Renal involvement in primary Sjo¨gren’s syndrome

Transcription

Renal involvement in primary Sjo¨gren’s syndrome
Q J Med 2000; 93:297–304
Renal involvement in primary Sjo¨gren’s syndrome
K. AASARØD, H.-J. HAGA1, K.J. BERG2, J. HAMMERSTRØM and S. JØRSTAD
From the Department of Medicine, University Hospital of Trondheim, 1Center for
Rheumatology, Haukeland University Hospital, Bergen, and 2Laboratory for Renal Physiology,
The National Hospital, Oslo, Norway
Received 21 December 1999
Summary
patient (1.6%). Seven patients (11.3%) had complete or incomplete distal renal tubular acidosis
(dRTA), four had reduced creatinine clearance and
five had reduced maximum urine concentration
capacity. The ratio of citrate/creatinine in spot urine
was below the 2.5 percentile in all patients with
complete or incomplete dRTA. The prevalence of
dRTA was lower than in previous studies. There
were also few patients with signs of glomerular
disease (1.6%). The use of citrate:creatinine ratio
in spot urine can be a helpful method in identifying
patients with complete or incomplete dRTA.
Introduction
Sjo¨gren’s syndrome is a chronic inflammatory disease
characterized by lymphocyte-mediated infiltration of
exocrine glands, especially lacrimal and salivary
glands. It is a systemic disease, with manifestations
from several organ systems such as lungs, kidneys,
skin, blood vessels and muscles, and lymphomas
appear in about 5% of patients.1 Secondary Sjo¨gren’s
syndrome is seen in patients with auto-immune
diseases such as rheumatoid arthritis, systemic sclerosis, systemic lupus erythematosus and others. In the
absence of these, the disease is classified as primary
Sjo¨gren’s syndrome.
The prevalence of primary Sjo¨gren’s syndrome in
the general population is largely unknown. Diagnosis
and classification have been difficult and at least
five different classification criteria have been
proposed over the last years. In a British geriatric
population, clinical Sjo¨gren’s syndrome had a prevalence of 3.3%,2 and in a Swedish study the prevalence
was reported as 2.7% in the age group 52–72 years.3
There is a male to female ratio of 159.4
Renal involvement is reported to occur in 18.4%5
to 67%6 of patients with primary Sjo¨gren’s syndrome.
This considerable variation is probably due to the
different classification criteria used in the studies, as
well as the selection of the patients. An inability of
the distal renal tubule to secrete hydrogen ions
leading to complete or incomplete distal renal tubular
acidosis is the most common manifestation of renal
involvement, but hyposthenuria is also found, due
to an abnormality in the urine concentration mechanism.7 Clinically distal renal tubular acidosis is mostly
silent, but there is an increased tendency to stone
formation, and some patients may develop nephro-
Address correspondence to Dr K. Aasarød, Department of Medicine, University Hospital of Trondheim, Olav Kyrres gate
17, N-7006 Trondheim, Norway. e-mail: [email protected]
© Association of Physicians 2000
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Renal involvement was evaluated in 62 patients with
primary Sjo¨gren’s syndrome, classified according to
criteria proposed by The European Classification
Criteria Group. Urine concentration capacity was
tested using intranasal 1-desamino-8-D-argininevasopressin. For patients with urine pH>5.5 without metabolic acidosis (n=28), an acidification test
with ammonium chloride was performed. Urinary
citrate, albumin, NAG, ALP and b2-microglobulin
were measured and creatinine clearance was calculated. Maximum urine concentration capacity and
creatinine clearance were reduced in 13 (21%).
Albumin excretion was >30 mg/min in only one
298
K. Aasarød et al.
calcinosis and even renal failure.8 The histopathological renal lesion most often reported in primary
Sjo¨ gren’s syndrome is interstitial nephritis.9
Glomerular disease is rare, and when it occurs it is
often associated with mixed cryoglobulinaemia.10
In the present study, we analysed renal involvement in 62 patients with primary Sjo¨ gren’s syndrome,
diagnosed according to the preliminary classification
criteria proposed by The European Classification
Criteria Group.11 We also examined whether biochemical markers of renal tubular damage were
useful tools in identifying renal disease in these
patients.
Methods
Patient selection
Laboratory investigations
On the first day, all patients completed a 24-h urine
collection which was kept in polyvinyl cans without
additives. When the patients arrived at the hospital
they voided, and a measurement of urine pH was
done within 10 min using a pH meter (Radiometer).
Before samples were drawn, the cans were thoroughly stirred and the urine mixed. A specimen of
the spot urine and of the 24 h urine was frozen at
−20 °C and analysed after 2 months (see later).
Blood analyses
A capillary blood sample was drawn for the determination of pH, standard bicarbonate and base
excess (Ciba-Corning 865). The procedure was completed within 20 min and the specimen was kept on
ice until the analyses were done. From venous blood,
serum sodium, potassium, chloride, phosphate, creatinine and urate were measured by autoanalyser
techniques (Technicon Chemicals). Serum b -micro2
globulin was analysed by immunfluorescence (Abbot
IMX), and ionized calcium with the use of an ionselective electrode (Ciga-Corning 865).
Urine analyses
A sample of the 24-h urine was analysed for calcium,
creatinine, sodium, potassium and chloride using an
autoanalyser (Technicon Chemicals). The analyses
were done on the day the urine collection was
Table 1 Laboratory and clinical values in 62 patients with primary Sjo¨ gren’s syndrome
Variable
Results
Reference range
Male/female
Age median, years (range)
Duration of symptoms median, years (range)
Time from diagnosis median, years (range)
B haemoglobin median, g/dl (range)
B leucocytes median, ×109/l (range)
S creatinine median, mmol/l (range)
S IgG median, g/l (range)
Antibody to SSA/SSB antigen, n (%)
Anti nuclear antibodies, n (%)
Rheumatoid factor, n (%)
Focus score 1*, n (%)
6/56
59.5
12
3
13.3
5.6
87.5
12.6
20
50
23
34
11.5–17.4
3.7–10.0
60–120
6.1–15.3
(25–79)
(3–32)
(1–9)
(10.0–15.0)
(2.3–32)
(64–159)
(7.4–33.0)
(32.3)
(80.6)
(37.1)
(64.2)
* Refers to the number of inflammatory foci in biopsies from the salivary gland of the lower lip, performed in 53 patients*
(reference 12)
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Since 1992, patients with primary Sjo¨ gren’s syndrome
living in the County of Hordaland have been registered consecutively at Haukeland university hospital.
The diagnosis of primary Sjo¨ gren’s syndrome is
established using the criteria proposed by The
European Classification Criteria Group.11 Seventy of
these patients who lived in and around the city of
Bergen, and who were able to reach the hospital
within an hour or less, were invited to take part in
the present study. Sixty-two (88.6%) responded and
were included. Table 1 shows the overall patient
characteristics. The entire study was done on an outpatient basis. Onset of primary Sjo¨ gren’s syndrome
was defined as the first subjective experience of
symptoms of any items in the classification criteria
or of arthritis/arthralgia, elevated long-standing ESR
without any obvious cause, peripheral neuropathy,
long-standing fever without infection or chronic
fatigue leading to examination by the patient’s
doctor. A biopsy from the minor salivary gland of
the lower lip was performed in the majority of the
patients at the time of the diagnosis, and evaluated
with focus scoring according to the method described
by Greenspan.12 The patients had all given their
written consent, and the study was approved by the
local Ethical Review Committee.
Renal involvement and Sjo¨ gren’s syndrome
Renal concentration capacity
As a test for renal concentration capacity, the patients
received 40 mg 1-desamino-8-D-arginine-vasopressin
(DDAVP) intranasally at 8 am. They voided immediately thereafter, and 4 h later, they voided again and
urine osmolality was measured by freezing point
depression (Fiske). The patients were allowed to
drink no more than 150 ml of fluid from the time
that DDAVP was given until urine was voided.
Reference values were adjusted for age.17
Urine acidification
For patients with a fasting urine pH<5.5 a normal
acidification capacity was assumed. A diagnosis of
complete distal renal tubular acidosis (dRTA) was
made if patients had urinary pH>5.5 and a metabolic acidosis.18
For the remaining patients a short duration acidification test was performed on a later day using
ammonium chloride loading.19 If urine pH decreased
below 5.5 at any time, the patients were assumed
not to have a dRTA. If the urinary pH was constantly
above 5.5, a diagnosis of incomplete dRTA was
made.
Statistical analyses
The Mann-Whitney U-test was used to compare
continuous variables, and Fisher’s exact test to compare categorical variables between groups. Pearson’s
correlation coefficient was used to measure the
degree of association between continuous variables.
The level of significance used was p<0.05, and all
tests were two-tailed. The positive predictive value
(PPV) and the negative predictive value (NPV) of the
tests that were used to identify patients with
distal renal tubular acidosis were calculated as
follows: PPV=(True positives/true positives+false
positives)×100. NPV=(True negatives/true negatives+false negatives)×100. Cut-off values for the
analyses were the 2.5 or 97.5 percentile of the
results obtained in healthy controls as provided by
the laboratories.
Results
The glomerular filtration rate was reduced in 13
patients (21%) (Table 2). No patient had overt proteinuria, but one had microalbuminuria. Five patients
(8.1%) had a history of renal calculi and one patient
(1.6%) had recurrent upper urinary tract infections.
Thirteen patients (21%) had reduced maximal urine
concentration capacity (Figure 1).
Thirty patients had urinary pH<5.5 and were
assumed not to have a urine acidification defect.
Four patients (6.5%) had complete dRTA (Table 3).
After ammonium chloride loading in the 28 patients
who had urinary pH>5.5 without metabolic acidosis, three (4.8%) were found to have incomplete
dRTA. Two of the three patients with complete dRTA
(patients 2 and 3) had serum chloride of 107 mmol/l
and 108 mmol/l, respectively; the other five patients
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completed and immediately after the patient had
arrived at the hospital. A sample for urine cultivation
was also taken at that time, and urine glucose
concentration was measured with a semi-quantitative
method (Combur-10-test, Meditron jr, BoehringerMannheim). Urine albumin was determined by nephelometry (Boehringer Nephelometer). Sulphuric acid
was added to the urine until a pH of approximately
3 was reached before analyses of calcium were done.
A specimen each of the 24-h urine and of the
spot urine was kept frozen at −20 °C until it was
analysed for citrate, N-acetyl-b-glucosaminidase
(NAG), alkaline phosphatase (ALP), kallikrein, b 2
microglobulin, and creatinine. The analyses were
performed with a Cobas Mira analyzer (Cobas
Instruments, Roche Diagnostic Systems) at 37 °C.
Citrate was analysed by an enzymic method13
and NAG by a colorimetric method (Boehringer
Mannheim), based upon the release of 3-cresolsulfonphtalein from 3-cresol-sulfonphtaleinyl-Nacetyl-b-D-glucosaminide at 600 nm as an end-point
analysis. ALP was analysed colorimetrically at pH 9.8
and 405 nm by a kinetic method as p-nitrophenol
liberated from p-nitrophenyl phosphate (Boehringer
Mannheim). Kallikrein was measured spectrophotometrically using the tripeptide H-D-Val-Leu-Arg pNA
as substrate (AB Kabi).14 b -microglobulin was deter2
mined by a commercial RIA kit (Pharmacia &
Upjohn), and creatinine by a modification of the
Jaffe reaction (Beckman creatinine analyser Model II).
Citrate and kallikrein in 24-h urine were expressed
as mmol and units, respectively and b -microglobulin
2
as mg/mmol creatinine. For the enzymes and for
citrate in spot urine, results were expressed as
units/mmol creatinine. Median values (2.5–97.5 percentile) for citrate in normal controls were 3.09
(1.24–5.67) mmol in 24-h urine and 0.22
(0.10–0.50) mmol/mmol creatinine in spot urine. For
kallikrein in 24-h urine reference range was 14–201
U×10−2. Reference values for NAG, ALP and b 2
microglobulin, taking into consideration the length
of time the urine had been frozen, were provided
by the laboratory (Rikshospitalet, Oslo).15 Fractional
sodium excretion was calculated as follows:
(U-Na×S-creatinine/U-creatinine×S-Na)×100. As
a marker for glomerular filtration rate, creatinine
clearance was calculated and normalized to 1.73 m2
body surface area. Reference values were adjusted
for age.16
299
300
K. Aasarød et al.
Table 2 Overview of markers of renal disease in 62 patients with primary Sjo¨ gren’s syndrome
Variable
Fraction abnormal
Reference values
Creatinine clearance/1.73 m2
Urine concentration capacity
Citrate in 24-h urine
Citrate in spot urine
b -microglobulin in 24-h urine
2
NAG in 24-h urine
ALP in 24-h urine
Kallikrein in 24-h urine
Fractional sodium excretion
Glucosuria
Albumin in 24-h urine
dRTA
21.0%
21.0%
25.8%
19.4%
45.2%
41.9%
14.5%
29.0%
1.6%
1.6%
1.6%
11.3%
Age-adjusted
Age-adjusted
3.09 (1.24–5.67) mmol
0.22 (0.10–0.50) mmol/mmol creatinine
3.36–21.92 mg/mmol creatinine
0.02–0.27 U/mmol creatinine
0.05–0.65 U/mmol creatinine
14–201 U×10−2
<2%
0 arb. units
<30 mg/min
(13/62)
(13/62)
(16/62)
(12/62)
(28/62)
(26/62)
(9/62)
(18/62)
(1/62)
(1/62)
(1/62)
(7/62)
NAG, N-acetyl-beta-glucosaminidase; ALP, alkaline phosphatase; arb., arbitrary; dRTA, distal renal tubular acidosis.
had normal values of chloride (96–106 mmol/l).
Patient 2 was hypokalaemic, with serum potassium
3.2 mmol/l, and patient 4 was hyperkalaemic, with
serum potassium 5.5 mmol/l. For the remaining
patients, serum potassium was within normal limits
(3.5–5.0 mmol/l). Serum b -microglobulin was elev2
ated in patient 4. Two patients (1 and 2) had
nephrocalcinosis as judged from ultrasound investigation. A percutaneous renal biopsy was performed
in patient 4 and showed interstitial nephritis.
Duration of disease was not significantly different
between patients with or without dRTA.
Urinary citrate, NAG, ALP and b -microglobulin
2
were significantly higher in patients with dRTA
compared to patients without dRTA (Table 4). Citrate
in 24-h urine and in spot urine was below the 2.5
percentile of the reference range for all patients with
dRTA. Citrate in spot urine in patients without dRTA
showed a considerable variation but was not agedependent (R=−0.12, p=0.38) nor was it signific-
Discussion
Complete or incomplete distal renal tubular acidosis
(dRTA) was confirmed in 11.3% of our 62 patients
with primary Sjo¨ gren’s syndrome. Earlier studies5,6
reported higher frequencies, and in a major textbook
of rheumatology,20 35% are said to have an abnormal
urine acidification test. In the present study, we used
the new European classification criteria, with a higher
sensitivity but a lower specificity for primary
Sjo¨ gren’s syndrome than criteria used in previous
studies.11 According to these criteria, patients can be
classified as having primary Sjo¨ gren’s syndrome even
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Figure 1. Maximum urine concentration capacity as a
function of age. Patients with dRTA, filled squares; patients
without dRTA, open squares.
antly correlated to creatinine clearance (R=−0.24,
p=0.06) (Figure 2). The sensitivity of analysis by
urinary citrate in identifying patients with dRTA was
100% when measured both in 24-h urine and in
spot urine (Table 5). Specificity was 83.6% and
90.9%, respectively. Hence the negative predictive
value of the test was 100%, the positive predictive
values 43.8% and 58.3%, respectively. For the two
tubular enzymes and for b -microglobulin, the sensit2
ivity in identifying patients with dRTA ranged from
42.9% to 85.7%, and the specificity from 60.0% to
89.1% (Table 5).
All patients with dRTA had positive ANA (Table 6).
Six of the seven patients (85.7%) with dRTA tested
positive for antibodies towards SSA or SSB antigens,
compared to 14/55 (25.5%) patients without dRTA.
The difference was statistically significant ( p=
0.003). Mean±SD serum IgG was 18.0±6.5 g/l and
13.9±5.2 g/l in patients with and without dRTA,
respectively ( p=0.10). The average number of
inflammatory foci in biopsies taken from salivary
glands of the lower lip was 4.7 in patients with
dRTA, compared to 1.8 in patients without
( p=0.002).
* Lowest values obtained after ammonium chloride loading, for patients with incomplete dRTA. ** Values after 40 mg DDAVP. *** Reference value<30 mg/min.
† Reference value 1.24–5.67 mmol. ‡ Reference value 0.10–0.50 mmol/mmol creatinine. § Pathological values when adjusted for age.
0.05
0.01
0.04
0.05
0.07
0.06
0.03
0.22
0.10
1.04
0.92
0.34
1.16
0.22
5.29
8.57
2.88
2.30
3.12
1.89
2.22
4.0
6.8
0.0
38.0
4.6
0.0
12.8
761
332§
501§
521§
809
501§
518§
Complete
Complete
Complete
Complete
Incomplete
Incomplete
Incomplete
1
2
3
4
5
6
7
6.77
6.91
6.35
5.71
5.88
5.83
5.78
−4.8
−8.0
−7.0
−5.7
−5.7
−6.9
−4.9
61§
47§
87
37§
65
76
43§
24-h urine
calcium
(mmol)
24-h urine
albumin
(mg/min)***
Creatinine
clearance
(ml/min/1.73m2)
Max.
urine
osmolality**
(mosmol/kg)
Base
excess*
Urine
pH*
dRTA
Patient
301
without autoantibodies or inflammatory foci on salivary gland biopsies. It is therefore of interest that all
our patients with dRTA had positive ANA, 85.7%
tested positive to either SSA or SSB, and the number
of focus scores were significantly higher than for
patients without dRTA. The association between
hypergammaglobulinaemia and dRTA has been noted
earlier,7 and in our study there was a tendency
toward higher IgG in patients with dRTA, but the
difference was not significant. The present report
indicates that patients with dRTA represents a cohort
within the primary Sjo¨ gren’s syndrome population
with more extensive immunological and histological
involvement.
Reduced creatinine clearance was found in 21%
of our patients. Case reports have mostly addressed
the question of reduced glomerular filtration rate
(GFR) in patients with primary Sjo¨ gren’s syndrome,
and the prevalence has been said to be very low. In
a retrospective study by Vitali,21 2% of the 104
patients had a creatinine clearance <60 ml/min.
This is in striking contrast to a recent Swedish paper
where 33% were found to have reduced 51Cr-EDTA
clearance.22 The prevalence of dRTA in their study
was very high (67%) and 11/27 patients had a history
of renal calculi, both of which may account for the
high frequency of reduced GFR.
As none of the patients in the present study had
overt proteinuria and only one had microalbuminuria, it is reasonable to conclude that the cause of the
reduced GFR was not primarily glomerular but rather
was secondary to tubulointerstitial dysfunction. A
renal biopsy was performed in only one patient,
showing interstitial nephritis.
An abnormality of the urine concentration mechanism was found in 21% of all patients and in 5/7
patients with dRTA. The results in earlier studies
have shown considerable variation, from 16%23 to
58%24 of patients. The methods used have varied,
and the results have not always been adjusted for
age. It seems obvious from our and other studies
that hyposthenuria can be seen in primary Sjo¨ gren’s
syndrome, even in patients without concomitant
acidification defects.
All our patients with complete or incomplete dRTA
had citrate values below the 2.5 percentile of normal
controls, both in 24-h urine and in spot urine. Two
of the patients with complete dRTA had nephrocalcinosis, and one experienced an episode of urinary
calculi. Hypocitraturia is a frequent finding among
patients with coexistent dRTA and nephrolithiasis.25,26
Citrate is an inhibitor of the crystallization of stoneforming calcium salts, and hypocitraturia is therefore
an important risk factor for urolithiasis. During acidosis, an increased mitochondrial oxidation of citrate
facilitates citrate reabsorption into the proximal tubular cells resulting in hypocitraturia.27 Among our
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Table 3 Renal characteristics in seven patients with primary Sjo¨ gren’s syndrome and distal renal tubular acidosis (dRTA)
Citrate in
24-h urine†
(mmol)
Citate in
spot urine‡
(mmol/mmol creatinine)
Renal involvement and Sjo¨ gren’s syndrome
302
K. Aasarød et al.
Table 4 Urinary markers in patients with and without dTRA among 62 patients with primry Sjo¨ gren’s syndrome
Variable
dRTA (n=7)
No dRTA (n=55)
p
Citrate in spot urine
Citrate in 24-h urine
NAG in 24-h urine
ALP in 24-h urine
Kallikrein in 24-h urine
b -microglobulin in 24-h urine
2
0.05
0.34
0.30
0.65
12.9
46.2
0.28
1.96
0.24
0.34
24.0
16.2
0.001
0.001
0.025
0.010
NS
0.010
(0.01–0.07)
(0.10–1.16)
(0.23–0.97)
(0.19–4.59)
(1.4–57.7)
(18.9–6620)
(0.04–0.58)
(0.47–5.10)
(0.03–0.61)
(0.10–1.36)
(3.9–109.9)
(5.1–72.8)
Values are medians (ranges). Citrate in spot urine expressed in mmol/mmol creatinine; citrate in 24-h urine in mmol; NAG
in 24-h urine in units/mmol creatinine; ALP in 24-h urine in units/mmol creatinine; kallikrein in 24-h urine in units,
b -microglubuline in 24-h urine in mg/mmol creatinine. For reference values and abbreviations see Table 2.
2
Table 5 The predictive value of markers for the identification of dRTA in 62 patients with primary Sjo¨ gren’s syndrome
Markers
Cut-off values*
Sensitivity
Specificity
PPV
NPV
Citrate (24-h urine)
Citrate (spot urine)
ALP (24-h urine)
NAG (24-h urine)
b -microglobulin (24-h urine)
2
<1.24**
<0.10**
>0.652***
>0.269***
>21.92***
100%
100%
42.9%
71.4%
85.7%
83.6%
90.9%
89.1%
61.8%
60.0%
43.8%
58.3%
33.3%
19.2%
21.4%
100%
100%
92.5%
94.4%
97.1%
* Cut off values, 2.5** or 97.5*** percentile of reference values. PPV, positive predictive value. NPV, negative predictive
value (see Methods for derivations).
patients with primary Sjo¨ gren’s syndrome, normal
values of citrate in urine excluded the possibility of
either complete or incomplete dRTA, but low values
did include some false positives. This of course
would be expected, as the cut-off value was the 2.5
percentile in normal controls.
b -microglobulin is a freely filterable protein
2
which under normal circumstances is almost totally
reabsorbed in the proximal tubule.28 Damage to this
section of the nephron leads to increased recovery
of b -microglobulin in the urine. In the face of
2
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Figure 2. Citrate in spot urine expressed as mmol/mmol
creatinine and displayed as a function of age. Patients
with dRTA, filled squares; patients without dRTA, open
squares.
elevated serum levels, the reabsorptive capacity can
be surpassed even in the normal tubule, resulting in
increased urinary b -microglobulin. Only one patient
2
(Table 3, patient 4) had a serum concentration above
the upper limit (4 mg/l) however, so this cannot
account for the high proportion of patients with
increased excretion of b -microglobulin in our mat2
erial. Urinary NAG and ALP, both markers of proximal tubular damage, were also elevated in a
considerable fraction of our patients. Both enzymes
showed a negative correlation to creatinine clearance
(results not shown) accounting for part of the
increase. Eriksson and co-workers found elevated
urinary NAG and a -microglobulin in 29% and 46%,
1
respectively, of patients with primary Sjo¨ gren’s syndrome in the absence of other clear evidence of
proximal renal tubular damage.6 We cannot yet fully
explain the significance of these findings, and
although urinary excretion of b -microglobulin, ALP
2
and NAG were significantly higher in patients with
than without dRTA, they were not especially helpful
in identifying patients with this abnormality.
In conclusion, the prevalence of dRTA was lower
than previously reported, and it was mainly found
in patients with extensive immunological and histological involvement. Creatinine clearance was
reduced in more patients than was found in earlier
studies, but clear evidence of glomerular disease was
lacking. All patients with dRTA had low values of
urinary citrate, both in spot urine and in 24-h urinary
303
Renal involvement and Sjo¨ gren’s syndrome
Table 6 Immunological and histopathological characteristics of seven patients with primary Sjo¨ gren’s syndrome and distal
renal tubular acidosis
Patient
ANA
present
Rheumatoid
factor
Anti-SSA
or SSB
Serum IgG
Focal
score*
1
2
3
4
5
6
7
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
No
No
No
Yes
Yes
No
Yes
Yes
Yes
Yes
Yes
Yes
No
21.2
18.9
26.1
14.5
24.4
10.9
9.4
4
4
3
5
8
4
ND
* See explanation in Table 1. ND, not done.
collections. The measurement of citrate5creatinine
ratio in spot urine is less cumbersome for the patients
than a 24-h urine collection, and normal values
seem to exclude the possibility of dRTA. In the event
of low values, ammonium chloride loading is still
necessary to exclude dRTA.
8.
9.
Acknowledgements
10.
11.
12.
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This study was supported by grants from the
Norwegian Society of Nephrology and from the Lions
Club, Norway. We greatly appreciate the technical
assistance of Gunn Nøstdal, Janicke Narverud and
Els Breistein with the laboratory analysis, and we are
grateful for the comments offered by Dr Per Eriksson,
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