19.1Introduction

One of the parenchymal organs that can be affected in patients with Sjögren’s syndrome (SS) is the kidney [1]. Kidneys in primary SS (pSS) can be a target of the immune system either by activated lymphocytes that infiltrate the renal interstitium resulting in interstitial nephritis (IN) or by an immune complex mediated process appearing as glomerulonephritis (GN). Furthermore, epidemiologic and immunologic data suggest an association between SS and painful bladder syndrome/interstitial cystitis (PBS/IC), a chronic pelvic pain syndrome that produces lower urinary symptoms such as discomfort related to bladder, nocturia, frequency, and urge to void [1]. The term interstitial cystitis is reserved for patients with specific histologic lesions including lymphocytic inflammatory infiltrate of the submucosa and detrusor mastocytosis.

19.2Interstitial Nephritis in Primary Sjögren’s Syndrome

19.2.1Historical Aspects

IN is by far the most common type of renal involvement in pSS. In 1962, Kahn et al. performed renal function studies in eight SS patients and found that half had persistent hyposthenuria, suggesting a primary concentrating defect due to impaired water permeability of the distal convoluted tubules and collecting ducts [2]. Shearn et al. described a patient with SS who presented with nephrogenic diabetes insipidus, renal tubular acidosis (RTA), and Fanconi syndrome and proposed that SS could be a cause of acquired Fanconi syndrome due to renal tubular dysfunction [3]. Nephrogenic diabetes insipidus has been reported to occur in pSS patients with IN and was clinically expressed by polydipsia and polyuria as a result of inadequate response of the distal renal tubules to the action of vasopressin [4]. Latent distal RTA (dRTA) in SS, manifested by an inability to lower urinary pH below 5.5 after an acid loading test (i.e., administration of ammonium chloride), was first described by Shearn and Tu [5]. Subsequently, Tu et al. reported histologic features of IN in six out of eight patients with SS [6]. Talal et al. demonstrated that the major histologic finding in patients with SS and dRTA was a chronic lymphocytic infiltration of interstitium, strongly supporting that these periepithelial lesions could be the cause of renal tubular defects [7]. These data were then confirmed by Shioji et al., who described similar histologic findings in SS patients with dRTA but not in SS patients without this complication [8]. Hence, the clinical manifestations and urinary abnormalities of IN in pSS were pathogenetically associated with periepithelial lymphocytic infiltration of renal tubules.

19.2.2Clinical Features

IN is an early complication of pSS, and dRTA may be present many years before disease onset. Eriksson et al. after evaluating ten patients with dRTA and urolithiasis without subjective sicca symptoms, found that eight of them had anti-Ro/SSA and anti-La/SSB autoantibodies and seven of them developed SS after a mean of 15 years [9]. Pertovaara et al. reported that high serum levels of gammaglobulin, total serum protein, and beta-2 microglobulin were the best predictors of dRTA in pSS [10] but these findings have not been confirmed by other investigators.

In large series, the prevalence of dRTA and IN among pSS patients ranges from 11% to 48% [11–16]. Although IN occurs in almost one third of patients with pSS, it usually remains asymptomatic [17]. Most of these patients may present with complete or incomplete dRTA. Latent dRTA is characterized by impaired urinary acidification and evolves subclinically. This specific disorder seems to represent an incomplete form of dRTA that remains clinically silent but can be revealed after an acid loading test. Patients with latent dRTA are able to maintain normal acid–base balance with the usual dietary and endogenous hydrogen ion quantities, but exhibit an impaired urinary acidification under conditions of acid excess. On the other hand, complete dRTA constitutes the clinically apparent form of IN and may present with persistent alkaline urinary pH and hyposthenuria, hyperchloremic metabolic acidosis with an anion gap, hypokalemia, and hypercalciuria [18]. Longstanding dRTA, complete or incomplete, can lead to nephrolithiasis/nephrocalcinosis, renal colics and renal insufficiency (Fig. 19.1).

Hypercalciuria due to chronic acidosis, alkaline urine, and low levels of urine citrate contribute to renal stone formation. In some cases, hypokalemia is severe enough to cause muscular weakness expressed by periodic paralysis [12, 19–23]. Nephrogenic diabetes insipidus is centered in this particular spectrum of complete dRTA since inadequate response to vasopressin represents a tubular defect at this specific portion of the nephron. Some pSS patients may present with type 2 RTA and Fanconi syndrome rather than dRTA [3, 23–25]. Proximal renal tubule, although less frequently, can also be affected in pSS leading to impaired reabsorption of various nutrients and minerals. Fanconi syndrome is characterized by glucosuria, phosphaturia, aminoaciduria and tubular proteinuria but the complete form of the syndrome is rarely observed in pSS. In Table 19.1, the major clinical and laboratory findings of IN are presented.

Severe renal involvement due to IN is rare and has a good prognosis at least for several years. In a study of 471 pSS patients who were followed up from 1 to 15 years, 20 (4.2%) patients presented overt renal disease that was severe enough to warrant a kidney biopsy [26]. Ten patients were diagnosed as having IN, eight with GN, and two fulfilled criteria for both entities. Clinically significant IN was manifested by renal colics, polydipsia, polyuria, and nocturia. The major urinary abnormalities were persistently low specific gravity and alkaline urinary pH.

Fig. 19.1 Plain abdominal film of a patient with primary Sjögren’s syndrome and nephrocalcinosis due to renal tubular acidosis

Table 19.1 The major clinical and laboratory findings of IN in pSS

Abbreviations: IN interstitial nephritis, pSS primary Sjögren’s syndrome, RTA renal tubular acidosis

These data suggest that most cases of IN are asymptomatic and may escape clinical attention. Thus, the prevalence of severe IN in pSS is low and does not exceed 2.5% of pSS population. In addition, IN follows a rather benign course in pSS and has a favorable outcome, since none of the patients developed end-stage renal failure.

Fig. 19.2 Focal lymphocytic infiltration of kidney interstitium in a patient with primary Sjögren’s syndrome and interstitial nephritis (Hematoxylin and eosin × 200)

19.2.3Histology

The histologic hallmark of IN is periepithelial lymphocytic infiltration of renal tubules (Fig. 19.2) similar to that observed around the epithelium of salivary and lacrimal glands. This fact implies a common immunological process that occurs early in the disease course. The inflammatory infiltrate consists mainly of mature lymphocytes; plasma cells and monocytes participate to a lesser extent [7, 8, 27, 28]. Variable degree of interstitial fibrosis and tubular atrophy, along with hyaline casts and degeneration of tubular epithelial cells, can be also observed [7, 8]. Another histologic feature is the presence of a subset of lymphocytes that invades the epithelium and produces the histologic picture of tubulitis [27]. Immunofluorescence studies rarely reveal trace staining of the interstitium and the tubular basement membrane with immunoglobulins and C3 [28].

19.2.4Pathogenesis

Almost 50% of the infiltrating cells bear the CD4 phenotype, while CD8-positive cells account for 25% of the total population [27]. This increased CD4/CD8 ratio is similar to that observed in the salivary gland lesion. However, the majority of these T lymphocytes express a restricted repertoire of TCR Vb genes compared to that of salivary glands, suggesting that T cells that infiltrate the kidney of SS patient with IN, might recognize different autoantigens than those that infiltrate the salivary glands [29]. On the contrary, monocytes and B cells comprise only minor components of the infiltrating cell population [27].