1 Division of Nephrology and 2 Service of Clinical Immunology, Spedali Civili and Università, Brescia and 3 Division of Nephrology, Università dell'Insubria, Varese, Italy
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Abstract |
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Methods. We studied the prevalence and nature of kidney involvement in 60 Italian patients with primary Sjögren's syndrome, diagnosed according to the European classification criteria. The following renal laboratory tests were performed in all patients: electrolytes in serum and in 24-h urine, creatinine in serum and in 24-h urine, venous pH and HCO3, urinalysis, urine culture, urinary osmolality and urine pH. A water deprivation test was performed in patients with morning urine osmolalities below the reference values adjusted for age. An oral ammonium chloride loading test was performed in patients with urine pH above 5.5 from morning samples. Renal biopsy was performed in patients with renal involvement.
Results. Sixteen patients (27%) had laboratory evidence of tubular and/or glomerular dysfunction. A variable degree of creatinine clearance reduction was found in eight patients (13%); frank distal tubular acidosis in three (5%); hypokalaemia in four (7%); and pathological proteinuria in 12 (20%). Urine concentrating capacity was defective in 10 out of 48 (21%) tested patients. Only four patients presented with overt clinical manifestations, including hypokalaemic tetraparesis (1), nephrotic syndrome (2), recurrent renal stones with flank pain and haematuria (1). In two patients, signs of renal involvement preceded the onset of sicca syndrome. Renal biopsies from nine patients showed tubulo-interstitial nephritis in six and glomerular disease in three. Patients with renal involvement had a significantly shorter disease duration compared with patients without renal abnormalities.
Conclusions. Kidney involvement is a frequent extraglandular manifestation of primary Sjögren's syndrome. It is rarely overt and may precede the onset of subjective sicca syndrome.
Keywords: defective urine concentrating capacity; glomerulonephritis; renal tubular acidosis; Sjögren's syndrome; tubulointerstitial nephritis
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Introduction |
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The presence of renal involvement in Sjögren's syndrome has been known since the 1960s. Most commonly, a tubulointerstitial nephritis with defects in tubular function has been found [58]. However, glomerular diseases, such as membrano-proliferative glomerulonephritis and membranous nephropathy, have also been reported [910]. The true prevalence of renal involvement in primary Sjögren's syndrome has not been clearly assessed. This is due, in part, to the fact that different sets of diagnostic criteria have been used by various authors [11]. In addition, primary and secondary Sjögren's syndrome patients have been occasionally analysed together. Recently, a new set of classification criteria, defined by a multicentre European study, showed a high sensitivity and specificity for the disease [12,13].
In this report, we evaluated the prevalence of kidney involvement in 60 Italian patients with primary Sjögren's syndrome, and analysed whether this disorder is a cause of renal impairment. Our purpose was to examine relationships between the clinical and serological features of the syndrome and the presence of renal disease.
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Patients and methods |
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General laboratory examinations
The patients underwent the routine laboratory tests, including peripheral blood cell count, erythrocyte sedimentation rate (ESR), serum C-reactive protein (CRP), hepatitis viral markers, protein electrophoresis, serum levels of total IgG, complementaemia, rheumatoid factor (RF), cryoglobulins, screening for antinuclear antibodies (ANA), antibodies to native DNA and antibodies to extractable nuclear antigens (ENA), including anti-Ro/SSA and anti-La/SSB, detected by counter-immunoelectrophoresis with rabbit thymus extract and human spleen extract as substrates.
Renal laboratory investigations
Renal laboratory investigations included Na+, K+, Cl-, Ca2+, PO42-, creatinine in serum and in 24-h urine, venous pH and HCO3-, urinalysis, 24-h urine protein excretion, urine culture, serum osmolality, urinary osmolality and urine pH. Microscopic haematuria was defined by the presence of 2+ occult blood by dipstick analysis (Ames) and/or more than five red cells per high-power field. Pathological proteinuria was defined as 2+ protein by dipstick analysis (Ames) and/or protein excretion of more than 250 mg/24 h, measured by the turbidimetric assay with sulfosalicylic acid. Glomerular filtration rate (GFR) was evaluated by creatinine clearance (normalized to 1.73 m2 body surface area), estimated by three determinations over a period of 35 weeks. Normal renal function was defined as a creatinine clearance of more than 75 ml/min in women and 95 ml/min in men [14,15].
Tubular function tests
In the absence of metabolic acidosis, the renal acidification capacity was assumed to be normal when the urine pH was 5.5 or below in morning samples. Complete distal renal tubular acidosis (dRTA) was diagnosed in patients with metabolic acidosis (blood base excess below -6 mmol/l in at least two different specimens), a urine pH persistently above 5.5, and a positive value of the urine net charge (urine anion gap) evaluated in a 24-h urine sample. The urine anion gap, considered to be an indirect estimate of urinary ammonium excretion, was calculated by the following equation:
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The urinary concentrating capacity was considered to be normal when urine osmolality, determined cryoscopically, from a fresh morning specimen reached a normal level defined according to the following age-related intervals: 850 mOsm/kg (20 years); 800 mOsm/kg (40 years); 700 mOsm/kg (60 years); 600 mOsm/kg (80 years) [19]. In patients with morning urine osmolality below the reference value adjusted for age, the water deprivation test was performed. Baseline values for plasma osmolality, plasma sodium, and urinary osmolality were obtained. Since no patient was clearly polyuric (daily urine volume, determined on two different occasions, was less than 2000 ml per day; polyuria was arbitrarily defined as a urine output exceeding 3 l/day), the first part of the water deprivation test was performed overnight. No water intake was allowed after a dry dinner, and breakfast was not allowed the following morning until the test was concluded. The water restriction test was continued for 1618 h, until the urine osmolality reached the above-mentioned normal age-related level, or the urine osmolality was stable on three successive measurements despite increases in plasma osmolality to above 295 mOsmol/kg. In patients who failed to achieve a normal age-related urine osmolality following the dehydration period, the second part of the water deprivation test was carried out. This consisted of 20 µg of dDAVP administration by nasal insufflation followed by urine osmolality determination after 90 and 180 min. A defective concentrating ability due to varying degrees of nephrogenic diabetes insipidus was diagnosed in patients having a urine osmolality persistently lower than expected for age and having increases in urine concentration less than 10% after dDVAP administration with otherwise normal renal function [19].
Renal biopsy
A percutaneous renal biopsy was proposed to patients presenting with a variable reduction of creatinine clearance, tubular defects, and urinary abnormalities. Renal specimens were processed for both light microscopy and immunofluorescence study.
Statistical analysis
Patients without renal involvement and patients with renal abnormalities were compared using Fisher's exact tests for frequencies, and unpaired t-tests for interval data. Statistical significance was accepted at P<0.05.
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Results |
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Renal routine laboratory investigation
The results of the routine nephrological tests and tubular function tests are shown in Table 3. A variable reduction in creatinine clearance, usually slight (range 4770 ml/min), was found in eight patients (13%). A frank distal tubular acidosis was observed in three patients (5%). One of these patients showed severe hypokalaemia and a slight reduction in creatinine clearance and a second patient had tubular acidosis, associated with hypokalaemia, and a reduced creatinine clearance that was complicated by nephrocalcinosis. Pathological proteinuria was found in 12 patients (20%). In nine of these patients, protein excretion was less than 1 g/day; in one patient, proteinuria was 1.52 g/day; in two patients, proteinuria was in the nephrotic range. The electrophoretic appearance of urinary proteins was available for nine patients. In three patients, proteinuria was glomerular in origin, consisting overwhelmingly of albumin; these patients had biopsy-proven glomerular disease. A tubular pattern of proteinuria, characterized by a small albumin fraction (less than 20% of total urinary protein) and by the predominance of low molecular weight protein, was identified in six patients; in five of these, renal biopsy indicated tubulo-interstitial nephritis. Microscopic haematuria was associated with proteinuria in five patients. None of the patients showed renal glycosuria and/or hypophosphataemia. Hypokalaemia was found in four patients and in two of these it was associated with frank distal tubular acidosis. No patient had hyperkalaemia.
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Tubular function tests
Morning urine pH measured by dipstick was below 5.5 in 37 patients. Of the 23 patients with urine pH >5.5, three had frank tubular acidosis, and BRE after acidosis correction was less than 5%. The remaining 20 patients having urine pH>5.5 in the absence of complete dRTA agreed to participate in an oral ammonium chloride loading test. In eight of them the test failed due to nausea or vomiting. The acidification capacity was normal in the 12 patients who completed the test, and all exhibited a serum HCO3- concentration <20 mEq/l after ammonium chloride loading (Table 3).
Morning urine osmolality reached a normal age-related value in 20 of the 59 tested patients (Table 3); 39 patients showed urine osmolality levels below the reference value adjusted for age, and 38 of these agreed to participate in a water deprivation test. Ten patients interrupted the test, because of xerostomia. In the 28 patients who completed the water deprivation test, baseline values for plasma osmolality and plasma sodium were within normal limits (275290 mosmol/kg and 137143 mmol/l, respectively). Following dehydration, dDVAP was administered in 20 patients, to cause a further increase in urine concentration of less than 10%. The water deprivation test revealed a defective urine concentrating ability in 10 patients (21% of the 48 tested patients). In five of these, the concentrating defect was associated with a variable and usually slight reduction in creatinine clearance; the remaining five patients had normal creatinine clearances, and in three of these the urine concentrating defect was the sole sign of renal involvement.
In summary, 16 patients (27%) showed laboratory evidence of tubular and/or glomerular dysfunction (Table 4). However, only four of these patients presented overt clinical manifestations, including hypokalaemic tetraparesis (one patient), nephrotic syndrome (two patients), and recurrent renal stones with flank pain and haematuria (one patient). The patient with renal stones had also nephrocalcinosis and a complete distal tubular acidosis. In two patients, sicca syndrome developed after the onset of renal disease. In one of these (Table 4
; patient 5), renal biopsy at the first sign of mild renal insufficiency revealed tubulointerstitial nephritis. Positive Ro/La antibodies combined with negative sicca symptoms indicated the need for lip biopsy which turned out to be negative for Sjögren's syndrome. After 6 months, xerostomia and keratoconjunctivitis appeared and Shirmer-test and parotid scialography were positive. In the second patient (Table 4
; patient 12), a mild renal insufficiency and tubular proteinuria were discovered but in the absence of systemic signs. One year later, ocular and oral symptoms consistent with sicca syndrome appeared. Shirmer and rose bengal score tests were positive and Ro/La antibodies were also positive. Renal biopsy indicated tubulointerstitial nephritis.
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Histological studies
Nine patients with kidney involvement agreed to undergo renal biopsy. In six patients, mild to severe tubulo-interstitial nephritis was found. It was characterized by focal (Figure 1) or diffuse (Figure 2
) lymphoplasmocellular infiltrate of mononuclear cells with variable tubular atrophy; mild to intense interstitial fibrosis was also observed. The six patients with tubulointerstitial nephritis had one or more of the following renal abnormalities: reductions in creatinine clearance (five patients); complete dRTA (three patients); concentrating renal defects (four patients); and tubular proteinuria (five patients) (Table 4
). Chronic glomerulonephritis was diagnosed in three patients. One patient showed membranous nephropathy and another showed mesangio-proliferative glomerulonephritis with C3 deposits. In these two patients, a variable degree of interstitial infiltrative changes were also noted (Figure 3
), but no circulating cryoglobulins were detected. In the third patient, renal biopsy disclosed membrano-proliferative cryoglobulinaemic glomerulonephritis, with intraluminal thrombi and diffuse IgM deposition in the capillary loops on immunofluorescence microscopy; no signs of hepatitis C viral (HCV) infection were detected.
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Comparison of patients with and without renal abnormalities
The patients were divided into two groups, according to the presence or absence of renal involvement. Thus, 16 patients with both tubulointerstitial and glomerular involvement were compared with 36 patients showing normal routine nephrological and tubular function tests. Table 5 summarizes several factors as they relate to occurrence of renal involvement. Patients with renal involvement had a shorter disease duration compared with patients without renal abnormalities (P=0.002). Otherwise, no significant differences were observed.
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Discussion |
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Our study was designed to evaluate the frequency of renal involvement in a large group of patients with primary Sjögren's syndrome diagnosed according to the European classification criteria. The homogeneous make-up of our study gave us the opportunity to outline certain aspects of renal involvement in primary Sjögren's syndrome, which have been controversial in the literature.
The prevalence and type of renal involvement in primary Sjögren's syndrome are unclear. In the literature, the frequency of renal abnormalities varies from 16% to 67% [58,2024]. Several reasons may account for this discrepancy. The first is that only small groups of patients with Sjögren's syndrome were studied for renal involvement. The second is the lack of well-defined and commonly accepted criteria for diagnosing primary Sjögren's syndrome. Third, in some studies, primary and secondary forms of Sjögren's syndrome were analysed together making it difficult to understand whether renal involvement should be ascribed to Sjögren's syndrome per se, or to associated disorders. Thus, the true prevalence of renal disease in primary Sjögren's syndrome remains uncertain, and studies involving larger patient groups with diagnoses according to highly valid and reliable criteria are still needed.
In our patient population, the prevalence of renal disease was 27%, confirming kidney involvement as a frequent extraglandular manifestation of primary Sjögren's syndrome. The majority of patients with renal involvement had one or more laboratory signs of tubular dysfunction. A frank distal tubular acidosis was found in 5% of our patients. In contrast with previous reports [8,2024], the present tubular function studies did not reveal incomplete distal tubular acidosis. A selection bias, as well as the failure of the ammonium chloride loading test in some of our patients, may account for this difference.
In our series, a defective urine-concentrating ability was found in 10 patients (21%). The water deprivation test revealed that this submaximal rise in urine osmolality was consistent with the presence of a mild, asymptomatic form of nephrogenic diabetes insipidus. A similar response to water deprivation is observed in primary polydipsia. In patients with Sjögren's syndrome who have a history of xerostomia possibly causing excessive fluid intake, primary polydipsia should be considered as an alternative diagnosis. In our patients, however, the absence of a frank poliuria and normal baseline plasma sodium concentration and plasma osmolality did not indicate polydipsia. In five patients, the concentrating defect was associated with a slight to mild reduction in renal function, a condition which per se may be associated with a reduction in maximum concentrating ability. In the remaining five patients, renal function was normal and the defective urine-concentrating capacity was attributable to the presence of a tubulo-interstitial nephritis. The urine-concentrating defect was the sole renal abnormality in three patients, suggesting that urine-concentrating capacities may be the first renal mechanisms that are damaged. Since there are few systematic studies of urine-concentrating capacity in patients with Sjögren's syndrome, estimates of its frequency are difficult to evaluate. The three largest population studies cite incidences from 16% to 82%, suggesting that a defective concentrating capacity, although usually overlooked, is not uncommon [1,22,24]. This form of acquired nephrogenic diabetes insipidus is frequently mild. The ability to elaborate a hypertonic urine is usually preserved, in spite of an impaired maximal concentrating ability of the nephrons. In our patients, the reduced concentrating ability was usually modest, and not severe enough to produce symptomatic polyuria; however, some patients complained of nocturia.
Histological studies confirmed that the renal involvement can be primarily ascribed to a tubulointerstitial nephritis [5,8]. The drug histories of our patients excluded a contributory role of analgesic usage in the development of interstitial nephritis; moreover, clinical and ultrasonographic features of chronic pyelonephritis were absent. Pathological examination revealed predominantly a focal or diffuse lymphocytic cell infiltrate in the interstitial tissue. The interstitial lymphocytic infiltrate is a part of the multiple organ-system involvement characteristic of Sjögren's syndrome and may be considered an indicator of underlying disease activity. Advanced renal changes indicating chronic interstitial nephritis, including interstitial fibrosis and tubular atrophy, which probably represented an advanced stage of the disease process, were also present. Whether a florid interstitial infiltrate would be reversible with steroids treatment remains uncertain, since only occasional cases of renal tubular acidosis and/or renal insufficiency remitted with steroid therapy [25,26].
In spite of the prevalent tubulo-interstitial involvement, our study revealed an immuno-mediated glomerulonephritis in 5% of patients. This is an intriguing finding, since glomerular involvement is rare in primary Sjögren's syndrome. Up to 1995, less than 20 cases of glomerulonephritis have been reported. Membrano-proliferative glomerulonephritis, membranous nephropathy, and focal mesangio-proliferative glomerulonephritis were the most common pathological lesions encountered [9,10,19,20]. The occurrence of glomerular disease in a Sjögren's syndrome patient raises the possibility of an associated connective tissue disorder, particularly systemic lupus erythematosus. This was highly unlikely in our series, since no patient fulfilled the classification criteria for systemic lupus erythematosus.
The pathogenesis of glomerular disease, including the possible aetiological relationship to the Sjögren's syndrome, remains poorly understood. Increases in the circulating immune complexes may play a key role and result in their glomerular deposition [9,10]. A recent study by Skopouli et al. [27] indicated that palpable purpura, decreased C4 complement concentration, and mixed monoclonal cryoglobulinaemia are significant predictors for the development of glomerulonephritis in patients with primary Sjögren's syndrome, suggesting that glomerulonephritis pathogenesis in the majority of patients may be attributed to deposition of immune complexes formed by cryoprecipitating monoclonal IgM along with polyclonal IgG and IgA. However, glomerular disease may occur in the absence of circulating cryoglobulins. Also, in the present setting, the nature of antigen involvement and the factors responsible for triggering the nephritogenic immune response remain unclear. In our series, one case had membranous nephropathy and another had mesangial proliferative glomerulonephritis, and both had a variable degree of interstitial infiltrative changes. The third patient showed specific histological findings indicating cryoglobulin-induced membranoproliferative glomerulonephritis, and type II mixed cryoglobulinaemia was detected in her serum. HCV infection, a condition increasingly recognized a cause of Sjögren's-like syndrome and which has been associated with 95% of cases of type II mixed cryoglobulinaemia cases, was not documented. Thus, in this patient, type II cryoglobulinaemia probably belongs to the spectrum of lymphoproliferation associated with Sjögren's syndrome. This spectrum may extend from an increased frequency of circulating monoclonal Ig, free light chains, mixed monoclonal cryoglobulinaemia to non-Hodgkin's lymphoma (24). In our patients, glomerulonephritis was indicated by urinary protein excretion in excess of 1 g/24 h or in nephrotic range. In addition, the electrophoretic appearance of urinary proteins, showing a glomerular rather than a tubular pattern, further suggested the presence of glomerular disease.
Renal involvement in Sjögren's syndrome may be frequently latent. Clinically overt signs of renal disease were found in a minority of our patients. One patient manifested a hypokalaemic paralysis, two patients had overt nephrotic syndrome, and one patient had a history of recurrent stone disease complicated by nephrocalcinosis. Signs of renal involvement, such as urine abnormalities and tubular defects, were most commonly identified in the absence of apparent clinical manifestations. This suggests that clinically evident renal disease is rare in patients with primary Sjögren's syndrome and that the presence of subclinical renal dysfunction, usually ascribed to tubulo-interstitial nephritis of variable degrees, may be detected by means of appropriate tests.
Renal disease may precede the onset of the subjective sicca syndrome, considered to be the classical manifestation of Sjögren's syndrome. In two of our patients, renal disease antedated by several months the onset of ocular and oral symptoms. Renal disease preceding the onset of sicca syndrome has already been reported in patients with primary Sjögren's syndrome. Tu et al. [5] first described a patient whose chief manifestation of Sjögren's syndrome was nephrogenic diabetes insipidus, which antedated by many years the onset of ocular and articular abnormalities. Subsequently, distal renal tubular acidosis and urolithiasis preceding subjective sicca symptoms have been reported in three different studies examining Sjögren's syndrome [5,28,29]. These findings make it clear that evidence for Sjögren's syndrome should be sought in adult patients with unexplained clinical and laboratory features of interstitial nephritis that lack the typical characteristics of chronic pyelonephritis, even in the absence of subjective sicca syndrome.
An additional important finding of the current study was the lack of serological and clinical differences between patients with and without renal involvement. There were also no differences between the two groups with respect to the patient age. However, the patients with renal involvement had a shorter disease duration compared with patients without renal abnormalities. In a previous study, Shiozawa et al. [22] found that patients with Sjögren's syndrome showing tubular defects were significantly younger, had a longer disease duration and had a lower creatinine clearance. Subsequently, Viergever and Swaak [24] found that ANA was more frequent in patients with abnormal tubular tests, suggesting that more severe autoimmunity may increase the risk of renal involvement. A bias in patient selection may explain these differences. However, the observation that our patients with renal involvement had a shorter disease duration is equally noteworthy, and may further support the concept that there is no set temporal order symptom appearance in this disease [1,5,7]. Thus, it should be expected that some patients show visceral involvement, such as a renal defect, before the clinical occurrence of sicca symptoms, which usually determine the diagnosis of Sjogren's syndrome.
In conclusion, the present study indicates that kidney involvement is a frequent extraglandular manifestation of primary Sjögren's syndrome. The renal involvement is rarely overt, and more often follows a subclinical course. In some cases, it may precede the onset of subjective sicca syndrome.
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Notes |
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References |
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