Tubulointerstitial Nephritis and Uveitis Syndrome - Cuses, Symptoms, Diagnosis, and Treatment

What Is Tubulointerstitial Nephritis and Uveitis Syndrome (TINU)?

TINU is the simultaneous occurrence of tubulointerstitial nephritis (TIN) and uveitis without other systemic diseases. TIN is an inflammatory condition affecting the kidney's tubule, and uveitis is a form of eye inflammation. All age groups are affected equally, even though it is frequently seen in children and adolescents. The actual cause of the condition is not determined yet, but it is believed to be a response to environmental triggers like drugs and pathogens.

Many clinical features of TINU resemble sarcoidosis (an inflammatory condition that affects lungs and lymph glands), which makes it difficult and under-recognized. Because of this, there is no established protocol to treat the condition, but most cases can be treated with corticosteroids and immunomodulatory drugs.

What Causes Tubulointerstitial Nephritis and Uveitis Syndrome (TINU)?

The exact cause of TINU syndrome has not been determined yet, although it has been associated with the following conditions; they are:

1. Infection: A few infections that trigger TINU are chlamydia (a sexually transmitted disease caused by a bacteria known as Chlamydia trachomatis, herpes zoster virus, Epstein-Barr virus, etc.)

2. Drugs: This includes certain non-steroidal anti-inflammatory drugs, antibiotics, and a Chinese herb called goreisan.

3. Autoimmune Diseases: Autoimmunity is a condition where the body mistakenly attacks its own organs and tissues, resulting in an autoimmune disorder. Some autoimmune disorders that can cause TINU are primary hypoparathyroidism, hyperthyroidism, rheumatoid arthritis, lymphoid interstitial lung disease, ankylosing spondylitis (an inflammatory condition that causes the vertebrae to fuse), and IgG4-related autoimmune disease.

It is postulated that the conditions mentioned above will activate cellular and humoral autoimmunity in a few predisposed individuals. This activation will transport T cells, monocytes/macrophages, antibodies, and other immune-related cells to the kidney and eyes, where they start attacking the healthy cells resulting in inflammation (TIN and uveitis).

Further, a few studies have observed that individuals with genetic mutations in the HLA (human leukocyte antigen) are predisposed to TINU. The HLA complex is a part of the immune system that helps distinguish the body's tissue from pathogens. Any mutations (alterations) in this system will lead to autoimmunity.

What Are the Symptoms of TINU?

TINU has renal and ocular symptoms of varying degrees; they are-

1. Renal Symptoms: Renal symptoms depend on the areas of involvement; the below symptoms are seen when the renal interstitium is infiltrated.

2. Sterile Pyuria: It is the persistent presence of white blood cells in the urine without any bacteria.

3. Hematuria: The presence of blood in the urine is known as hematuria.

4. Subnephrotic Proteinuria: Also known as functional proteinuria, it is a condition where the urine has excess protein. A protein-to-creatinine ratio greater than 0.2 and less than 3.5 can be considered subnephrotic proteinuria.

5. Renal Insufficiency: This condition is characterized by gradual loss of kidney function over time. A glomerular filtrate rate between 40 milliliters/minute to 20 milliliters/minute can be considered renal insufficiency.

The below-mentioned symptoms are seen when the immune cells have infiltrated the proximal and distal tubule of the nephron (functional unit of the kidney); they are:

1. Polyuria: It is a term used to describe excess urination.

2. Nocturia: A term used to describe frequent nighttime urination.

3. Aminoaciduria: A condition where the urine contains abnormal amounts of amino acids.

4. Glycosuria: Glycosuria connotes the presence of glucose in the urine.

5. Phosphaturia: It is the kidney’s inability to reabsorb phosphate from the glomerular filtrate, leading to urinary phosphate wasting.

6. Acidification Defects: Any kidney abnormalities that cause the inability of the renal tubules (especially the proximal tubules) to acidify urine are known as acidification defects.

7. Ocular Symptoms: These are usually seen before two months or after fourteen months of renal involvement. Some of them are:

8. Uveitis: It is the most commonly seen bilateral ocular symptom that affects the eye wall's middle layer (uvea). Uveitis is the inflammation of the uvea leading to redness, pain, blurred vision, and photophobia.

9. Chorioretinitis: The choroid is the vascular layer of the eye that lies between the sclera and the retina. Chorioretinitis is the inflammation of this layer.

10. Neuroretinitis: It is the inflammation of the retina and the optic nerve of the eye.

11. Optic Disk Edema: The swelling of the intraocular portion of the optic nerve.

12. Macular Edema: The swelling of the macula (a light-sensitive area of the retina responsible for central vision) that often leads to blurry vision.

13. Nodular Scleritis: The inflammation of the sclera that often presents with nodules that are tender to palpation.

Extrarenal and extraocular symptoms of TINU include fever, weight loss, and generalized fatigue.

How Is TINU Diagnosed?

The diagnosis of TINU requires the presence of TIN and uveitis, along with the exclusion of other known systemic conditions. However, this alone cannot be used to reach a definitive diagnosis because many other systemic conditions, like sarcoidosis, systemic lupus erythematosus, Sjogren's syndrome, Behcet disease, etc., also comprise the same symptoms without other manifestations.

This can be prevented with the help of laboratory investigations. Urinalysis of TINU typically shows elevation of three biomarkers (measurable indicators):

1. Urinary beta-2 microglobulin.

2. Serum Krebs von de lunge-6 protein.

3. Anti-mCRP autoantibodies.

Along with the typical abnormalities, urinalysis of patients with TINU also show routine abnormalities like elevated serum creatinine, low-grade proteinuria, microscopic hematuria, and leukocytosis. Therefore, the presence of biomarkers and exclusion of systemic conditions provide the basis for the definitive diagnosis of TINU.

How Is TINU Treated?

Since there is no standard treatment for TINU, management of the symptoms is given priority; this includes:

1. Management of Renal Symptoms: Corticosteroids are the mainstay for treating renal symptoms. A dose of 1 milligram/kilogram (usually 40 milligrams/day to 60 milligrams/day) of Prednisone will help to treat nephritis and renal insufficiency seen in TINU. Patients with recurrent and progressive nephritis will benefit from a short course of Cyclophosphamide or Mycophenolate. Although effective, corticosteroids tend to cause renal scarring after prolonged therapy; they should always be used as immunosuppressive agents to prevent this.

2. Management of Ocular Symptoms: Topical and systemic corticosteroids effectively treat uveitis seen in TINU. However, the chances of recurrence and relapse are frequent. Immunomodulatory agents such as Methotrexate, Azathioprine, or Cyclosporin A can prevent relapses.

Conclusion

TINU is often under-recognized due to its similarity with other systemic autoimmune disorders. The non-specific symptoms make the condition hard to diagnose and contribute to its rarity. Once diagnosed, the condition can be effectively managed with corticosteroids and immunomodulatory agents with fewer chances of relapse.