nephritis and uveitis syndrome in children: a prospective multicenter study. Ophthalmology. 2013;120:1476–81. 5. Paladini A, Venturoli V, Mosconi G, Zambianchi L, Serra L, Valletta L. Tubulointerstitial nephritis and uveitis syndrome in a twelve-year-old girl. Case Rep Pediatr. 2013;2013:652043. 6. Goda C, Kotake S, Ichiishi A, Namba K, Kitaichi N, Ohno S. Clinical features in tubulointerstitial nephritis and uveitis (TINU) syndrome. Am J Ophthalmol. 2005;140:637–41.
ARCHIVOS DE LA SOCIEDAD ESPAÑOLA DE OFTALMOLOGÍA www.elsevier.es/oftalmologia
Short communication
Tubulointerstitial nephritis and uveitis syndrome (TINU). Treatment with immunosuppressive therapy夽,夽夽 T. Rueda-Rueda, J.L. Sánchez-Vicente, A. Moruno-Rodríguez ∗ , M. Castilla-Martino, F. López-Herrero, M. Contreras-Díaz, F. Molina-Socola, L. Sáez-Ortega, ˜ A. Munoz-Morales Departamento de Oftalmología, Hospital Universitario Virgen del Rocío, Sevilla, Spain
a r t i c l e
i n f o
a b s t r a c t
Article history:
Case report: Two cases of tubulointerstitial nephritis and uveitis are presented. Immuno-
Received 15 November 2016
suppressive therapy was required to control the uveitis. Contrary to that usually described,
Accepted 2 January 2017
uveitis became chronic, which made immunosuppressive therapy necessary. Nephritis was
Available online xxx
successfully treated with steroids.
Keywords:
and requires clinical suspicion due to there being no specific laboratory study available.
Discussion: Tubulointerstitial nephritis and uveitis syndrome is an under-diagnosed disorder Tubulointerstitial nephritis and uveitis syndrome Immunosuppressive therapy
Recurrences and relapses of ocular inflammation are common. Immunosuppressive therapy is not often needed. ˜ ˜ S.L.U. All rights © 2017 Sociedad Espanola de Oftalmolog´ıa. Published by Elsevier Espana, reserved.
Uveitis Nephritis
Síndrome de nefritis túbulo-intersticial y uveítis (TINU). Tratamiento con inmunosupresores r e s u m e n Palabras clave:
Caso clínico: Presentamos 2 casos de síndrome de nefritis túbulo-intersticial y uveítis que
Síndrome de nefritis
necesitaron tratamiento con inmunosupresores para lograr el control de la uveítis. Al con-
túbulo-intersticial y uveítis
trario de lo habitualmente descrito, la uveítis adquirió un carácter crónico, siendo necesario
Inmunosupresores
el tratamiento inmunosupresor. La nefritis sí respondió al tratamiento con corticoides.
Uveítis
Discusión: El síndrome de nefritis túbulo intersticial y uveítis constituye una condición infra-
Nefritis
˜ diagnosticada que requiere un alto índice de sospecha diagnóstica, ya que no se acompana
夽 Please cite this article as: Rueda-Rueda T, Sánchez-Vicente JL, Moruno-Rodríguez A, Castilla-Martino M, López-Herrero F, ContrerasDíaz M, et al. Síndrome de nefritis túbulo-intersticial y uveítis (TINU). Tratamiento con inmunosupresores. Arch Soc Esp Oftalmol. 2017. http://dx.doi.org/10.1016/j.oftal.2017.01.008 夽夽 ˜ de Uveítis This paper was partially presented at the Congress of the Uveitis and Ocular Inflammation Group of Spain [Grupo Espanol e Inflamation Ocular (GEMU)] held in Madrid on February 26, 2016. ∗ Corresponding author. E-mail address: antoniomoruno [email protected] (A. Moruno-Rodríguez). ˜ ˜ S.L.U. All rights reserved. 2173-5794/© 2017 Sociedad Espanola de Oftalmolog´ıa. Published by Elsevier Espana,
OFTALE-1157; No. of Pages 5
ARTICLE IN PRESS 2
a r c h s o c e s p o f t a l m o l . 2 0 1 7;x x x(x x):xxx–xxx
de alteraciones específicas. La inflamación ocular cursa con frecuentes recurrencias, siendo necesario, en raras ocasiones, el tratamiento inmunosupresor. ˜ ˜ S.L.U. Todos de Oftalmolog´ıa. Publicado por Elsevier Espana, © 2017 Sociedad Espanola los derechos reservados.
Introduction The tubulointerstitial nephritis and uveitis syndrome was described by Dobrin in 1975.1 It is characterized by the combination of acute tubulointerstitial nephritis (TIN) and uveitis, the latter generally being anterior, bilateral and nongranulomatous. It occurs more frequently in adults and young females, although it can also present unilaterally, granulomatous and as intermediate uveitis or panuveitis. It accounts for approximately 2% of uveitis cases in a third level hospital, and is probably an infradiagnosed entity.2 Diagnostic could be difficult because renal and ocular involvement may not
appear concurrently. Uveitis could appear up to one year after kidney disease and in some cases it could appear in the first place.3 In general, uveitis responds positively to treatment with topical corticoids and cycloplegic. In the absence of response, oral corticoid treatment should be established. Immunosuppressants such as cyclosporine, methotrexate or mycophenolate3 are required only exceptionally. Nephritis usually resolves spontaneously, with rapid recovery of kidney function parameters.2 Two cases of TINU with anterior and posterior pole involvement are presented, that required immunosuppressants for controlling ocular inflammation.
Fig. 1 – Posterior pole retinography and fluorescein angiography of patient 2 during the second anterior uveitis episode.
ARTICLE IN PRESS a r c h s o c e s p o f t a l m o l . 2 0 1 7;x x x(x x):xxx–xxx
3
Fig. 2 – Patient 2. Papillitis and vitritis that appeared in the course of the disease.
Clinic case Case 1 Female, 37, diagnosed at age 13 with TIN through biopsy. After being diagnosed with nephropathy, she exhibited a first episode of anterior uveitis, being diagnosed with TINU. For a number of years, the patient endured repeated episodes of bilateral anterior uveitis. Subsequently, several crises arose with posterior involvement and cystic macular edema that required systemic corticoids, cyclosporine and mycophenolate, achieving complete remission and preserving a visual acuity of 1.0 in both eyes (BE). In April 2014, the patient visited the authors’ practice due to a new episode of bilateral anterior uveitis with Tyndall, non-pigmented thin keratic precipitates, pupil synechiae and posterior nuclear and subcapsular cataract. Best corrected visual acuity (BCVA) was 0.4 in the right eye (RE) and 0.6 in the left eye (LE). At the posterior level, vitritis,
papillitis and lesions similar to Dalen-Fuchs nodules were ® observed. Optical coherence tomography (Topcon 3D OCT1000, Topcon Corporation, Tokyo, Japan) showed bilateral cystic macular edema. Due to posterior pole involvement, treatments with systemic corticoids was prescribed. In the absence of improvement, cyclosporine and mycophenolate were added at a dose of 1 g/12 h orally and, in the absence of response, of 3 g/day). Due to poor evolution, infliximab was added. Despite said treatment, evolution was poor, with the patient developing intense papillary paleness and macular atrophy with a final BCVA of 0.05 in BE.
Case 2 Female, 14, with anterior uveitis episode in the LE 3 years earlier who visited due to new non-granulomatous bilateral anterior uveitis (Fig. 1). Urine sediments identified data compatible with TIN (glycosuria, proteinuria, hypouricemia and potassium in urine).
ARTICLE IN PRESS 4
a r c h s o c e s p o f t a l m o l . 2 0 1 7;x x x(x x):xxx–xxx
Fig. 3 – Vasculitis in patient 2. Hyper-florescent lesions involving to atrophy. The depigmented chorioretinal nummular scars are reminiscent of Dalen-Fuchs nodules.
Fig. 4 – Depigmented chorioretinal nummular scars corresponding to the hyper-florescent lesions of Fig. 3.
Treatment was established with topical and systemic corticoids as well as cycloplegic, with diagnostic being confirmed through kidney biopsy. Despite said treatment, inflammation in anterior chamber persisted with appearance of vitritis, for which reason it was decided to add cyclosporine (200 mg/day) and mycophenolate (500 mg/12 h in the beginning and 1 g/12 h later on). Said treatment was not effective, with increased vitritis and retinal involvement in the form of vasculitis and papillitis (Figs. 2 and 3) as well as the development of Dalen-Fuchs nodule-like lesions (Figs. 3 and 4). When infliximab was added, inflammation was controlled. Final BCVA was 1.0 in BE.
Discussion TIN is an inflammatory disease of the kidneys, either idiopathic or due to infectious agents or numerous medicaments,
including nonsteroid anti-inflammatories.4 It can be accompanied by uveitis, generally anterior and bilateral. Posterior involvement can also arise in the form of vitritis, chorioretinitis, intraretinal hemorrhages, vasculitis and retinal edema. Diagnostic requires the presence of TIN and uveitis without other associated diseases that could account for renal and ocular involvement. The TIN confirmation diagnostic is based on kidney biopsy demonstrating the presence of edema and tubulointerstitial inflammation, respecting glomeruli and vascular structures.5 Even though TINU uveitis usually has a good and responds to topical or oral corticoids treatment,3,6 the present cases required immunosuppressants treatment. One evolved toward poor VA with papillary and macular atrophy, while the other preserved a final VA of 1.0 in BE. The presence of similar lesions at the clinic and angiographic level, such as Dalen-Fuchs nodules (Figs. 3 and 4) is
ARTICLE IN PRESS a r c h s o c e s p o f t a l m o l . 2 0 1 7;x x x(x x):xxx–xxx
worthy of note. The presence of these lesions in TINU has not been described previously. By way of conclusion, the TINU syndrome constitutes an underdiagnosed entity requiring a high level of clinical suspicion because on many occasions uveitis and TIN do not appear concurrently. In addition, even though in the majority of cases uveitis has a positive prognosis, responding to treatment with topical and oral corticoids, immunosuppressants are required in some cases and a poor end result could occur.
Conflict of interests No conflict of any type of interests was declared by the authors.
Acknowledgments The authors wish to acknowledge the Ophthalmology Society of Spain and the editors of this journal.
5
references
1. Dobrin RS, Vernier RL, Fish AL. Acute eosinophilic interstitial nephritis and renal failure with bone marrow-lymph node granulomas and anterior uveitis. A new syndrome. Am J Med. 1975;59:325–33. 2. Mackensen F, Billing H. Tubulointerstitial nephritis and uveitis syndrome. Curr Opin Ophthalmol. 2009;20:525–31. 3. Thomassen VH, Ring T, Thaarup J, Baggesen K. Tubulointerstitial nephritis and uveitis (TINU) syndrome: a case report and review of the literature. Acta Ophthalmol. 2009;87:676–9. 4. Saarela V, Nuutinen M, Ala-Houhala M, Arikoski P, Rönnholm K, Jahnukainen T. Tubulointerstitial nephritis and uveitis syndrome in children: a prospective multicenter study. Ophthalmology. 2013;120:1476–81. 5. Paladini A, Venturoli V, Mosconi G, Zambianchi L, Serra L, Valletta L. Tubulointerstitial nephritis and uveitis syndrome in a twelve-year-old girl. Case Rep Pediatr. 2013;2013:652043. 6. Goda C, Kotake S, Ichiishi A, Namba K, Kitaichi N, Ohno S. Clinical features in tubulointerstitial nephritis and uveitis (TINU) syndrome. Am J Ophthalmol. 2005;140:637–41.