Renal involvement in sarcoidosis can occur in a variety of ways. Most commonly, patients have hypercalcemia secondary to increased production of 1,25-dihydroxyvitamin D3 by the activated macrophages in the characteristic granulomatous tissues. Such hypercalcemia can lead to other renal manifestations such as nephrogenic diabetes insipidus, hypercalciuria-related nephrolithiasis, and, in some cases, renal failure.
Sarcoidosis can also present as a form of interstitial nephritis with associated “noncaseating granulomas” (Figure 37–3).
Noncaseating granulomatous inflammation in a patient with sarcoidosis. Periodic acid–Schiff (×400). (Courtesy of Dr. Shane Meehan, Department of Pathology, University of Chicago.)
Typical tubular manifestations include mild proteinuria, sterile pyuria, and impaired ability to concentrate urine.
Treatment is with corticosteroids 1 mg/kg/day, which has been reported to lead to improved renal function. More commonly, however, because the renal involvement is long standing, recovery is usually incomplete, even in those treated with steroids.
Sjögren's syndrome-associated CIN characteristically presents as type 1 RTA, with hypokalemia and a normal anion gap metabolic acidosis. Although the mechanism for this is incompletely understood, it is believed to be related to autoantibodies against carbonic anhydrase II. Treatment with high-dose corticosteroids has resulted in a dramatic improvement in renal function.
Tubulointerstitial Nephritis with Uveitis Syndrome
- Presents as acute renal failure.
- Commonly affects young adult females and adolescents.
- Accompanying “uveitis” develops in relation to underlying interstitial nephritis.
- Pathology: Predominance of CD4 and CD8 T lymphocytes in renal biopsy.
Tubulointerstitial nephritis with uveitis (TINU) was first described in 1975. It is usually seen in adolescents and young adults, with a female preponderance and no particular racial predilection.
The exact pathogenesis remains unclear, but the predominance of T lymphocytes in the tissues and possible association with Chlamydia and Epstein–Barr virus suggest that delayed type hypersensitivity and suppressed cell-mediated immunity may play major roles.
Clinically, patients present with nonspecific signs and symptoms, ie, fever, generalized malaise, anemia, and asthenia. Typically, uveitis of the anterior chamber is seen bilaterally, presenting as redness and pain over the eyes. Occasionally, patients complain of accompanying blurring of vision and photophobia. Uveitis can occur as quickly as 2 months prior to, simultaneously with, or up to 14 months after the onset of interstitial nephritis, presenting as acute renal failure.
Renal manifestations include both proximal and distal tubular dysfunction, ie, tubular proteinuria. Increased urine β2-microglobulin (a marker of tubulointerstitial disease) has been noted. Ultrasonography may reveal enlarged swollen kidneys.
A definitive diagnosis is established by demonstrating typical findings of interstitial nephritis, ie, tubulointerstitial edema with infiltration of lymphocytes, plasma cells, and histiocytes. A predominance of CD4 and CD8 T lymphocytes, monocytes, and macrophages has been described. Eosinophils and noncaseating granulomas may also be seen.
The above findings combined with the temporal relation to the concomitant uveitis make the diagnosis likely.
Other common causes of tubulointerstitial disease process with uveitis include sarcoidosis and Sjögren's syndrome.
Renal disease frequently resolves spontaneously over the course of 12 months without steroid therapy. However, for those with moderately advanced chronic kidney disease, prednisone 1 mg/kg/day (usually 40–60 mg orally daily) can be given for 3–6 months depending on the response, and then tapered subsequently. Note that this steroid regimen is somewhat similar to that given for patients with persistent ATIN, except that the duration of therapy is slightly more prolonged because of more frequent relapses noted with TINU. While the renal manifestations may resolve spontaneously and respond well to a course of systemic steroids, the uveitis often has a chronic or relapsing course that may require more aggressive therapy. For uveitis, topical or systemic corticosteroids have been used.
As in other chronic tubulointerstitial diseases, there is a positive correlation between prognosis and the degree of interstitial fibrosis.
Idiopathic Hypocomplementemic Interstitial Nephritis
This disease is usually seen in older men, and as the name implies, is characterized by decreased levels of C3 and C4 (hypocomplementemia) in the absence of evidence of systemic lupus erythematosus (SLE) or Sjögren's syndrome. Histopathology reveals extensive tubulointerstitial infiltration with lymphocytes as well as Ig and complement deposits; these suggest local immune complex formation as the pathogenetic mechanism. Treatment consists of glucocorticoids and cyclophosphamide.