The invading cells consist exclusively of CD8-positive cells that exhibit cytotoxic properties and may participate in tissue damage [27]. On the other hand, epithelial cells seem to play a central role in the pathogenesis of IN. Renal tubular epithelium has been found to express adhesion molecules such as ICAM-1 in and around the foci of cellular infiltration, implying that tubular epithelial cells contribute to the induction and maintenance of lymphocytic infiltrates of IN [30]. Furthermore, it has been demonstrated that tubular epithelial cells from SS patients with IN express the CD86 costimulatory molecule, activating the adjacent CD28 positive T cells [31]. Finally, Fas-FasL-mediated apoptotic changes of tubular epithelial cells have been observed in patients with SS and IN [32]. The above data confirm the notion that extraglandular manifestations share common immunopathological features with the primary glandular lesion and justify the term autoimmune epithelitis for SS.

Considering the pathogenesis of dRTA in pSS, antibodies against carbonic anhydrase (CA) II are implied to be involved. Anti-CA II autoantibodies have been found to induce autoimmune sialadenitis in experimental animal models [33] and have been detected in the serum of pSS patients [34–36]. In this context, Takemoto et al. measured the levels of anti-CA II in 46 subjects with pSS from whom 16 had been diagnosed with dRTA [37]. Antibody levels were found significantly higher in pSS patients with dRTA than those without, and correlated with increased b2 microglobulin in the urine and disease duration. Furthermore, anti-CA II antibodies have been shown to induce RTA in a mouse model of SS [38]. Whether anti-CA II antibodies are produced in response to tubular damage or are pathogenetically associated with dRTA in pSS remains to be elucidated.

19.2.5Differential Diagnosis

The other most important medical conditions that lead to dRTA (type 1 RTA) are drugs such as lithium and ifosfamide and hereditary forms of dRTA that most commonly affect children [39]. A careful family and personal history along with clinical evaluation will differentiate SS from other causes of dRTA. In SS patients with dRTA, the clinical picture is dominated by sicca symptoms and autoantibodies such as antinuclear antibodies (ANA), anti-Ro/SSA, and/or anti-La/SSB antibodies are usually present. In idiopathic cases of dRTA and nephrolithiasis, the patients should be evaluated for SS because these complications may precede the main disease by many years. The differential diagnosis of type 2 RTA and Fanconi syndrome includes various types of familial disorders, drugs (e.g., acetazolamide, a carbonic anhydrase inhibitor), toxins such as heavy metals, and multiple myeloma [39, 40]. Thus, before proximal RTA is attributed to SS, these entities should be excluded.

19.2.6Treatment

Alkali supplements are the cornerstone of therapy for the management of patients with dRTA to control acidosis and prevent renal stone formation. The dose ranges