Q J Med 2000; 93: 297-304
© 2000 Association of Physicians
Renal involvement in primary Sjögren's syndrome
From the Department of Medicine, University Hospital of Trondheim 1 Center for Rheumatology, Haukeland University Hospital, Bergen, and 2 Laboratory for Renal Physiology, The National Hospital, Oslo, Norway
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Renal involvement was evaluated in 62 patients with primary Sjögren's syndrome, classified according to criteria proposed by The European Classification Criteria Group. Urine concentration capacity was tested using intranasal 1-desamino-8-D-arginine-vasopressin. 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 ß2-microglobulin were measured and creatinine clearance was calculated. Maximum urine concentration capacity and creatinine clearance were reduced in 13 (21%). Albumin excretion was >30 µg/min in only one 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.
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Introduction |
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Sjögren'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 Sjögren'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 Sjögren's syndrome.
The prevalence of primary Sjögren'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 Sjögren'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 1 : 9.4
Renal involvement is reported to occur in 18.4%5 to 67%6 of patients with primary Sjögren'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 nephrocalcinosis and even renal failure.8 The histopathological renal lesion most often reported in primary Sjögren'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 Sjögren'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.
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Patient selection
Since 1992, patients with primary Sjögren's syndrome living in the County of Hordaland have been registered consecutively at Haukeland university hospital. The diagnosis of primary Sjögren'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 out-patient basis. Onset of primary Sjögren'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.
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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 ß2-microglobulin was analysed by immunfluorescence (Abbot IMX), and ionized calcium with the use of an ion-selective 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 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, Boehringer-Mannheim). 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-ß-glucosaminidase (NAG), alkaline phosphatase (ALP), kallikrein, ß2-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-N- acetyl-ß-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 ß2-microglobulin was determined 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 ß2-microglobulin as µg/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 Ux10-2. Reference values for NAG, ALP and ß2-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-NaxS-creatinine/U-creatininexS-Na)x100. 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
Renal concentration capacity
As a test for renal concentration capacity, the patients received 40 µg 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)x100. NPV=(True negatives/true negatives+false negatives)x100. 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.
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Results |
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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).
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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 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 ß2-microglobulin was elevated 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.
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Urinary citrate, NAG, ALP and ß2-microglobulin 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 age-dependent (R=-0.12, p=0.38) nor was it significantly 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 ß2-microglobulin, the sensitivity in identifying patients with dRTA ranged from 42.9% to 85.7%, and the specificity from 60.0% to 89.1% (Table 5).
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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).
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Discussion |
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Complete or incomplete distal renal tubular acidosis (dRTA) was confirmed in 11.3% of our 62 patients with primary Sjögren'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 Sjögren's syndrome than criteria used in previous studies.11 According to these criteria, patients can be classified as having primary Sjögren's syndrome even 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 Sjögren'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 Sjögren'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 Sjögren'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 stone-forming 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 patients with primary Sjögren'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.
ß2-microglobulin is a freely filterable protein 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 ß2-microglobulin in the urine. In the face of elevated serum levels, the reabsorptive capacity can be surpassed even in the normal tubule, resulting in increased urinary ß2-microglobulin. Only one patient (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 ß2-microglobulin in our material. 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 
1-microglobulin in 29% and 46%, respectively, of patients with primary Sjögren'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 ß2-microglobulin, ALP 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 collections. The measurement of citrate : creatinine 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.
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Acknowledgments |
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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, Linköping in the initial phase of the study.
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Notes |
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Address correspondence to Dr K. Aasarød, Department of Medicine, University Hospital of Trondheim, Olav Kyrres gate 17, N-7006 Trondheim, Norway. e-mail: knut.aasarod{at}medisin.ntnu.no
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References |
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1. Tzioufas AG, Moutsopoulos HM, Talal N. Lymphoid malignancies and monoclonal proteins. In: Talal N, Moutsopoulos HM, Kassan SS, eds. Sjögren's syndrome: Clinical and immunological aspects. Berlin, Springer-Verlag, 1987:129–36.
2.
Drosos AA, Andonopoulos AP, Costopoulos JS, Papadimitriou CS, Moutsopoulos HM. Prevalence of primary Sjogren's syndrome in an elderly population. Br J Rheumatol1988; 27:123–7.
3. Jacobsson LT, Axell TE, Hansen BU, Henricsson VJ, Larsson A, Lieberkind K, et al. Dry eyes or mouth—an epidemiological study in Swedish adults, with special reference to primary Sjögren's syndrome. J Autoimmun1989; 2:521–7.[Web of Science][Medline]
4. Haga HJ, Rygh T, Jacobsen H, Johannessen AC, Mjanger O, Jonsson R. Sjogrens syndrom. Nye synspunkter pa diagnostikk. Tidsskr Nor Laegeforen1997; 117:2197–200.[Medline]
5. Pokorny G, Sonkodi S, Ivanyi B, Mohacsi G, Csati S, Ivanyi T, et al. Renal involvement in patients with primary Sjogren's syndrome. Scand J Rheumatol1989; 18:231–4.[Web of Science][Medline]
6. Eriksson P, Denneberg T, Larsson L, Lindstrom F. Biochemical markers of renal disease in primary Sjogren's syndrome. Scand J Urol Nephrol1995; 29:383–92.[Web of Science][Medline]
7. Kassan SS, Talal N. Renal disease with Sjögren's syndrome. In: Talal N, Moutsopoulos HM, Kassan SS, eds. Sjögren's syndrome. Clinical and immunological aspects. Berlin, Springer-Verlag, 1987:96–102.
8. Moutsopoulos HM, Cledes J, Skopouli FN, Elisaf M, Youinou P. Nephrocalcinosis in Sjogren's syndrome: a late sequela of renal tubular acidosis. J Intern Med1991; 230:187–91.[Web of Science][Medline]
9. Enestrom S, Denneberg T, Eriksson P. Histopathology of renal biopsies with correlation to clinical findings in primary Sjogren's syndrome. Clin Exp Rheumatol1995; 13:697–703.[Web of Science][Medline]
10. Moutsopoulos HM, Balow JE, Lawley TJ, Stahl NI, Antonovych TT, Chused TM. Immune complex glomerulonephritis in sicca syndrome. Am J Med1978; 64:955–60.[Web of Science][Medline]
11. Vitali C, Bombardieri S, Moutsopoulos HM, Balestrieri G, Bencivelli W, Bernstein RM, et al. Preliminary criteria for the classification of Sjogren's syndrome. Results of a prospective concerted action supported by the European Community. Arthritis Rheum1993; 36:340–7.[Web of Science][Medline]
12. Greenspan JS, Daniels TE, Talal N, Sylvester RA. The histopathology of Sjogren's syndrome in labial salivary gland biopsies. Oral Surg Oral Med Oral Pathol1974; 37:217–29.[Web of Science][Medline]
13.
Tompkins D, Toffaletti J. Enzymic determination of citrate in serum and urine, with use of the Worthington ‘ultrafree’ device. Clin Chem1982; 28:192–5.
14. Amundsen E, Putter J, Friberger P, Knos M, Larsbraten M, Claeson G. Methods for the determination of glandular kallikrein by means of a chromogenic tripeptide substrate. Adv Exp Med Biol1979; 120A:83–95.
15. Berg KJ, Kristoffersen DT, Djoseland O, Hartmann A, Breistein E, Lund KK, et al. Reference range of some enzymes and proteins in untimed overnight urine and their stability after freezing. Clin Chim Acta1998; 272:225–30.[Web of Science][Medline]
16. Rowe JW, Andres R, Tobin JD, Norris AH, Shock NW. Age-Adjusted Standards for Creatinine Clearance. Ann Intern Med1976; 84:567–9.
17. Tryding N, Berg B, Ekman S, Nilsson JE, Sterner G, Harris A. DDAVP test for renal concentration capacity. Age-related reference intervals. Scand J Urol Nephrol1988; 22:141–5.[Web of Science][Medline]
18. Backman U, Danielson BG, Sohtell M. A short duration renal acidification test. Scand J Urol Nephrol1976; Suppl. 35:33–48.
19.
Wrong O, Davies HEF. The excretion of acid in renal disease. Q J Med1959; 28:259–313.
20. Moutsopoulos HM, Athanasios GT. Sjögren's syndrome. In: Klippel JH, Dieppe PA, eds. Rheumatology [0080-2727]. St Louis, Mosby, 1994.
21. Vitali C, Tavoni A, Sciuto M, Maccheroni M, Moriconi L, Bombardieri S. Renal involvement in primary Sjogren's syndrome: a retrospective-prospective study. Scand J Rheumatol1991; 20:132–6.[Web of Science][Medline]
22. Eriksson P, Denneberg T, Granerus G, Lindstrom F. Glomerular filtration rate in primary Sjogren's syndrome with renal disease. Scand J Urol Nephrol1996; 30:121–7.[Web of Science][Medline]
23. Bloch KH, Buchanan WW, Wohl MJ, Bunim JJ. Sjögren's syndrome. A clinical, pathological, and serological study of sixty-two cases. Medicine (Baltimore)1965; 44:198–231.
24.
Shiozawa S, Shiozawa K, Shimizu S, Nakada M, Isobe T, Fujita T. Clinical studies of renal disease in Sjogren's syndrome. Ann Rheum Dis1987; 46:768–72.
25. Nicar MJ, Skurla C, Sakhaee K, Pak CY. Low urinary citrate excretion in nephrolithiasis. Urology1983; 21:8–14.[Web of Science][Medline]
26.
Hess B, Michel R, Takkinen R, Ackermann D, Jaeger P. Risk factors for low urinary citrate in calcium nephrolithiasis: low vegetable fibre intake and low urine volume to be added to the list. Nephrol Dial Transplant1994; 9:642–9.
27. Pak CY. Citrate and renal calculi: new insights and future directions. Am J Kidney Dis1991; 17:420–5.[Web of Science][Medline]
28. Schardijn GH, Statius van Eps LW. Beta 2-microglobulin: its significance in the evaluation of renal function. Kidney Int1987; 32:635–41.[Web of Science][Medline]
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