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Nephrol Dial Transplant (2000) 15: 975–980 Prevalence and characterization of renal tubular acidosis in patients with
osteopenia and osteoporosis and in non-porotic controls

Wolfgang Weger, Peter Kotanko, Martin Weger, Hannes Deutschmann and Falko Skrabal Department of Internal Medicine, Krankenhaus der Barmherzigen Bru¨der, Graz, Austria Abstract
trations and capillary pH did not differ between the Background. Chronic metabolic acidosis may increase
alkali mobilization from the bone and thus promote Conclusion. Incomplete RTA I may be prevalent in a
the development of osteoporosis. The objective of the significant proportion of patients suffering from osteo- current study was to compare urinary acidification in penia or osteoporosis. The outcome of the frusemide patients with reduced bone mineral content with that test suggests either a defect of the H+ATPase in the in control subjects with normal bone density.
cortical collecting tubule (CCT ) or a defective Na+ Methods. Forty-six subjects (41 females, 5 males) with
reabsorption in the CCT. Prospective studies are osteopenia or osteoporosis were studied. In none of needed to further elucidate the impact of incomplete the subjects were overt metabolic acidosis, derange- RTA I on the development of reduced bone mineral ment of potassium homeostasis, or renal insufficiency present. Distal tubular acidification was studied bymeans of oral ammonium chloride loading test Keywords: acidosis; metabolic acidosis; osteopenia;
(0.1 g/kg body weight) and the oral frusemide test osteoporosis; renal tubular acidosis; RTA I (40 mg). In addition the frusemide test was performedin 20 healthy age- and sex-matched controls (17females, 3 males).
Introduction
Results. In all control subjects a urinary pH <5.5 was
observed following the ingestion of 40 mg frusemide.
In Western industrialized countries an average 70-kg In contrast, in patients with reduced bone mineral adult ingests a diet that generates approximately 70 density incomplete renal tubular acidosis type I (RTA mEq of acid per day. Physiologically, this acid chal- I ) was diagnosed in 10 of 46 subjects (22%) by oral lenge is dealt with by the kidneys, which excrete 70 ammonium chloride loading test. Disorders possibly mEq of acid, 40 mEq/day as ammonium ions and 30 related to RTA I were detected in eight of these 10 mEq as titratable acid [1]. In steady state the renal patients. Thirty-six patients had a normal urinary pH acid excretion equals the endogenous acid production response following oral ammonium chloride loading.
and thus acid–base balance is neutral. A positive body Oral frusemide, 40 mg, failed to lower urinary pH acid balance may be induced either by a significant <5.5 in sixteen patients (35%), these included 10 rise of endogenous acid production that exceeds the subjects with incomplete RTA I, and six subjects with renal acid excretion capacity, or by defects of the renal a normal oral ammonium chloride loading test. An acid excretion [1]. In response to a positive acid abnormal frusemide test was found in 35% of patients with reduced bone mass and in none of the normal and pH decrease and activate homeostatic mechanisms controls ( x2=7.39; P<0.01). With the ammonium to restore acid–base balance. The renal excretion of chloride test as the gold standard for diagnosis of 4 may more than double, whereas the excretion of distal RTA, the frusemide test showed a sensitivity of titratable acid shows only a minor increase [1]. Despite 1.0 (95% CI, 0.69–1.0) and a specificity of 0.89 (95% these homeostatic mechanisms, the acid balance may CI, 0.78–0.96) for the diagnosis of distal RTA. Patients remain positive, triggering a release of alkali from the with incomplete RTA I were younger than those with- bone. A prolonged alkali release from the bone will out incomplete RTA I (42±16 vs 54±14 years; P= eventually lead to reduction of total bone mass [2].
0.025; mean±SD). Basal serum bicarbonate concen- Subjects with a reduced renal acid excretory reserve, e.g. in the setting of incomplete distal renal tubularacidosis (renal tubular acidosis type I (RTA I )), may Correspondence and offprint requests to: Peter Kotanko MD, be at extra risk of bone mineral loss especially when Department of Internal Medicine, Krankenhaus der BarmherzigenBru¨der, Marschallgasse 12, A-8020 Graz, Austria.
ingesting the usual mixed Western diet. Recently we 2000 European Renal Association–European Dialysis and Transplant Association observed a high prevalence of incomplete distal tubular >1500 g (n=4), autoimmune thyroid disease (n=3), nephro-calcinosis due to medullary sponge kidney (n=1), and a acidosis and ‘primary’ osteoporosis [3]. The current familial history of incomplete RTA I (n=1). The patients study was undertaken to estimate the prevalence of with thyroid disease had been prescribed thyroid hormone incomplete RTA I in subjects with a reduced bone to achieve normal basal TSH levels. Hypercalciuria was mineral content as compared to subjects with a normal defined as a daily urinary excretion of calcium >4 mg/kg bone density and to further define the mechanism of body weight. Patients with hypercalciuria had not been RTA I in this group of patients. A secondary goal was advised to follow a Ca-restricted diet.
to study the test characteristics of the frusemide test.
The classical causes of secondary osteoporosis (glucocort- icoid excess, hyperthyroidism, primary hyperparathyroidism)were ruled out by measurement of thyroid hormone (free Subjects and methods
T3, free T4, basal TSH ), serum calcium and iPTH, and onthe basis of clinical examination and patient history.
In none of the patients were renal insufficiency or overt Study population and biochemical methods metabolic acidosis present. The presence of RTA type IV(due to hyporeninaemic hypoaldosteronism) was considered Sixty-six subjects, 58 females and 8 males, were studied.
unlikely because of normal serum potassium concentrations.
Forty-six subjects (41 females, 5 males) suffered from osteo- Urinary pH was measured with a KCl electrode (pH-meter porosis or osteopenia, 20 subjects were matched healthy E 512, Metrohm, Herisau, Switzerland ). Urinary tract controls (age 46±7 years; 17 females, 3 males) with a normal infection was ruled out by urinalysis.
bone mineral density. The patients were referred by primary In all 46 patients both an oral ammonium chloride care physicians to our hospital for suspected osteoporosis.
(NH Cl ) loading test and an oral frusemide test was per- The subjects do not resemble a cohort of patients with formed; in 20 controls the frusemide test was done. In osteoporosis and incomplete RTA I described recently [3].
addition, three patients with a positive frusemide test and a All subjects were on standard hospital diet, which provides negative NH Cl loading test consented to a fludrocortisone- on average 120 mmol sodium chloride, 1000 mg of calcium, and 70 g of protein per day. No dietary extremes (e.g. high- Prior to the frusemide loading test patients were off or low-protein diet, low-sodium diet) were given.
In all subjects (patients and controls) bone mineral density (NSAID) for at least 2 days. The patients were given 40 mg was assessed at the lumbar site (L2–L5) using dual energy of frusemide orally and urinary pH was measured 0, 2, 4, X-ray absorptiometry on a Sophos XLA machine. According and 6 h after the frusemide dose [6 ]. In case of the fludrocort- to the criteria proposed by the World Health Organization isone-modified frusemide test, oral frusemide was preceded ( WHO), osteopenia and osteoporosis were diagnosed by a on the previous evening by 0.5 mg of fludrocortisone. At reduced bone mineral density (t-score −1.0 to −2.5, or least 2 days after the frusemide test the standardized short t-score <−2.5 respectively) measured by DXA [4]. Any course oral NH4Cl test was performed [7]. Briefly, patients radiological evidence of vertebral fractures was also taken as ingested 0.1 g/kg body weight of NH4Cl in gelatin capsules.
a diagnostic criterion of osteoporosis. Applying these dia- Blood gas analysis was performed from capillary blood with gnostic criteria, 20 patients (43%) had osteopenia and 26 an AVL 995 Hb automatic blood gas system (AVL, Graz, patients (57%) had osteoporosis. The baseline characteristics Austria) on an hourly basis. The metabolic acidosis induced of the study population are shown in Table 1.
by the NH4Cl load was documented by a fall of serum Sixteen patients had disorders possibly associated with 3 concentrations >3 mmol/1 and a pH <7.35. Urinary impaired renal distal tubular acidification, namely hypercalci- pH was measured at baseline and 2, 4, and 6 h after the uria with (n=2) and without nephrolithiasis (n=2), past completion of NH Cl intake. Failure to lower urinary pH to history of nephrolithiasis without current hypercalciuria less than 5.5 is consistent with some form of distal RTA I (n=3), habitual analgesic abuse with a cumulative amount [4]. Each subject drank at least 500 ml of water duringthe test.
Table 1. Baseline characteristics of the patients with reduced bone
mass
The t-test of untransformed data was used for group compar-ison of patients with and without a normal response in the NH4Cl test. A P value <0.05 was considered as significant.
Data are shown as mean and ±SD. The 95% confidence interval (CI ) of relative frequencies was derived from the binomial distribution. Absolute frequencies were compared 4Cl test as the gold standard for the diagnosis of distal RTA, the diagnostic performance of the frusemide test was evaluated in terms of sensitivity and specificity. The failure to lower urinary pH <5.5 both in the NH Cl and the frusemide test was considered as a true positive ( TP) result, whereas an appropriate urinary acidification in both tests was scored as a true negative ( TN ) outcome. False positive ( FP) and false negative ( FN ) frusemide testswere Mean±standard deviation; aP=0.025 (two-sided).
TP/(TP+FN ), specificity was defined as TN/( TN+FP) [8].
Incomplete RTA I in osteopenia and osteoporosis Patients with incomplete RTA I presented on average 12 years younger as compared to patients withoutRTA I (95% CI, 1.6–22.4 years; P=0.025; Table 1).
In all control subjects (100%; 95% CI, 83–100%) the Four of 26 (15%) patients with osteoporosis and six administration of oral frusemide resulted in a fall of of 20 patients with osteopenia (30%) had incomplete the urinary pH below 5.5 (Figure 1).
Overt metabolic acidosis, impaired renal function, In eight of the 10 subjects with incomplete RTA I, or disturbances of potassium metabolism were not the following disorders possibly related to incomplete observed in the patients studied. In 30 patients (65%) RTA I were present: nephrolithiasis and hypercalciuria both NH Cl testing and the oral frusemide test revealed (n=2), autoimmune thyroid disease (n=2), long-term normal responses, i.e. a fall of urinary pH <5.5 habitual analgesic abuse (n=2), nephrocalcinosis due to medullary sponge kidney disease (n=1), and a Ten patients (22%) failed to lower urinary pH below familial history of RTA I in one patient. In two 5.5 ( Table 1, Figure 2c) despite the induction of sys- patients with incomplete RTA I, no associated dis- temic metabolic acidosis following the ingestion of orders were revealed. In those six subjects with a NH Cl. In these 10 patients the diagnosis of incomplete normal NH4Cl test but an abnormal urinary pH RTA I was made. All of these patients with incomplete response to oral frusemide, a past history of nephroli- RTA I showed also a urinary pH above 5.5 during the thiasis without current hypercalciuria (n=1), and auto- frusemide test (Figure 2c). Additionally, six subjects immune thyroid disease (n=1) were present. In the 30 (13%) with a normal NH4Cl test failed to lower urinary patients with both a normal frusemide and NH Cl pH <5.5 during the frusemide test (Figure 2b). In test, hypercalciuria (n=2), habitual analgesic (n=2), three patients of the latter group a fludrocortisone- and a past history of nephrolithiasis without current modified frusemide test resulted in essentially the same hypercalciuria (n=2) were recognized.
outcome, i.e. the failure to lower urinary pH below 5.5 With the NH Cl test as the gold standard for (nadir urinary pH, 6.5, 6.0, and 6.1 respectively). An diagnosis of distal RTA the frusemide test showed a abnormal frusemide test was significantly more fre- sensitivity of 1.0 (95% CI, 0.69–1.0) and a specificity quent in osteopenic/osteoporotic patients as compared to the control group ( x2=7.39; P<0.01).
Serum bicarbonate, capillary pH, pCO2, serum creat- inine, and potassium were within the normal range Discussion
and did not differ between the two groups (Table 1).
In the group of patients with normal NH4CI testing Bone is critically involved in buffering during the but an abnormal frusemide test (n=6) serum bicarbon- chronic stages of metabolic acidosis [9,10]. A chronic- ate (23.5±1.2 mmol/l ), capillary pH (7.4±0.02), ally positive acid balance, e.g. due to an impairment and capillary pCO2 (38.3 mmHg), serum creatinine of renal acid excretion, may trigger the release of alkali (0.9±0.15 mg/dl ), and serum potassium (4.2± and calcium from the bone and eventually lead to 0.39 mmol/l ) were also not different from those in reduction of bone mass and osteoporosis. In the past, subjects (n=30) with normal responses in either dia- the idea of chronic retention of acid as a possible cause of osteoporosis, particularly in postmenopausalwomen, was put forward by Sebastian et al. [11].
Sanchez and Libman [12] described both proximal anddistal renal tubular acidosis in eight patients withosteoporosis. Recently we described a high prevalenceof incomplete RTA I in patients with ‘primary’ osteo-porosis [3].
The RTA syndromes encompass a disparate group of disorders that have in common an inability toexcrete acid that is out of proportion to any reductionin glomerular filtration rate. RTA type I involvesdefects of acid excretion confined to the distal tubule.
The hallmark of overt RTA type I is a hyperchloraemicmetabolic acidosis accompanied by a reduced net acidexcretion and the inability to lower urinary pH below5.5 in the face of spontaneous acidaemia or after acidloading. In the complete form of RTA I plasmaHCO− 3 concentration is typically reduced. Incomplete RTA I may be suspected if in random urine spotsamples urinary pH is Á5.5 [4]. The definite diagnosis Fig. 1. Urinary pH in response to oral frusemide in 20 healthy
of incomplete RTA I requires the induction of a controls. All subjects were given an oral dose of 40 mg frusemide.
systemic metabolic acidosis by means of acid loading.
Data represent the baseline and the nadir urinary pH during aperiod of 6 h following oral administration of frusemide.
Among the various acid-loading protocols the NH Cl Fig. 2. Urinary pH in response to a short-course oral NH Cl loading and to frusemide. All subjects were given 0.1 g
encapsulated NH Cl and an oral dose of 40 mg frusemide. Data represent the base line and the nadir urinary pH during a period of 6 h following the NH Cl ingestion and frusemide respectively. (a) Results obtained in patients with both normal NH Cl and frusemide testing
(n=30). Note that in nine subjects the individual urinary pH responses to NH Cl loading were similar. (b) Results in six patients with a
normal NH Cl test but an insufficient fall of urinary pH following the frusemide test. (c) Individual urinary pH data in 10 patients with
loading test introduced by Wrong and Davies [13] has was not observed in these patients which is compatible recognized wide-spread clinical application. Since dis- solved NH Cl may cause abdominal discomfort and Unfortunately, the NH Cl test is frequently accom- even vomiting we preferred to administer NH Cl in panied by abdominal discomfort, even when encapsul- gelatin capsules. In this gelatin form the test was better ated NH4Cl is used. None of the patients studied by tolerated and no vomiting was observed. To give us agreed to a prolonged NH Cl loading test over reliable results systemic acidosis has to be induced by RTA I resembles a diagnosis with a variety of 4Cl load. A fall of capillary pH below 7.35 in conjunction with a fall of serum HCO− concentration underlying aetiologies. Despite a recognized associ- >3 mmol/l is considered to reflect a sufficient degree ation of RTA I with disorders such as medullaryof acidaemia [5], which was observed in all test sub- sponge kidney, hypercalciuria, analgesic nephropathy, jects. The NH Cl loading test was performed in all 46 and immuno-mediated diseases such as lupus nephritis, subjects, resulting in an inadequate urinary acid- Sjo¨gren syndrome, and Graves disease [14], the cause ification in 10 patients, who therefore were diagnosed of RTA I in some patients remains obscure. Recently, having incomplete RTA I. Overt metabolic acidosis in some of these idiopathic forms of RTA I the absence Incomplete RTA I in osteopenia and osteoporosis of H+ATPase in the intercalated cells has been shown renal function showed that the oral dose of 40 mg may [15]. In all but two patients of the RTA I group a be too low in obese subjects; in this subject, 80 mg of thorough work-up revealed disorders with a recognized frusemide were necessary to produce a normal urinary association with RTA I. In addition, in two of the six acidification. None of the patients studied was over- patients with an abnormal frusemide test and a normal weight. It has been suggested recently that the adminis- NH Cl test disorders possibly related to distal tubular tration of a mineralocorticoid such as fludrocortisone acidification disturbances were present. One may on the evening preceding the frusemide test may reduce speculate that in some of these patients these disorders the frequency of false positive results of the frusemide may have contributed to the blunted urinary pH test [5]. In our hands, a fall of urinary pH <5.5 was not observed in the three frusemide-positive and Acidification in the collecting tubules (CT ) is primar- NH Cl-negative subjects who agreed to a fludrocorti- ily achieved via H+ secretion by a luminal H+ATPase sone-modified frusemide test, supporting the view that [16 ]. This pump is located in the intercalated cells of some form of tubular dysfunction is present. In future the cortex and in the medulla. The H+ secretion by studies, the additional measurement of urinary citrate intercalated cells of the cortical collecting tubule (CCT ) and NH+ excretion may provide additional insights is indirectly influenced by the Na+ reabsorption of the adjacent principal cells, since the removal of Na+ from A distal acidification defect was found in 10 of 46 the tubular fluid generates a lumen-negative potential patients (22%; CI, 11–36%) with reduced bone mineral which facilitates net H+ secretion by minimizing the content patients when tested by the NH4Cl test and in degree of passive proton back-diffusion. Any reduction as many as 16 of 46 (35%; CI, 21–50%) by the of Na+ reabsorption in the CCT diminishes the degree frusemide test. When interpreting these frequencies one of lumen negativity (a condition called voltage- has to appreciate that the primary aim of the study dependent defect) and results in a reduced H+ net was not to estimate the prevalence rates of RTA I in secretion and an inability to lower the urinary pH.
patients with osteoporosis or osteopenia. However, it Application of frusemide provides a means of increas- is noteworthy that renal acidification was normal in ing the delivery of sodium to the sites of distal Na+ all 20 subjects with normal bone density. Since the reabsorption. Following a rise in intraluminal sodium patients studied were referred to the hospital because the Na+ reabsorption in the CCT increases [6 ] fol- of suspected osteoporosis, data are not controlled for lowed by a decrease of tubular fluid pH. In RTA I a referral bias. Studies in a randomly selected group of common problem is thought to be a defect in the patients with osteopenia or osteoporosis as compared H+ATPase pump that may be present in the cortex to matched controls with normal bone densities are and/or the medulla. Patients with this type of RTA I needed to obtain an unbiased estimation of the may or may not respond normally to the administra- prevalence of renal acidification defects.
tion of frusemide. In situations where the H+ATPase It is interesting to note that subjects with incomplete defects are limited to the medullary collecting duct, an RTA I presented at an earlier age ( Table 1).
acidification of the urine may be expected, since the Admittedly, this observation may arise from patient medullary H+ secretion is essentially Na+ independent selection due to referral bias, but it is attractive to [17]. In contrast, a defective H+ secretory pathway in speculate that subjects with incomplete RTA I are the CCT is expected to cause an inability to lower the prone to a more rapid loss of bone mineral and urinary pH following frusemide application. The therefore present at a younger age. Clearly, an addi- response of urinary pH to frusemide may be blunted tional prospective study in an age- and sex-matched by the presence of amiloride-type diuretics [18], group of patients with and without incomplete RTA I NSAIDs, and volume contraction. Therefore we took is needed to define the rate of bone loss in patients care to perform the tests in clinically euvolaemic patients being off diuretics and NSAIDs for at least 2 In conclusion, incomplete RTA I, both primary and days. The outcome of the frusemide test in the 10 secondary, is prevalent in patients suffering from patients with incomplete RTA I studied by us suggests reduced bone mineral content. Because of a reduced either a defect of the H+ATPase in the CCT or a renal acid excretory reserve in these subjects the inges- defective Na+ reabsorption in the CCT, whereas a tion of nutrients stimulating the endogenous acid pro- defective H+ secretion in the medullary collecting duction (e.g. a diet rich in proteins) may induce a positive acid balance which eventually promotes the A dose of 40 mg frusemide given orally was chosen release of alkali and calcium from the bone.
since none of the patients studied had renal insuffi- Acknowledgements. This study was supported by the Fonds zur ciency (the maximum serum creatinine concentration Forderung der wissenschaftlichen Forschung, Austria, SFB 007 in the study population was 1.1 mg/dl ) and since we wanted to avoid significant volume depletion. Inpatients with renal insufficiency a dose of 80 mg References
frusemide has been advocated in order to overcomethe accompanying resistance to frusemide [19].
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CG, ed. Oxford Textbook of Clinical Nephrology. Oxford University Press, London: 1998: 311–358 17. Lombard WE, Kokko JP, Jacobson HR. Bicarbonate transport 8. Griner PF, Mayewski RJ, Mushlin AI, Greenland P. Selection in cortical and outer medullary collecting tubules. Am J Physiol and interpretation of tests and procedures. Ann Intern Med 18. Batlle D, Flores G. Underlying defects in distal renal tubular 9. Barzel US. The effect of excessive acid feeding on bone. Calcif acidosis: new understandings. Am J Kidney Dis 1996; 27: 896–915 19. Rose H, O’Malley K, Pruitt A. Depression of renal clearance 10. Green J, Kleeman CR. Role of bone in regulation of systemic of furosemide in man with azotemia. Clin Pharmacol Ther 1976; acid–base balance. Kidney Int 1991; 39: 9–26 Received for publication: 1.3.99Accepted in revised form: 9.2.00

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