from 1 to 2 mEq/kg body weight divided in four doses per day and is gradually raised until hypercalciuria and acidosis are both eliminated [39]. Potassium alkali salts are indicated if persistent hypokalemia is present. For patients with proximal RTA, alkali salts of 10–15 mEq/kg body weight per day may be required to compensate for renal losses [39]. Alkali replacement must be administered as potassium salts because of increased renal loss of potassium due to bicarbonaturia. The addition of a thiazide diuretic may reduce the amounts of alkali salts requirements [41]. Although in one study, steroid administration was beneficial [42], the role of immunosuppressive agents in the treatment of IN has not been addressed yet.

19.3Glomerulonephritis in Primary Sjögren’s Syndrome

19.3.1Historical Aspects

GN can occur in pSS, but relatively few cases have been reported in the literature. In 1966, Meltzer et al. described an SS patient with proliferative GN related to type II mixed cryoglobulinemia who presented with facial edema, increased arterial pressure, hematuria, and proteinuria [43]. Similarly, in a series of 86 patients with cryoglobulinemia, 3 had SS and signs of glomerular disease, although not biopsy proven [44]. Moutsopoulos et al. described three cases of pSS with GN [45]. The clinical picture of GN included typically hypertension and pitting edema. The major laboratory findings were renal insufficiency and active urine sediment accompanied by proteinuria. Circulating immune complexes were detected in all three patients and cryoglobulinemia was found in two of them. Thus, GN was associated with cryoglobulinemia and an immune complex mediated process.

19.3.2Clinical Features

GN occurs later during the disease course of pSS compared to IN [26]. Hypertension, periorbital or facial pitting edema, and renal insufficiency due to decreased glomerular filtration rate (GFR) are the presenting features [26, 43, 45]. Some patients may also present with other extraepithelial manifestations such as purpura, peripheral neuropathy, and necrotizing vasculitis [44]. GN has also been observed as a part of systemic vasculitis, resulting from deposition of immune complexes at various sites. A patient with pSS and focal cresentic GN in the setting of necrotizing vasculitis affecting the central nervous system, the gastrointestinal tract, the pancreas, and the lungs was reported by Sato et al. [46]. Similarly, Tsokos et al. described three pSS patients with small and/or medium vessel vasculitis, without aneurysmal formation, resembling polyarteritis nodosa who had evidence of glomerular disease [47].

The most common urinary abnormalities are hematuria of glomerular origin with or without red blood cell casts and proteinuria of more than 500 mg/day [26, 43, 45]. Proteinuria of nephrotic range and full-blown nephrotic syndrome have been also

Fig. 19.3 Mesangial proliferation of glomerulus in a patient with primary Sjögren’s syndrome and glomerulonephritis (Hematoxylin and

eosin × 400) (Image kindly provided by Dr. Hariklia Gakiopoulou, Lecturer in Pathology, First Department of Pathology, Medical School of Athens)

reported but are not common manifestations among pSS patients with GN [12, 13, 17, 23]. Almost half of pSS patients with GN may develop non-Hodgkin’s lymphoma of B cell origin during follow-up [26]. This observation has also been reported in the past by Bruet et al [44]. GN, purpura, and peripheral neuropathy are extraepithelial manifestations that arise from an underlying immune complex-mediated process and define a distinct subset of patients who have a tendency to develop lymphomas.

The largest series of pSS patients with biopsy documented GN has been published from our department [26]. Among 471 pSS patients, 20 had overt renal involvement and 10 had clinical and laboratory findings indicative of glomerular disease, suggesting that severe renal impairment due to GN occurs in approximately 2.5% of pSS population. Two patients from the GN group required hemodialysis because of endstage renal failure, implying that GN carries a less favorable prognosis.

19.3.3Histology

The most common histologic types of GN in pSS are membranoproliferative, membranous, and mesangial GN. Membranoproliferative GN is characterized by diffuse proliferation of mesangial cells and infiltration of glomeruli by macrophages, increased mesangial matrix, and thickening along with reduplication of the glomerular basement membrane [12, 17, 23, 26, 45]. In most cases, C3 and IgM deposits are observed on immunofluorescence microscopy [12, 26]. In membranous GN, the major histologic findings are diffuse thickening of the glomerular basement membrane and subepithelial electron dense deposits [12, 17, 23, 45]. Mesangial proliferative GN is characterized by proliferation of mesangial cells and matrix, and probably represents an early stage of the disease that may evolve into more aggressive forms (Fig. 19.3) [12, 13, 23, 26]. Other rare forms of GN include focal segmental glomerulosclerosis [23, 42], cresentic GN [46], and proliferative GN [13, 43]. The limited

Abbreviations: FSGS focal segmental glomerulosclerosis, pSS primary Sjögren’s syndrome

number of cases and the lack of relevant data do not allow any correlation between a particular histologic type of GN and the severity of renal involvement in GN of pSS. However, it seems that patients with histologic lesions of membranous or membranoproliferative GN are more likely to develop nephrotic range proteinuria while mesangial GN is associated with mild proteinuria [12, 13, 26]. Table 19.2 summarizes all the biopsy documented cases of GN in pSS as well as the major clinical and laboratory findings that led to kidney biopsy.

19.3.4Pathogenesis

The pathogenesis of GN in pSS is closely related to type II mixed cryoglobulinemia. This association connotes an underlying oligoclonal or monoclonal B cell activation that becomes clinically apparent late in the disease course as a result of the ongoing antigenic stimulation of B lymphocytes. Cryoglobulins are serum immunoglobulins, which precipitate at temperatures below 37°C and redissolve after rewarming. According to the Brout classification, type II cryoglobulins are composed of IgG and an IgM of monoclonal origin with rheumatoid factor activity (anti IgG-RF) [48].

Type II cryoglobulinemia has been described in association with chronic infections, autoimmune diseases, and lymphoproliferative disorders. IgM-kappa cryoglobulins are detected in the majority of pSS patients with GN [26]. Low C4 complement levels is another common finding, indicative of complement activation in these patients [26]. These data, in combination with the presence of C3 and IgM deposits in biopsy specimens, suggest an immune complex-mediated process as a possible pathogenetic mechanism of GN in pSS [12, 26].

19.3.5Differential Diagnosis

The differential diagnosis of GN in pSS includes those diseases that can cause type II cryoglobulinemia and similar clinical manifestations. The most important are chronic HCV infection, HIV infection, and lymphoproliferative disorders [48, 49]. Patients with HCV infection may present with chronic sialadenitis, purpura, peripheral neuropathy, and glomerulonephritis due to cryoglobulinemia. However, in these patients, liver involvement is more common than in pSS patients and the prevalence of parotid enlargement is lower. In addition, the frequency of anti-HCV antibodies among patients with SS is low [50]. HIV infection may produce sicca manifestations, parotid swelling, lymphadenopathy, and rarely type II cryoglobulinemia [49]. SS can be distinguished from HIV infection serologically, since HIV patients generally lack anti-Ro/SSA and anti-La/SSB antibodies but they have anti-HIV antibodies. In a patient with pSS who presents with low C4 complement levels, cryoglobulinemia, purpura, and GN, an underlying lymphoproliferative disorder should be excluded, particularly if generalized lymphadenopathy is apparent. Systemic lupus erythematosus (SLE) should be also included in the differential diagnosis of a patient with cryoglobulinemic GN. Lupus nephritis may present with either nephritic or nephrotic syndrome and is usually accompanied by low C4 complement levels and elevated titers of anti-dsDNA antibodies. The presence of lupus-specific skin lesions, serositis, and hematologic abnormalities such as leukopenia, hemolytic anemia, or thrombocytopenia can distinguish lupus nephritis from GN of pSS.

19.3.6Treatment

Management of pSS patients with GN is based on clinical judgment since no clinical trials have been conducted to address this issue. In our series, six patients with membranoproliferative or mesangial GN and proteinuria with an active urine sediment received a combination of methylprednisolone and intravenous pulses of cyclophosphamide [26]. The fact that this combination has been proven beneficial in other types of immune complex-mediated glomerulonephritides such as lupus nephritis makes it a reasonable option for aggressive forms of pSS GN. Despite this regimen, two of the six patients developed end-stage renal failure and required