INTRODUCTION — Primary Sjögren syndrome (PSS) is typically associated with a lymphocytic and plasmacytic infiltrate in the salivary, parotid, and lacrimal glands, leading to a sicca syndrome. This immune process can also affect nonexocrine organs, including the kidneys, producing a tubulointerstitial nephritis and defects in tubular function. (See "Clinical manifestations of Sjögren's syndrome: Extraglandular disease".)
The reported prevalence of kidney involvement has varied widely, ranging from 1 to 33 percent [1-4]. This variability is due in part to different definitions of kidney involvement. In a kidney biopsy series of 25 patients, systemic features of PSS preceded kidney manifestations by a median of 5.5 years [5]. Twenty-two patients were female, and the median age at the time of biopsy was 55 years. Thirteen patients had proteinuria >1 g, and estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m2 was seen in 21 patients; more than one-half of the patients had eGFR <30 mL/min/1.73 m2. In another series, kidney involvement occurred in 4.9 percent of 715 patients with PSS, with glomerular involvement occurring more frequently than tubulointerstitial disease; 37 percent had tubulointerstitial nephritis alone, 49 percent had glomerulonephritis alone, and 14 percent had both. The prognosis appears to be worse in patients with predominantly glomerular involvement, with lower survival rates and higher incidence of lymphoma compared with patients with predominantly tubulointerstitial involvement [6].
TUBULOINTERSTITIAL NEPHRITIS — Chronic tubulointerstitial nephritis is the most common kidney manifestation of PSS [5,7]. The clinical presentation may be subtle, asymptomatic, and detectable only by laboratory testing.
The tubulointerstitial nephritis in PSS is characterized histologically by an interstitial infiltrate that can invade and damage the tubules [3,8,9]. In some cases, granuloma formation is seen, and there may be a concurrent uveitis, suggesting the possible presence of sarcoidosis or the tubulointerstitial nephritis and uveitis (TINU syndrome) [7,10]. (See "Kidney disease in sarcoidosis" and "Tubulointerstitial nephritis and uveitis (TINU syndrome)".)
More chronic disease is associated with tubular atrophy and interstitial fibrosis. The glomeruli are usually normal, although an immune complex-mediated glomerulonephritis has rarely been described [11]. (See 'Glomerular disease' below.)
The clinical manifestations of the tubulointerstitial nephritis include a variable but generally mild elevation in the plasma creatinine concentration, a relatively benign urinalysis, and abnormalities in tubular function, including the Fanconi syndrome, distal (type 1) renal tubular acidosis (RTA), nephrogenic diabetes insipidus (tubular resistance to antidiuretic hormone), and hypokalemia [9,12-18].
There are few data defining the optimal treatment of tubulointerstitial nephritis in PSS. In the absence of such data, it seems reasonable to prescribe a course of glucocorticoids if the tubulointerstitial nephritis is severe and active (eg, if interstitial fibrosis is mild-moderate with significant interstitial inflammation and especially tubulitis) [19]; stabilization or improvement in kidney function has been reported anecdotally. Prednisone, starting at 1 mg/kg/day (up to 60 mg per day), has been used followed by a taper according to clinical response. Following stabilization or improvement of kidney function, glucocorticoids may be gradually withdrawn over six to eight weeks. If there is relapse of disease as evidenced by worsening kidney function or pyuria, azathioprine maintenance therapy at doses of 1 to 2 mg/kg/day can be instituted as a steroid-sparing agent in patients who appear to be steroid dependent [19]. Mycophenolate mofetil has also been used in this setting [20].
Distal renal tubular acidosis — A defect in distal acidification occurs in up to 25 percent of patients with PSS [12,14]. The associated metabolic acidosis is usually mild, but some patients present with a plasma bicarbonate concentration below 10 mEq/L and a plasma potassium concentration below 1.5 to 2 mEq/L due to concurrent urinary potassium wasting. A brief review of the mechanisms by which distal acidification might be impaired and the effect of these abnormalities on distal potassium secretion is available elsewhere (see "Overview and pathophysiology of renal tubular acidosis and the effect on potassium balance"). Muscle paralysis and respiratory arrest have been reported as consequences of the severe hypokalemia [12,14]; in some cases, hypokalemic paralysis has been the presenting symptom of PSS [12].
The mechanism by which PSS leads to distal RTA is incompletely understood. Several patients have been described in whom immunocytochemical analysis of tissue obtained by kidney biopsy showed complete absence of the H-ATPase pump in the intercalated cells in the collecting tubules that is largely responsible for distal proton secretion [15,16]. How the immune injury leads to loss of H-ATPase activity is not known. Another possible mechanism is the presence of high titers of an autoantibody directed against carbonic anhydrase II; inhibition of this enzyme would result in the generation within the cell of fewer hydrogen ions available for secretion [21].
Some patients present with a normal anion gap metabolic acidosis due to distal RTA without a prior diagnosis of PSS [12]. It is therefore important to consider the possible presence of this disorder in any adult with otherwise unexplained distal RTA since treatment aimed at the immunologic disease (as described above) may at least partially correct the acidification defect. (See "Etiology and diagnosis of distal (type 1) and proximal (type 2) renal tubular acidosis" and 'Tubulointerstitial nephritis' above.)
Clinical manifestations and treatment of patients with distal RTA are discussed elsewhere. (See "Overview and pathophysiology of renal tubular acidosis and the effect on potassium balance" and "Treatment of distal (type 1) and proximal (type 2) renal tubular acidosis".)
Nephrogenic diabetes insipidus — Polyuria and polydipsia due to nephrogenic diabetes insipidus is another manifestation of impaired tubular function in PSS [17]. Once again, patients may present with these complaints rather than a sicca syndrome. It is therefore important to exclude PSS in any adult with symptomatic nephrogenic diabetes insipidus who does not have the two most common causes of this disorder: chronic lithium ingestion or hypercalcemia. (See "Clinical manifestations and causes of nephrogenic diabetes insipidus".)
Hypokalemia without renal tubular acidosis — The tubular injury induced by the tubulointerstitial nephritis indirectly leads to potassium wasting and potentially severe hypokalemia [12,18]. The primary defect is thought to be sodium wasting, which has two effects that augment potassium secretion: It increases sodium delivery to the potassium secretory site in the collecting tubules and, via volume depletion, enhances the release of aldosterone [18]. These clinical features mimic Gitelman syndrome, and PSS is in the differential diagnosis in patients with Gitelman-like syndrome [22]. (See "Bartter and Gitelman syndromes in adults: Diagnosis and management", section on 'Acquired syndromes' and "Inherited hypokalemic salt-losing tubulopathies: Pathophysiology and overview of clinical manifestations".)
This mechanism is different from that in RTA, and these patients can acidify the urine normally and do not have metabolic acidosis [18].
GLOMERULAR DISEASE — Glomerular involvement is much less common than tubulointerstitial nephritis in PSS. Membranoproliferative glomerulonephritis (MPGN) and membranous nephropathy (MN) are the most common glomerular pathologies associated with PSS [7,9,23-25]. Other glomerular lesions including minimal change disease, immunoglobulin A (IgA) nephropathy, and antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis have been reported [5]. The pathogenesis of the glomerular disease, including the possible etiologic relationship to PSS, is unclear but may be related to the deposition of circulating immune complexes, sometimes with underlying cryoglobulinemia [9,26,27]. Evidence of hepatitis C infection may exist in 14 percent of patients with PSS [28] and 47 percent of patients with PSS with cryoglobulinemia [29]. Low complement C3 and cryoglobulinemia (both type II and III) are more common with glomerular disease (compared with tubulointerstitial disease) [6].
Optimal therapy is uncertain. Some patients with MPGN, for example, have been treated with prednisone without or with cytotoxic therapy (such as cyclophosphamide) or rituximab with varying reports of success [7,9,19,23,27]. The treatment of MPGN and cryoglobulinemic GN is discussed at length elsewhere. (See "Mixed cryoglobulinemia syndrome: Treatment and prognosis" and "Membranoproliferative glomerulonephritis: Treatment and prognosis".)
DIAGNOSIS — We believe a kidney biopsy should be done to define the nature of the kidney involvement when there is impaired/worsening kidney function, with or without significant proteinuria or hematuria. The kidney findings in PSS are not specific for this disorder, as the diagnosis generally requires a sicca syndrome be present with objectively abnormal ocular tests and lymphocyte infiltration around the salivary glands in a biopsy specimen. However, similar ocular findings can be seen in sarcoidosis, and the sensation of dry mouth can be induced by a variety of drugs. The autoantibodies anti-Ro (SSA) and anti-La (SSB) are relatively specific for PSS and, if present, can help confirm the diagnosis in the proper clinical setting [30] (see "Diagnosis and classification of Sjögren's syndrome"). In addition, patients with immunoglobulin G4 (IgG4)-related disease may have salivary and lacrimal gland involvement, as well as tubulointerstitial nephritis. (See "Pathogenesis and clinical manifestations of IgG4-related disease".)
Patients with PSS should be screened for hepatitis C virus. (See 'Glomerular disease' above.)
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Chronic kidney disease in adults" and "Society guideline links: Sjögren's syndrome".)
SUMMARY AND RECOMMENDATIONS
●The reported prevalence of kidney involvement in patients with primary Sjögren syndrome (PSS) varies from 2 to 67 percent due in part to different definitions of kidney involvement. (See 'Introduction' above.)
●Kidney disease in PSS is usually characterized by chronic tubulointerstitial nephritis, marked clinically by a variable but generally mild elevation in the serum creatinine, a relatively benign urinalysis, and abnormalities in tubular function (eg, distal [type 1] renal tubular acidosis [RTA], nephrogenic diabetes insipidus, and hypokalemia) (see 'Tubulointerstitial nephritis' above):
•A defect in distal acidification occurs in up to 25 percent of patients with PSS. The associated metabolic acidosis is usually mild, but some patients present with a plasma bicarbonate concentration below 10 mEq/L and a plasma potassium concentration below 1.5 to 2 mEq/L due to concurrent urinary potassium wasting. Occasionally, distal RTA may occur without a prior diagnosis of PSS. Thus, it is important to consider the possibility of PSS in any adult with otherwise unexplained distal RTA since treatment aimed at the immunologic disease may at least partially correct the acidification defect. (See 'Distal renal tubular acidosis' above.)
•Polyuria and polydipsia due to nephrogenic diabetes insipidus is another manifestation of impaired tubular function that, like distal RTA, may occur without a prior diagnosis of PSS. It is therefore important to exclude PSS in any adult with symptomatic nephrogenic diabetes insipidus who does not have chronic lithium ingestion or hypercalcemia. (See 'Nephrogenic diabetes insipidus' above.)
•The tubular injury induced by the tubulointerstitial nephritis indirectly leads to potassium wasting and potentially severe hypokalemia. (See 'Hypokalemia without renal tubular acidosis' above.)
●A course of glucocorticoids (eg, prednisone 1 mg/kg/day up to 60 mg/day followed by tapering doses depending upon clinical response) may be prescribed in patients with severe active tubulointerstitial nephritis. In patients who appear to be steroid dependent, azathioprine (1 to 2 mg/kg/day) may be used as a steroid-sparing agent. Progression to end-stage kidney disease is a rare event. (See 'Tubulointerstitial nephritis' above.)
●Glomerular involvement is much less common than tubulointerstitial nephritis in PSS. Membranoproliferative glomerulonephritis (MPGN) and membranous nephropathy (MN) are the most common. Optimal therapy in such cases is uncertain. (See 'Glomerular disease' above.)
●Patients with PSS should be screened for hepatitis C virus. (See 'Diagnosis' above and 'Glomerular disease' above.)
●The kidney findings in PSS are not specific for this disorder; the diagnosis generally requires a sicca syndrome be present with objectively abnormal ocular tests and lymphocyte infiltration around the salivary glands in a biopsy specimen. However, similar ocular findings can be seen in sarcoidosis, and the sensation of dry mouth can be induced by a variety of drugs. In addition, patients with immunoglobulin G4 (IgG4)-related disease may have salivary and lacrimal gland involvement, as well as tubulointerstitial nephritis. The autoantibodies anti-Ro (SSA) and anti-La (SSB) are relatively specific for PSS and, if present, can help confirm the diagnosis in the proper clinical setting. (See 'Diagnosis' above.)
