Incomplete renal tubular acidosis and bone mineral density: a population survey in an area of endemic renal tubular acidosis
Chatlert Pongchaiyakul1,
Somnuek Domrongkitchaiporn2,
Wasana Stitchantrakul2,
La-or Chailurkit2 and
Rajata Rajatanavin2
1 Srinakarin Hospital, Khon Kaen University and 2 Ramathibodi Hospital, Mahidol University, Thailand
Correspondence and offprint requests to: Somnuek Domrongkitchaiporn, MD, Department of Medicine, Ramathibodi Hospital, Rama 6, Bangkok 10400, Thailand. Email: rasdr{at}mahidol.ac.th
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Abstract
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Background. Primary osteoporosis has been associated with a high incidence of a renal acidification defect, incomplete renal tubular acidosis (iRTA). An acid loading test, to exclude the defect, has been recommended for inclusion in the work-up of osteoporosis. However, there is no community-based study to confirm its utility.
Method. A community-based survey was conducted in the Khon Kaen province, Thailand, between January and June, 2000. We randomly enrolled 361 apparently healthy adults, 146 men and 215 women, in this study. The bone mineral densities (BMDs) of the spine and femur were determined in all subjects. The diagnosis of iRTA was based on: normal serum electrolytes and one or both of first morning urinary pH >5.5 or the failure of an acid loading test to decrease it to >5.5. Dietary diaries, serum electrolyte tests and 24 h urine collections were obtained from all iRTA subjects.
Results. There were 23 (6.4%) iRTA subjects in the population studied. The age, height, weight and calcium intake were comparable between iRTA and normal subjects, as were the BMDs of spine and femur. There was no difference between the two groups in the distributions of BMD with age for either area. Multiple regression analyses of the studied population demonstrated that age, body weight, duration of menopause and gender (only for the femoral neck) were independent variables that affected BMD.
Conclusion. Incomplete distal renal tubular acidosis alone was not associated with lower bone mass in this cohort. It may nevertheless be valuable to monitor serum electrolytes and BMD in patients with iRTA due to their tendency to develop intermittent metabolic acidosis.
Keywords: bone mineral density; calcium; osteopenia; osteoporosis; renal tubular acidosis
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Introduction
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Distal renal tubular acidosis (dRTA) is a syndrome characterized by an acidification defect of the collecting tubule that is out of proportion to any reduction in glomerular filtration rate [1]. The defect results in a positive systemic acid balance, and therefore systemic acidosis. Subjects with overt dRTA present with persistent hyperchloraemic metabolic acidosis, hypokalaemia and the inability to reduce urinary pH below 5.5 in the presence of systemic acidosis [1]. Most subjects also suffer from recurrent nephrolithiasis [1,2], musculoskeletal symptoms [3] and markedly reduced bone mass early in life [3]. A reduced rate of bone formation was demonstrated by a histomorphometric study of bone biopsies from dRTA subjects [3]. Alkalinization results in the elevation of the rate of bone formation and in increased bone mineral density [4].
A partial defect in renal acidification, an incomplete form of dRTA, has also been described. Although acidification in the renal collecting tubules is defective, subjects with incomplete renal tubular acidosis (iRTA) do not develop acidosis as a matter of course. While their serum bicarbonate or blood pH may often be within normal limits, their urinary pH always stays above 5.5 [1] in the presence of systemic acidosis. Most iRTA patients also suffer from recurrent nephrolithiasis [1], but musculoskeletal symptoms are uncommon.
A recent study in patients with primary osteoporosis demonstrated a very high incidence of a renal acidification defect with normal serum electrolytes, a condition compatible with iRTA [5,6]. All subjects in those studies were referred for further investigations of the causes of osteoporosis. The findings of those studies are incomplete, however, because they lacked an acidification study in subjects with normal bone mineral density (BMD) as a control group, did not demonstrate a causal relationship between the presence of iRTA and osteoporosis, and had a potential referral bias. Therefore, their conclusions need to be confirmed. If they are confirmed, an acid loading test to exclude iRTA should become a part of the investigation of primary osteoporosis; and alkaline therapy, as prescribed in dRTA, would be highly valuable in iRTA, to prevent further bone loss.
Therefore, to study the association between iRTA and osteoporosis, we conducted the present community-based survey in Khon Kaen province, Thailand, where a high incidence of renal tubular acidosis has been reported [7].
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Subjects and methods
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Subjects
A community-based survey was conducted in the Koksri and Nongtoom subdistricts (Muang district, Khon Kaen province), Thailand, between January and June 2000. The studied areas are considered rural, with a total population of 1189 adults (age >20 years). The majority of the population are farmers and ethnically Thai. Individuals were excluded from the study for the following reasons: (i) diseases that affect bone remodelling (e.g. myeloma, classic dRTA or agromegaly); (ii) chronic diseases (e.g. cancer, chronic infection, collagen vascular disease, hepatic or renal impairments, or diabetes); (iii) a history of taking medications affecting calcium and bone metabolism (e.g. steroids, vitamin D or thyroid hormone); and (iv) a history of fracture or previous bone surgery. Also excluded were women who were pregnant or lactating, or who had delivered or had an abortion within the 3 months prior to this study, and those who had histories of oophorectomy or premature menopause. We enrolled 361 adults, 146 men and 215 women. The subjects were recruited from 14 villages within Khon Kaen province. In each village, a full list of subjects was obtained. There were 1189 subjects, from which 40 subjects were randomly selected from each village. Based on a previous estimate of the prevalence of iRTA in the studied area (
2%), it was estimated that a sample size of at least 334 subjects was required to make an estimate at the significance level of 5% and error of estimation 1.5%. The selected subjects were then invited to participate in the study.
Diagnosis of iRTA
The first morning voided urine was obtained from each subject. Urinary pH was determined immediately after receiving the sample, using a pH meter (Radiometer America, Inc., Westlade, OH). Subjects with urinary tract infections were treated before the screening. Subjects whose first morning voided urine had a pH <5.5 were considered to have normal acidification, and therefore not to have dRTA. Subjects whose first morning voided urinary pH was >5.5 received a single dose of 0.1 g/kg body weight of NH4Cl orally with a light meal (without fruit or vegetables), after which their urinary pH was determined every 2 h during a total observation time of 6 h. A blood sample was obtained at the sixth hour to measure serum electrolytes to confirm that adequate systemic acidosis had been achieved (serum bicarbonate <18 mmol/l or decreased by 4 mmol/l from baseline) [8]. If urinary pH was reduced to <5.5 within 6 h after the induction of systemic acidosis, the diagnosis of iRTA was excluded. If urinary pH remained above 5.5 throughout the 6 h, a defect in acidification was confirmed. The diagnosis of iRTA was made if a subject had normal baseline serum electrolytes and an abnormal ammonium loading test [8]. A second loading test with a higher dose of NH4Cl (0.15 g/kg body weight of NH4Cl) was done in subjects who failed to achieve adequate systemic acidosis in the initial ammonium loading test. For all iRTA subjects, we measured serum electrolytes, calcium, phosphorus, magnesium, creatinine, intact parathyroid hormone (iPTH), and 24 h urine creatinine excretion, sodium, potassium, chloride, calcium, magnesium, citrate and ammonia, and obtained plain X-rays of both kidneys and a 3 day dietary diary to estimate daily calcium intake. Calcium intakes were calculated using the INMUCAL computer program (Mahidol University, Bangkok). The database for food composition analysis was derived from Thai food composition tables developed by the Institute of Nutrition, Mahidol University [9]. The total individual energy intake was 2507±395.5 kcal/day, carbohydrate 525.3±79.8 g/day, protein 57.2±15.3 g/day and fat 22.3±7.9 g/day. In normal, non-iRTA, subjects, we measured only 24 h urinary excretions of creatinine, sodium and calcium.
Specimen collections
Urinary volumes and constituents, including sodium, potassium, calcium, magnesium, oxalate, phosphate and creatinine, were measured immediately after the completion of 24 h collections. Urine samples for citrate determination were collected separately, in containers with 10 g of boric acid as preservative. Creatinine, sodium, potassium, chloride, calcium and phosphate were measured by autoanalysers, magnesium by atomic absorption spectrometry, and citrate by the citrate lyase technique [10]. Serum iPTH was determined by an immunoradiometric assay (ELISA-PTH, CIS bio international, GIF-sur-Yvette Cedex, France). The normal range for iPTH was 1050 pg/ml, of urinary citrate 1.8±0.2 mmol/day. Hypercalciuria on low calcium diets (3.757.5 mmol/day of elemental calcium) was defined, in either sex, as a urinary calcium excretion >4.75 mmol/day. Hypercalciuria on normal to high calcium diets (1525 mmol/day of elemental calcium) was defined as a urinary calcium excretion >6 mmol/day (females) or >6.5 mmol/day (males); or >0.1 mmol/kg/day (either sex) [11,12].
Bone mineral density
BMDs of the lumbar spine and femoral neck were determined using a DEXA scanner (model DPX-IQ, Lunar Radiation Corp, USA) in all subjects. The coefficient of variation was 1.5% for BMD. The classification of normal BMD, osteopenia (Z score <1) and osteoporosis (Z score <2.5) is based on WHO criteria [13]. For comparison with subjects with classic dRTA from the same geographic area, in this study we also present data from our previous study on BMD in 14 classic dRTA subjects (three males and 11 females) [4].
Informed consent was obtained from all subjects. The study protocol was approved by the Ethics Committee of Khon Kaen University, Thailand. The study was in accord with the revised Declaration of Helsinki of 1983.
Statistical analysis
The data are presented as mean±SD. The sample size (n) determination was based on a prevalence of renal tubular acidosis (p) of
2% in the studied area [7],
error 0.05, and error of estimation (D) 1.5%. The study population was estimated using the formula [14]: n = [(Z
/2)2(p)(1 p)]/D2, which gave us a sample size of 334 adults. The Student t-test and
2 test were applied to compare group means and proportions, respectively. The paired t-test was also applied to compare group means of dependent variables. In order to identify independent factors that determine BMD in the cohort (excludes dRTA), multivariate analysis was applied. The input variables for multivariate analysis included age, sex, body weight, height, calcium intake, duration of menopause and the presence or absence of iRTA. Statistical significance was defined as a P<0.05. The statistical analyses were performed using SPSS version 9.0 (SPSS, Inc, Chicago).
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Results
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There were 338 subjects, 138 males and 200 females, with normal renal acidification function; 23 subjects, or 6.4% of the studied population, had iRTA, eight males and 15 females. Patients characteristics for iRTA and dRTA, and those of normal subjects are shown in Table 1. Serum iPTH was within normal limits in both iRTA (27.7±11.3 pg/ml) and dRTA (15.5±8.5 pg/ml) subjects. None of the subjects with iRTA had histories of severe bone pain leading to work limitation, hypokalaemic paralysis or passing renal stones; eight subjects, however, had asymptomatic renal stones demonstrated by the screening plain X-rays of their kidneys. Calcium intake was 8.31± 3.20 mmol/day for iRTA subjects, 7.89±3.25 mmol/day for normal subjects and 9.42± 3.68 mmol/day for dRTA subjects. There was no significant difference in calcium intake between the three groups. Serum biochemical parameters for the three groups are shown in Table 1. All iRTA subjects had normal baseline serum electrolytes, calcium and phosphate levels. Ammonium excretion was 41.9±14.8 mmol/day in iRTA subjects. Urinary citrate was markedly reduced (0.96±1.1 mmol/day) in iRTA subjects, but they did not have hypercalciuria (2.69±1.24 mmol/day for iRTA and 2.05±1.59 mmol/day in normal controls).
The BMDs of lumbar spines (L2L4) and femurs of iRTA, dRTA and normal subjects are shown in Table 2. The difference in the BMD between iRTA and normal subjects was not significant. Femoral BMD in iRTA and normal subjects tended to be higher than in dRTA subjects. A simple scatter plot of the BMD of lumbar spines (L2L4) and ages is shown in Figure 1 for iRTA and normal subjects. The distributions of BMD over age were similar between the two groups. The numbers and percentages of subjects classified according to BMD (normal, osteopenia or osteoporosis) are shown in Table 3. The proportions of individuals with osteopenia and osteoporosis in iRTA and normal subjects were not different. Multiple regression analyses for the determination of independent variables that affected BMD demonstrated that age, duration of menopause and body weight were the variables that determined BMD of both the lumbar spine and femoral neck. In addition, female gender was an independent variable for the BMD of the femoral neck. The underlying disease (presence or absence of iRTA), height and calcium intake were excluded from the regression model (Table 4). After we had completed the analyses of the data from our initial survey, a subsequent study of BMD in the 23 iRTA subjects was conducted in July, 2002 (
2 years after the initial BMD survey). The second BMD measurements were to determine whether or not there was a bone loss in the subjects. There was no significant change in the mean (±SD) of the BMD of the femoral neck from its baseline value, 0.92±0.19 and 0.91±0.02 g/cm2 for the initial and follow-up measurements, respectively.
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Table 3. Numbers (and percentages) of osteopenic and osteoporotic subjects in the iRTA group and of subjects with normal BMD
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Discussion
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The incidence of iRTA in our study was comparable to that reported previously in a study in this area [7]. The majority of cases in our study were females and asymptomatic; however, eight of them had urinary tract stones. The defects found in this subgroup of patients were abnormality in renal acidification and low urinary citrate excretion. Our iRTA subjects did not have hypercalciuria. This may result from a low calcium intake and no elevation in bone resorption in this group of subjects. Although a high incidence of low BMD was found in iRTA subjects, its incidence and severity were not different from those of age-matched normal subjects in the same geographic area. The high incidence probably results from age-related bone loss rather than from iRTA itself. This hypothesis is supported by: (i) the same distribution of BMD across age in both iRTA and normal subjects; (ii) the percentages of subjects with osteopenia and osteoporosis were similar between iRTA and normal subjects; and (iii) multivariate analysis excluded the presence of iRTA as an independent risk factor of reduced BMD.
Our finding contrasts with that of the studies by Weger et al. in patients with primary osteoporosis [5,6]. In their studies, 10 of 46 osteoporotic patients who were referred for further investigation had iRTA. The incidence was unusually high for a European population in whom RTA is rare. These investigators also recommended the ammonium loading test as a part of the work-up of patients with osteoporosis of unknown aetiology. However, they did not demonstrate any causal relationship between iRTA and osteoporosis. In addition, there was no acidification study in age-matched normal BMD subjects, and a selection bias cannot be excluded. In our study, the percentages of iRTA subjects with osteopenia or osteoporosis were not different from those in normal subjects. Our study was a population-based survey in an area with a very high incidence of RTA. All subjects were asymptomatic and were enrolled randomly. Therefore, selection bias was unlikely.
The finding, from our follow-up survey, of no significant bone loss in iRTA subjects provides additional support for our conclusion that iRTA has at most a minor impact on BMD. However, although iRTA patients do not have persistent systemic acidosis, they may episodically develop mild to moderate metabolic acidosis, due to high acid loads and their limited capacities to excrete acid. With high protein intakes, ketogenic diets or prolonged strenuous physical activity, iRTA patients may develop intermittent metabolic acidosis. The cumulative effect of systemic acidosis may finally lead to reduced bone formation [3] or increased bone resorption [15,16]. The difference between the findings of our study and those of Weger et al. might result from differences between the diets of our respective populations. In contrast to the low protein intake of Thais [3,17] (<60 g/day in this survey), the high animal protein content of the diets of industrialized countries generates
70 mEq of acid per day; moreover, many grain products, cheese and even a high salt intake may be acidogenic [18]. In this study, dRTA patients were excluded due to our selection criteria, which excluded all subjects with pre-existing bone diseases. In contrast to iRTA, low BMD is prominent and develops early in life in dRTA [3]. The BMD of the iRTA subjects in our present study tended to be higher than the BMD of dRTA patients we studied previously [3]. This might be due to the older age of the iRTA subjects, compared with dRTA. Correcting metabolic acidosis eliminates musculoskeletal symptoms and elevates BMD in dRTA patients [4]. Although alkaline therapy in iRTA can prevent recurrent nephrolithiasis [19,20], its effect on the BMD of iRTA subjects is still uncertain. There was no hypercalciuria among iRTA subjects, perhaps because iRTA subjects do not have systemic acidosis, and therefore, no enhanced bone resorption. Low protein intake in this population may also contribute to this absence of systemic acidosis; and the relatively low calcium intake in our population might also affect the amount of urinary calcium excretion. Although we did not determine vitamin D status in our cohort, it is unlikely for people who spend most of their time working outdoors to have vitamin D deficiency.
In conclusion, our community-based survey demonstrated that incomplete distal renal tubular acidosis alone was not associated with lower bone mass. Nevertheless, it may still be valuable to monitor serum electrolytes and BMD in this group of patients, because their bodies tend to accumulate acid and intermittently go into metabolic acidosis.
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Acknowledgments
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This study was supported by the Thailand Research Fund.
Conflict of interest statement. None declared.
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References
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- Buckalew VM Jr, Caruana RJ. The pathophysiology of distal (type 1) renal tubular acidosis. In: Gonick HC, Buckalew VM Jr, eds. Renal Tubular Disorder: Pathophysiology, Diagnosis, and Management. Dekker, New York; 1985: 357386
- Nilwarangkur S, Nimmanit S, Chovakul V et al. Endemic primary distal renal tubular acidosis in Thailand. Q J Med 1990; 74: 289301[ISI][Medline]
- Domrongkitchaiporn S, Pongsakul C, Stitchantrakul W et al. Bone mineral density and histology in distal renal tubular acidosis. Kidney Int 2001; 59: 10861093[ISI][Medline]
- Domrongkitchaiporn S, Pongsakul C, Sirikulchayanonta V et al. Bone histology and bone mineral density after correction of acidosis in distal renal tubular acidosis. Kidney Int 2002; 62: 21602166[CrossRef][ISI][Medline]
- Weger W, Kotanko P, Weger M, Deutschmann H, Skrabal F. Prevalence and characterization of renal tubular acidosis in patients with osteopenia and osteoporosis and in non-porotic controls. Nephrol Dial Transplant 2000; 15: 975980[Abstract/Free Full Text]
- Weger M, Deutschman H, Weger W, Kotanko P, Skrabal F. Incomplete renal tubular acidosis in primary osteoporosis. Osteoporosis Int 1999; 10: 325329[CrossRef][ISI][Medline]
- Nimmannit S, Malasit P, Susaengrat W et al. Prevalence of endemic distal renal tubular acidosis and renal stone in the northeast of Thailand. Nephron 1996; 72: 604610[ISI][Medline]
- Krapf R, Seldein DW, Alpern RJ. Clinical syndromes of metabolic acidosis In: Seldin DW, Giebisch G, eds. The Kidney: Physiology and Pathophysiology, 3rd edn. Lippincott Williams & Wilkins, Philadelphia; 2000: 20732130
- Institute of Nutrition, Mahidol University. Food composition database for INMUCAL program. Institute of Nutrition, Mahidol University, Salaya, Nakhonpathom, Thailand;1997
- Toftegaard Nielsen T. A method for enzymatic determination of citrate in serum and urine. Scand J Clin Lab Invest 1976; 36: 513519[ISI][Medline]
- Henneman PH, Benedict PH, Forbes AP, Dudley HR. Idiopathic hypercalciuria. N Engl J Med 1958; 259: 802807[ISI][Medline]
- Caruana RJ, Buckalew VM Jr. The syndrome of distal (type1) renal tubular acidosis. Medicine (Baltimore) 1988; 67: 8499[ISI][Medline]
- Kanis JA, WHO Study Group. Assessment of fracture risk and its application to screening for postmenopausal osteoporosis. WHO Technical Report Series 1994; 843: 13
- Lemeshow S, Hosmer DW, Klar J, Lwanga SK. Adequacy of Sample Size in Health Studies. John Wiley, Chichester; 1990: 239
- Bushinsky DA, Krieger NS, Geisser DI, Grossman EB, Coe FL. Effects of pH on bone calcium and proton fluxes in vitro. Am J Physiol 1983; 245: F204F209[ISI][Medline]
- Lemann J Jr, Litzow Jr, Lennon EJ. The effects of chronic acid loads in normal man: further evidence for the participation of bone mineral in the defense against chronic metabolic acidosis. J Clin Invest 1966; 45: 16081614[ISI][Medline]
- Domrongkitchaiporn S, Ongphiphadhanakul B, Stitchantrakul W et al. Risk of calcium oxalate nephrolithiasis after calcium or combined calcium and calcitriol supplementation in postmenopausal women. Osteoporosis Int 2000; 11: 486492[CrossRef][ISI][Medline]
- Barzel US, Massey LK. Excess dietary protein can adversely affect bone. J Nutr 1998; 129: 10511053
- Domrongkitchaiporn S, Khositseth S, Stitchantrakul W, Tapaneya-olarn W, Radinahamed P. Effect of potassium citrate supplement on urinary abnormalities in distal renal tubular acidosis. Am J Kidney Dis 2002; 39: 383391[ISI][Medline]
- Preminger GM, Sakhaee K, Skurla C, Pak CY. Prevention of recurrent calcium stone formation with potassium citrate therapy in patients with distal renal tubular acidosis. J Urol 1985; 134: 2023[ISI][Medline]
Received for publication: 11. 2.04
Accepted in revised form: 19. 7.04