Original Report: Patient-Oriented, Translational Research American
Journal of
Nephrology
Received: December 19, 2013 Accepted: June 9, 2014 Published online: August 20, 2014
Am J Nephrol 2014;40:123–130 DOI: 10.1159/000365199
Renal Tubular Acidosis in Sjögren’s Syndrome: A Case Series Rapur Ram a Gudithi Swarnalatha b Kaligotla Venkata Dakshinamurty b
Department of Nephrology, Sri Venkateswara Institute of Medical Sciences, Tirupati, and b Department of Nephrology, NIMS, Hyderabad, India
Key Words Renal tubular acidosis · Sjögren’s syndrome · Fractional excretion of bicarbonate · Anti-Ro (SS-A) · Anti-La (SS-B) · Hypokalemia · Hyperchloremic metabolic acidosis · Polyuria
Abstract Background: The exact frequency of distal and proximal renal tubular acidosis (RTA) in Sjögren’s syndrome is unknown. Other features of Sjögren’s syndrome like polyuria, glomerular manifestations, familial occurrence and pregnancy are not widely reported. The aim was to prospectively study the clinical features and outcome of distal and proximal RTA in Sjögren’s syndrome and also report on other renal manifestations of Sjögren’s syndrome. Methods: The present study is a prospective consecutive case series of patients who presented with a history suggestive of RTA and Sjögren’s syndrome. All patients were followed for 1 year. The diagnosis of RTA was by fractional excretion of bicarbonate. The diagnosis of Sjögren’s syndrome was according to the AmericanEuropean classification system [modified by Tzioufas and Voulgarelis: Best Pract Res Clin Rheumatol 2007; 21: 989– 1010]. Results: The total number of RTA patients diagnosed during this period was 149. Sjögren’s syndrome accounted for 34.8% (52 of 149) of RTA patients. The important symptoms and laboratory parameters were oral and ocular symptoms in 23 (44.2%), dental caries in 12 (23%), body pains in 47 (90.3%), mean serum pH 7.202 ± 0.03, mean serum bicar-
© 2014 S. Karger AG, Basel 0250–8095/14/0402–0123$39.50/0 E-Mail [email protected] www.karger.com/ajn
bonate, 14.03 ± 1.66 mmol/l, and mean urine pH, 7.125 ± 0.54. There were 30 (57.6%) patients with distal RTA and 22 (42.3%) patients with proximal RTA. Conclusions: The clinical implication of the present study is that RTA is a common feature of Sjögren’s syndrome. It may be missed if the presentation is not due to oral and ocular symptoms. The present study is also the only one with a 1-year follow-up. © 2014 S. Karger AG, Basel
Introduction
Sjögren’s syndrome represents a group of diseases characterized by a common pathological feature, namely inflammation and destruction of exocrine glands. It was originally described as the triad of dry eyes, dry mouth, and rheumatoid arthritis [1]. Sjögren’s syndrome may occur alone (primary Sjögren’s syndrome) or in association with other connective or autoimmune disorders (secondary Sjögren’s syndrome). In 1993 [2], a preliminary set of criteria for the diagnosis of Sjögren’s syndrome was defined. It was later validated in a prospective study [3]. At present, the diagnosis of Sjögren’s syndrome is according to the American-European classification system (modified by Tzioufas and Voulgarelis [4]). According to this classification, the diagnosis of primary Sjögren’s syndrome requires 4 of 6 of the criteria given below; in addition, either criterion No. 5 or criterion No. 6 must be inDr. Rapur Ram, MD, DM Department of Nephrology Sri Venkateswara Institute of Medical Sciences Tirupati 517507 (India) E-Mail ram_5_1999 @ yahoo.com
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a
Materials and Methods Study Design The study was a consecutive case series of patients with Sjögren’s syndrome with RTA. New patients between January 2002 and September 2011 were included in the study. All patients were prospectively followed for 1 year. Patients All patients were from a nephrology outpatient department of a government-run tertiary care apex center in South India. Patients with a history suggestive of proximal muscle weakness of the lower or upper limbs, polyuria, nephrolithiasis and impaired growth and bone deformities were evaluated for etiology of RTA. Sjögren’s syndrome was suspected in these patients when they presented with a history suggestive of dry mouth, dry eyes, gritty sensation
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Am J Nephrol 2014;40:123–130 DOI: 10.1159/000365199
of eyes, photosensitivity, red eyes, deposits of dried mucus in the corners of eyes, recurrent episodes of conjunctivitis, difficulty in swallowing food without fluid, joint pains, arthralagias and Raynaud’s phenomenon. Several patients (10, 19.23%) were referred to the nephrology department from the neurology department for evaluation of hypokalemic paralysis. Patients who presented with symptoms suggestive of RTA were then fully investigated to diagnose the cause of RTA. Sjögren’s syndrome patients with RTA, who completed 1 year of regular follow-up, were included in the study. Investigations Diagnosis of RTA: Patients were prospectively evaluated with arterial blood gas analysis for metabolic acidosis and anion gap, complete urinalysis which included urine pH. RTA was suspected when there was hyperchloremic (normal anion gap) metabolic acidosis associated with hypokalemia. Metabolic acidosis was considered when serum pH was 3% of baseline during the test. As there was no increase in urine osmolality after desmopressin, nephrogenic diabetes insipidus was suggested in these 7 (13.4%) patients by the water deprivation test.
Pregnancies There were four pregnancies in 3 patients. One of the patients had primary infertility for 6 years and could become pregnant after Sjögren’s syndrome was diagnosed and treated. Cesarean sections were done after 36 weeks of pregnancy in 2 patients. Cesarean sections were preferred by the obstetrician to avoid stress on pelvic bones. Medical termination of pregnancy was requested by the third patient – the request was honored. The fourth pregnancy ended as complete heart block of the male infant at birth. There were no skin lesions. The neonate did not survive; umbilical cord blood analysis revealed positive anti-Ro antibodies. None of these patients had complications like hypertension, eclampsia, premature labor or intrauterine deaths. In all 3 patients the doses of sodium bicarbonate and potassium citrate were modified based on monthly evaluation of serum bicarbonate and serum potassium. Chronic kidney disease developed in 4 (7.6%) patients with serum creatinine levels at the last follow-up – 1.9, 3.8, 2.0, and 1.7 mg/dl, respectively. These patients had no features of SLE or nephrotic syndrome. Renal biopsy could be done only in 2 patients who had kidneys >9.0 cm in size. The biopsies revealed chronic interstitial nephritis Renal Tubular Acidosis
with lymphocytic infiltration, moderate to severe tubular atrophy and interstitial fibrosis. Follow-Up At the end of the 1-year follow-up, all patients were withdrawn from prednisolone and were only on maintenance doses of sodium bicarbonate, 1,25-dihydroxyvitamin D and potassium citrate. Pulmonary tuberculosis developed in 2 patients; 1 of them had a recurrence of pulmonary tuberculosis after treatment for 6 months with antituberculous therapy. One patient died due to pulmonary arterial hypertension.
Discussion
In the present study, Sjögren’s syndrome was diagnosed according to the modified American-European classification system [4]. All patients had RTA with hyperchloremic (normal anion gap) metabolic acidosis and hypokalemia. Nephrogenic diabetes insipidus was confirmed in 7 (13.4%) patients. Renal biopsy was performed in 6 patients. We also reported familial involvement in siblings of two families and two successful pregnancies. Sjögren’s syndrome accounted for one third of patients with RTA. The present study was also the only one with a prospectively followed consecutive case series. Only a few studies [5–8, 18–21] in the past have examined the clinical and morphological features of kidney involvement in Sjögren’s syndrome (table 5). The sixth study [5] was a retrospective one and the rest were of patients with one-time investigations for renal manifestations. Though it was believed that the RTA presents mostly as a biochemical defect rather than with any symptom, there were case reports of muscle weakness [22], life-threatening paralysis due to hypokalemia [23], nephrocalcinosis [24, 25] and metabolic bone disease [26–32]. Am J Nephrol 2014;40:123–130 DOI: 10.1159/000365199
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II and another 2 had class III according to the revised classification, under the auspices of the International Society of Nephrology and the Renal Pathology Society [17]. A renal biopsy was performed in 2 more patients with nephrotic syndrome. Serum creatinine, 24-hour urine protein, serum bicarbonate and urine pH in these 2 patients were respectively 1.4 and 1.2 mg/dl, 12.2 and 8.5 g, 14.3 and 15.8 mmol/l, and 6.5 and 7.0. Both renal biopsies revealed membranous nephropathy with lymphoplasma cellular infiltration of the interstitium. There was no tubular atrophy or interstitial fibrosis.
Table 5. Major studies of Sjögren’s syndrome with RTA Patients, Mean age n (range), years
Mean Females, RTA, duration of n (%) n (%) symptoms (range), years
Low CrCl, n (%)
6
12
51.9 (41 – 72)
6.41 (2 – 16) 12 (100)
11 (91.6) 9 (75)
14
17
51
3.6 ± 2.9
13 (76.4) 3 (17.6) 6 (35.2)
15
21
50 (35 – 66)
6.5 (1 – 18)
21 (100)
7 (33)
7
78
58 ± 13 (29 – 82)
–
–
18 (23.0) 15 (19)
–
8
62
59.5 (25 – 79)
12 (3 – 32) 7 (11.3) 13 (62)
–
5
60
55 (24 – 80)
56 (93.3) 3 (5)
72%
80%
40%
35 (67.3)
29 (55.7)
18 (34.6) 7 (13.4)
Present 52 study
26.64 (10 – 53)
7 (0 – 23)
6 (50)
HyperAnti-Ro, gamman (%) globulinemia, n (%)
17 (100)
15 (71.4) –
8 (13)
36 (69.2) 52 (100) 4 (7.6)
Anti-La, ANA, n (%) n (%)
Kidney biopsy
–
–
5 (41.6)
1 FGN, 1 NA
–
–
–
–
11 (52.3)
6 (28.5)
10 (47.6) 1 MGN, 1 MPGN
16 (89)
13 (72)
17 (94)
Anti-Ro+La: 20 (32.3)
1 MesPG, 1 CIN, 1 endocapillary PGN with vasculitis
50 (80.6) 85%
6 interstitial changes, 1 MGN, 1 MesPGN, 1 Cryo-MPGN 2 MGN
FGN = Focal glomerulonephritis; NA = not available; MGN = membranous nephropathy; MPGN = membranoproliferative glomerulonephritis; MesPG = mesangioproliferative glomerulonephritis; CIN = chronic interstitial nephritis; PGN = proliferative glomerulonephritis; Cryo-MPGN = cryo-
globulin-induced membranoproliferative glomerulonephritis. In previous studies nephrogenic diabetes insipidus was identified in 11.1% [6], 16% [18], 21% [10] and 44% [14, 19] of the patients. In the present study it was identified in 7 of 52 patients (13.4%).
The similarities in the previous studies and the present one were a preponderance of females, time lag between symptoms and the diagnosis of Sjögren’s syndrome, and a similar percent of positivity of anti-Ro and anti-La antibodies. It is possible that Sjögren’s syndrome might present at an young age in Indian patients as it usually presented with musculoskeletal manifestations like difficulty in standing and gait disturbances (88.4%), muscle wasting (67.3%) and body pains (90.3%). In other Indian reports on Sjögren’s syndrome the patients were relatively young, i.e. 20–45 [32] and 26–48 [33] years of age. However, to date, the present study is the largest Indian study of RTA as a manifestation of Sjögren’s syndrome. Familial Sjögren’s syndrome has been well described [34, 35]. However, in English literature there are no reports of Sjögren’s syndrome presenting as RTA in siblings. The present study reports two such families. There were three such reports in Japanese literature. Pregnancies in Sjögren’s syndrome were found to occur at a later age (33.6 years). Mothers give birth to offspring with a lower birth weight and less commonly have normal partus [36]. Pregnancy is a state of mild alkalemia which is respiratory in origin. A secondary, compensa-
tory fall in plasma bicarbonate concentration occurs so that values between 18 and 22 mmol/l are normal [37]. However, the pregnant woman adapts to these new levels of bicarbonate. During pregnancy, patients may require increase in doses of potassium and bicarbonate, to maintain electrolyte balance [38]. Spontaneous vaginal delivery at term may be anticipated, provided treatment results in the disappearance of the metabolic acidosis and electrolyte disturbance. In our patients, however, cesarean section was preferred to avoid stress on pelvic bones. Complete heart block is reported in half of the fetuses born to mothers with Sjögren’s syndrome [39]. Anti-Ro antibodies were positive in 98% of reported fetuses. About one third will also have anti-La antibodies. These were IgG antibodies and pass the placenta to the fetus, but their simple presence does not necessitate clinical disease. Other factors such as inflammatory cells or complement activation may be necessary for disease to be expressed [40]. In recent series [41] of renal biopsy in primary Sjögren’s syndrome for the indication of renal impairment, out of 24 patients, 17 (71%) had acute or chronic interstitial nephritis, 3 (13%) had focal segmental glomerulonephritis, 2 (8%) had membranoproliferative glomerulonephritis,
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Ref.
and 1 each (4% each) had minimal change and membranous nephropathy. RTA itself was not a usual indication for the treatment of Sjögren’s syndrome. We preferred to treat the patients in the present study because of the following reasons: (a) The reported prevalence of RTA on a clinical basis is up to 50% (table 5), which merits it to be called an extraglandular manifestation. (b) There are reports of similarity of histologic findings in lacrimal and salivary glands and in kidneys. It is therefore conceivable that the RTA in Sjögren’s syndrome is an inherent manifestation [20, 42]. However, in a report of renal biopsies of 8 Sjögren’s syndrome patients [42], the interstitial changes were present even in patients without RTA. The explanation for this variance was that the occurrence of RTA is dependent upon the degree and distribution of renal changes. In a recent series of renal biopsy of Sjögren’s syndrome for the indication of renal failure [41], 6 of 24 (25%) cases had acute tubulointerstitial nephritis as the primary lesion and chronic tubule interstitial nephritis was found in 11 of 24 cases (45.83%). It was the most common histological lesion in that study [41] and it was possible that there was a transition interstitial change from acute to chronicity. The renal biopsies performed in 4 of our initial patients with Sjögren’s syndrome with renal failure had revealed features of chronic interstitial nephritis, hence the presumption that patients with Sjögren’s syndrome with normal renal function may merit steroid therapy for effective treatment of acute interstitial nephritis. (c) Though there was uncertainty of reversal of florid interstitial infiltrate with steroid treatment, there were reports of remission of RTA [43, 44] with the steroid therapy. (d) One opinion was that the interstitial nephritis was due to hypokalemia which was again due to RTA [9, 45].
Patients at the end of follow-up were only on maintenance doses of sodium bicarbonate, 1,25-dihydroxyvitamin D and potassium citrate. Chronic kidney disease was reported only in 4 of our patients. Serial kidney biopsies should have been done to confirm that the steroid therapy instituted in our patients had played a role in limiting the progression of the disease. We could not perform biopsies as it raised difficult questions about the lack of clear-cut indications. A limitation of the study was that all patients had Sjögren’s syndrome with RTA. Inclusion of patients with Sjögren’s syndrome without RTA would have given the prevalence of RTA in Sjögren’s syndrome. At our institute, patients with Sjögren’s syndrome were also treated by physicians and rheumatologists. The strengths of the study were the rigorous criteria used for the diagnosis of RTA using FEHCO3 and Sjögren’s syndrome and the 1-year follow-up of the patients. We also report familial involvement and successful pregnancies. The clinical implication of the present study is that RTA is a common feature of Sjögren’s syndrome. Sjögren’s syndrome as a cause of RTA may be missed if the presentation is not due to oral and ocular symptoms. Sjögren’s syndrome should be suspected in a young patient with complaints of body pains, breathlessness, growth retardation and signs of muscular weakness. Further studies are required to find out the common histology of nephrotic syndrome in Sjögren’s syndrome and long follow-up studies to recognize the frequency of chronic kidney disease.
Disclosure Statement The authors have no conflicts of interest to disclose.
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Journal of
Nephrology
Received: December 19, 2013 Accepted: June 9, 2014 Published online: August 20, 2014
Am J Nephrol 2014;40:123–130 DOI: 10.1159/000365199
Renal Tubular Acidosis in Sjögren’s Syndrome: A Case Series Rapur Ram a Gudithi Swarnalatha b Kaligotla Venkata Dakshinamurty b
Department of Nephrology, Sri Venkateswara Institute of Medical Sciences, Tirupati, and b Department of Nephrology, NIMS, Hyderabad, India
Key Words Renal tubular acidosis · Sjögren’s syndrome · Fractional excretion of bicarbonate · Anti-Ro (SS-A) · Anti-La (SS-B) · Hypokalemia · Hyperchloremic metabolic acidosis · Polyuria
Abstract Background: The exact frequency of distal and proximal renal tubular acidosis (RTA) in Sjögren’s syndrome is unknown. Other features of Sjögren’s syndrome like polyuria, glomerular manifestations, familial occurrence and pregnancy are not widely reported. The aim was to prospectively study the clinical features and outcome of distal and proximal RTA in Sjögren’s syndrome and also report on other renal manifestations of Sjögren’s syndrome. Methods: The present study is a prospective consecutive case series of patients who presented with a history suggestive of RTA and Sjögren’s syndrome. All patients were followed for 1 year. The diagnosis of RTA was by fractional excretion of bicarbonate. The diagnosis of Sjögren’s syndrome was according to the AmericanEuropean classification system [modified by Tzioufas and Voulgarelis: Best Pract Res Clin Rheumatol 2007; 21: 989– 1010]. Results: The total number of RTA patients diagnosed during this period was 149. Sjögren’s syndrome accounted for 34.8% (52 of 149) of RTA patients. The important symptoms and laboratory parameters were oral and ocular symptoms in 23 (44.2%), dental caries in 12 (23%), body pains in 47 (90.3%), mean serum pH 7.202 ± 0.03, mean serum bicar-
© 2014 S. Karger AG, Basel 0250–8095/14/0402–0123$39.50/0 E-Mail [email protected] www.karger.com/ajn
bonate, 14.03 ± 1.66 mmol/l, and mean urine pH, 7.125 ± 0.54. There were 30 (57.6%) patients with distal RTA and 22 (42.3%) patients with proximal RTA. Conclusions: The clinical implication of the present study is that RTA is a common feature of Sjögren’s syndrome. It may be missed if the presentation is not due to oral and ocular symptoms. The present study is also the only one with a 1-year follow-up. © 2014 S. Karger AG, Basel
Introduction
Sjögren’s syndrome represents a group of diseases characterized by a common pathological feature, namely inflammation and destruction of exocrine glands. It was originally described as the triad of dry eyes, dry mouth, and rheumatoid arthritis [1]. Sjögren’s syndrome may occur alone (primary Sjögren’s syndrome) or in association with other connective or autoimmune disorders (secondary Sjögren’s syndrome). In 1993 [2], a preliminary set of criteria for the diagnosis of Sjögren’s syndrome was defined. It was later validated in a prospective study [3]. At present, the diagnosis of Sjögren’s syndrome is according to the American-European classification system (modified by Tzioufas and Voulgarelis [4]). According to this classification, the diagnosis of primary Sjögren’s syndrome requires 4 of 6 of the criteria given below; in addition, either criterion No. 5 or criterion No. 6 must be inDr. Rapur Ram, MD, DM Department of Nephrology Sri Venkateswara Institute of Medical Sciences Tirupati 517507 (India) E-Mail ram_5_1999 @ yahoo.com
Downloaded by: University of Missouri-Columb. 128.206.9.138 - 10/1/2014 10:25:56 AM
a
Materials and Methods Study Design The study was a consecutive case series of patients with Sjögren’s syndrome with RTA. New patients between January 2002 and September 2011 were included in the study. All patients were prospectively followed for 1 year. Patients All patients were from a nephrology outpatient department of a government-run tertiary care apex center in South India. Patients with a history suggestive of proximal muscle weakness of the lower or upper limbs, polyuria, nephrolithiasis and impaired growth and bone deformities were evaluated for etiology of RTA. Sjögren’s syndrome was suspected in these patients when they presented with a history suggestive of dry mouth, dry eyes, gritty sensation
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of eyes, photosensitivity, red eyes, deposits of dried mucus in the corners of eyes, recurrent episodes of conjunctivitis, difficulty in swallowing food without fluid, joint pains, arthralagias and Raynaud’s phenomenon. Several patients (10, 19.23%) were referred to the nephrology department from the neurology department for evaluation of hypokalemic paralysis. Patients who presented with symptoms suggestive of RTA were then fully investigated to diagnose the cause of RTA. Sjögren’s syndrome patients with RTA, who completed 1 year of regular follow-up, were included in the study. Investigations Diagnosis of RTA: Patients were prospectively evaluated with arterial blood gas analysis for metabolic acidosis and anion gap, complete urinalysis which included urine pH. RTA was suspected when there was hyperchloremic (normal anion gap) metabolic acidosis associated with hypokalemia. Metabolic acidosis was considered when serum pH was 3% of baseline during the test. As there was no increase in urine osmolality after desmopressin, nephrogenic diabetes insipidus was suggested in these 7 (13.4%) patients by the water deprivation test.
Pregnancies There were four pregnancies in 3 patients. One of the patients had primary infertility for 6 years and could become pregnant after Sjögren’s syndrome was diagnosed and treated. Cesarean sections were done after 36 weeks of pregnancy in 2 patients. Cesarean sections were preferred by the obstetrician to avoid stress on pelvic bones. Medical termination of pregnancy was requested by the third patient – the request was honored. The fourth pregnancy ended as complete heart block of the male infant at birth. There were no skin lesions. The neonate did not survive; umbilical cord blood analysis revealed positive anti-Ro antibodies. None of these patients had complications like hypertension, eclampsia, premature labor or intrauterine deaths. In all 3 patients the doses of sodium bicarbonate and potassium citrate were modified based on monthly evaluation of serum bicarbonate and serum potassium. Chronic kidney disease developed in 4 (7.6%) patients with serum creatinine levels at the last follow-up – 1.9, 3.8, 2.0, and 1.7 mg/dl, respectively. These patients had no features of SLE or nephrotic syndrome. Renal biopsy could be done only in 2 patients who had kidneys >9.0 cm in size. The biopsies revealed chronic interstitial nephritis Renal Tubular Acidosis
with lymphocytic infiltration, moderate to severe tubular atrophy and interstitial fibrosis. Follow-Up At the end of the 1-year follow-up, all patients were withdrawn from prednisolone and were only on maintenance doses of sodium bicarbonate, 1,25-dihydroxyvitamin D and potassium citrate. Pulmonary tuberculosis developed in 2 patients; 1 of them had a recurrence of pulmonary tuberculosis after treatment for 6 months with antituberculous therapy. One patient died due to pulmonary arterial hypertension.
Discussion
In the present study, Sjögren’s syndrome was diagnosed according to the modified American-European classification system [4]. All patients had RTA with hyperchloremic (normal anion gap) metabolic acidosis and hypokalemia. Nephrogenic diabetes insipidus was confirmed in 7 (13.4%) patients. Renal biopsy was performed in 6 patients. We also reported familial involvement in siblings of two families and two successful pregnancies. Sjögren’s syndrome accounted for one third of patients with RTA. The present study was also the only one with a prospectively followed consecutive case series. Only a few studies [5–8, 18–21] in the past have examined the clinical and morphological features of kidney involvement in Sjögren’s syndrome (table 5). The sixth study [5] was a retrospective one and the rest were of patients with one-time investigations for renal manifestations. Though it was believed that the RTA presents mostly as a biochemical defect rather than with any symptom, there were case reports of muscle weakness [22], life-threatening paralysis due to hypokalemia [23], nephrocalcinosis [24, 25] and metabolic bone disease [26–32]. Am J Nephrol 2014;40:123–130 DOI: 10.1159/000365199
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II and another 2 had class III according to the revised classification, under the auspices of the International Society of Nephrology and the Renal Pathology Society [17]. A renal biopsy was performed in 2 more patients with nephrotic syndrome. Serum creatinine, 24-hour urine protein, serum bicarbonate and urine pH in these 2 patients were respectively 1.4 and 1.2 mg/dl, 12.2 and 8.5 g, 14.3 and 15.8 mmol/l, and 6.5 and 7.0. Both renal biopsies revealed membranous nephropathy with lymphoplasma cellular infiltration of the interstitium. There was no tubular atrophy or interstitial fibrosis.
Table 5. Major studies of Sjögren’s syndrome with RTA Patients, Mean age n (range), years
Mean Females, RTA, duration of n (%) n (%) symptoms (range), years
Low CrCl, n (%)
6
12
51.9 (41 – 72)
6.41 (2 – 16) 12 (100)
11 (91.6) 9 (75)
14
17
51
3.6 ± 2.9
13 (76.4) 3 (17.6) 6 (35.2)
15
21
50 (35 – 66)
6.5 (1 – 18)
21 (100)
7 (33)
7
78
58 ± 13 (29 – 82)
–
–
18 (23.0) 15 (19)
–
8
62
59.5 (25 – 79)
12 (3 – 32) 7 (11.3) 13 (62)
–
5
60
55 (24 – 80)
56 (93.3) 3 (5)
72%
80%
40%
35 (67.3)
29 (55.7)
18 (34.6) 7 (13.4)
Present 52 study
26.64 (10 – 53)
7 (0 – 23)
6 (50)
HyperAnti-Ro, gamman (%) globulinemia, n (%)
17 (100)
15 (71.4) –
8 (13)
36 (69.2) 52 (100) 4 (7.6)
Anti-La, ANA, n (%) n (%)
Kidney biopsy
–
–
5 (41.6)
1 FGN, 1 NA
–
–
–
–
11 (52.3)
6 (28.5)
10 (47.6) 1 MGN, 1 MPGN
16 (89)
13 (72)
17 (94)
Anti-Ro+La: 20 (32.3)
1 MesPG, 1 CIN, 1 endocapillary PGN with vasculitis
50 (80.6) 85%
6 interstitial changes, 1 MGN, 1 MesPGN, 1 Cryo-MPGN 2 MGN
FGN = Focal glomerulonephritis; NA = not available; MGN = membranous nephropathy; MPGN = membranoproliferative glomerulonephritis; MesPG = mesangioproliferative glomerulonephritis; CIN = chronic interstitial nephritis; PGN = proliferative glomerulonephritis; Cryo-MPGN = cryo-
globulin-induced membranoproliferative glomerulonephritis. In previous studies nephrogenic diabetes insipidus was identified in 11.1% [6], 16% [18], 21% [10] and 44% [14, 19] of the patients. In the present study it was identified in 7 of 52 patients (13.4%).
The similarities in the previous studies and the present one were a preponderance of females, time lag between symptoms and the diagnosis of Sjögren’s syndrome, and a similar percent of positivity of anti-Ro and anti-La antibodies. It is possible that Sjögren’s syndrome might present at an young age in Indian patients as it usually presented with musculoskeletal manifestations like difficulty in standing and gait disturbances (88.4%), muscle wasting (67.3%) and body pains (90.3%). In other Indian reports on Sjögren’s syndrome the patients were relatively young, i.e. 20–45 [32] and 26–48 [33] years of age. However, to date, the present study is the largest Indian study of RTA as a manifestation of Sjögren’s syndrome. Familial Sjögren’s syndrome has been well described [34, 35]. However, in English literature there are no reports of Sjögren’s syndrome presenting as RTA in siblings. The present study reports two such families. There were three such reports in Japanese literature. Pregnancies in Sjögren’s syndrome were found to occur at a later age (33.6 years). Mothers give birth to offspring with a lower birth weight and less commonly have normal partus [36]. Pregnancy is a state of mild alkalemia which is respiratory in origin. A secondary, compensa-
tory fall in plasma bicarbonate concentration occurs so that values between 18 and 22 mmol/l are normal [37]. However, the pregnant woman adapts to these new levels of bicarbonate. During pregnancy, patients may require increase in doses of potassium and bicarbonate, to maintain electrolyte balance [38]. Spontaneous vaginal delivery at term may be anticipated, provided treatment results in the disappearance of the metabolic acidosis and electrolyte disturbance. In our patients, however, cesarean section was preferred to avoid stress on pelvic bones. Complete heart block is reported in half of the fetuses born to mothers with Sjögren’s syndrome [39]. Anti-Ro antibodies were positive in 98% of reported fetuses. About one third will also have anti-La antibodies. These were IgG antibodies and pass the placenta to the fetus, but their simple presence does not necessitate clinical disease. Other factors such as inflammatory cells or complement activation may be necessary for disease to be expressed [40]. In recent series [41] of renal biopsy in primary Sjögren’s syndrome for the indication of renal impairment, out of 24 patients, 17 (71%) had acute or chronic interstitial nephritis, 3 (13%) had focal segmental glomerulonephritis, 2 (8%) had membranoproliferative glomerulonephritis,
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Ref.
and 1 each (4% each) had minimal change and membranous nephropathy. RTA itself was not a usual indication for the treatment of Sjögren’s syndrome. We preferred to treat the patients in the present study because of the following reasons: (a) The reported prevalence of RTA on a clinical basis is up to 50% (table 5), which merits it to be called an extraglandular manifestation. (b) There are reports of similarity of histologic findings in lacrimal and salivary glands and in kidneys. It is therefore conceivable that the RTA in Sjögren’s syndrome is an inherent manifestation [20, 42]. However, in a report of renal biopsies of 8 Sjögren’s syndrome patients [42], the interstitial changes were present even in patients without RTA. The explanation for this variance was that the occurrence of RTA is dependent upon the degree and distribution of renal changes. In a recent series of renal biopsy of Sjögren’s syndrome for the indication of renal failure [41], 6 of 24 (25%) cases had acute tubulointerstitial nephritis as the primary lesion and chronic tubule interstitial nephritis was found in 11 of 24 cases (45.83%). It was the most common histological lesion in that study [41] and it was possible that there was a transition interstitial change from acute to chronicity. The renal biopsies performed in 4 of our initial patients with Sjögren’s syndrome with renal failure had revealed features of chronic interstitial nephritis, hence the presumption that patients with Sjögren’s syndrome with normal renal function may merit steroid therapy for effective treatment of acute interstitial nephritis. (c) Though there was uncertainty of reversal of florid interstitial infiltrate with steroid treatment, there were reports of remission of RTA [43, 44] with the steroid therapy. (d) One opinion was that the interstitial nephritis was due to hypokalemia which was again due to RTA [9, 45].
Patients at the end of follow-up were only on maintenance doses of sodium bicarbonate, 1,25-dihydroxyvitamin D and potassium citrate. Chronic kidney disease was reported only in 4 of our patients. Serial kidney biopsies should have been done to confirm that the steroid therapy instituted in our patients had played a role in limiting the progression of the disease. We could not perform biopsies as it raised difficult questions about the lack of clear-cut indications. A limitation of the study was that all patients had Sjögren’s syndrome with RTA. Inclusion of patients with Sjögren’s syndrome without RTA would have given the prevalence of RTA in Sjögren’s syndrome. At our institute, patients with Sjögren’s syndrome were also treated by physicians and rheumatologists. The strengths of the study were the rigorous criteria used for the diagnosis of RTA using FEHCO3 and Sjögren’s syndrome and the 1-year follow-up of the patients. We also report familial involvement and successful pregnancies. The clinical implication of the present study is that RTA is a common feature of Sjögren’s syndrome. Sjögren’s syndrome as a cause of RTA may be missed if the presentation is not due to oral and ocular symptoms. Sjögren’s syndrome should be suspected in a young patient with complaints of body pains, breathlessness, growth retardation and signs of muscular weakness. Further studies are required to find out the common histology of nephrotic syndrome in Sjögren’s syndrome and long follow-up studies to recognize the frequency of chronic kidney disease.
Disclosure Statement The authors have no conflicts of interest to disclose.
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