ORIGINAL ARTICLES

Primary hyperparathyroidism and proximal renal tubular acidosis: Report of two cases f.r.cp.[c], f.r.cp.[c] Douglas Siddiqui,
Abdullah A.
m.d.,

and

R. Wilson, m.d.,

Toronto

Summary: Two cases of primary hyperparathyroidism due to single parathyroid adenomas presented with the additional feature of hyperchloremic acidosis. The defect in urinary acidification responsible was not of the distal or gradient-limited type since both patients could lower urine pH adequately. However, there was a defect of bicarbonate reabsorption, an abnormality referred to as the proximal or rate-limited type of renal tubular acidosis. It is suggested that this defect represents an exaggeration of the physiological effect of parathormone on bicarbonate reabsorption and may be responsible for the frequent finding of hyperchloremia in association with primary hyperparathyroidism as well as for the urinary bicarbonate-wasting associated with a variety of causes of secondary hyperparathyroidism.
From the Department of Medicine, University of Toronto, Toronto, Ontario and the Division of Nephrology, Toronto General Hospital. Reprintrequeststo: Dr. D. R. Wilson, Division of Nephrology, Toronto General Hospital, Toronto 2, Ontario.

Hyperchloremia is often observed in association with primary hyper as well as obvious parathyroidism1 and defective urinary acidification, The renal tubular acidosis, have also been reported.2"5 type of renal tubular acidosis occurring in patients with primary hyperparathyroidism has been stated to be of distal type, that is, due to an inability to establish an adequate pH gradient between blood and distal tubular fluid, since these patients were unable to lower urine pH normally after an acid load or in the presence of systemic acidosis. However, in view of the recent classification of renal tubular acidosis into proximal and distal types6"9 it seemed important to attempt to demonstrate or exclude a defect in bicarbonate reabsorption to account for the presence of hyperchloremic acidosis. The present report describes two patients with primary hyper the parathyroidism due to a parathyroid adenoma who appear to have which is acidosis renal tubular of or proximal bicarbonate-wasting type unassociated with other tubular defects. These two cases are of special interest in view of the previous observations of increased bicarbonate excretion following parathyroid hormone administration10"13 and the suggestion that secondary hyperparathyroidism may also be associated with bicarbonate-wasting.u
Case reports

P.G., a 21-year-old office secretary, was first admitted to hospital in March 1969 with a history of bilateral recurrent renal colic. She had been well until July 1967 when she developed right renal colic and a calculus was removed from theureter by cystoscopy at another hospital. Afterwards she continued to have intermittent bilateral flank discomfort until November 1968 when she had another major attack of renal colic, this time on the left side. Hypercalcemia and hypophosphatemia (serum calcium 11.8 mg./lOO ml., phosphorus 2.4 mg./lOO ml.) were discovered and she was admitted to hospital for investigation. There was no history of excessive milk, alkali, or vitamin D ingestion. The patient had experienced the recent onset of intermittent postprandial epigastric pain. She had been receiving cyclic doses of an estrogen-progesterone preparation because of dysmenorrhea. Past medical and family history were unremarkable. The patient's height was 5 ft. 5 in., she weighed 108 lbs., and appeared slim but healthy. Physical examination was normal. Urinalysis was normal and urine cultures were sterile. Hb. was 12.7 g./lOO ml., leukocyte count 7600/cu.mm. with a normal differential count, E.S.R. 18 mm./hr. Serum protein electrophoresis was normal. Serum electrolytes were sodium 139 mEq., potassium 3.7 mEq.,
106

Casel

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chloride 105 mEq., and C02 content 22 mEq./l. The remainder Case2 ofthe laboratory data are shown in Table I. Skeletal x-ray films B.U., a 35-year-old housewife, first noted hematufia in October revealed no evidence of osteitis fibrosa. An upper gastrointesti 1969 and during the next month she passed two renal calculi. nal x-ray series showed an ulcer crater in the duodenum. An Laboratory tests performed by her family physician revealed intravenous pyelogram was normal, with no evidence of renal hypercalcemia and hypophosphatemia, as well as hyper calculi or nephrocalcinosis. chloremia, and she was referred to hospital for investigation in The diagnosis of primary hyperparathyroidism was made March 1970. There was no history of excessive rhilk, alkali, or essentially by exclusion of other possible causes of hypercal- vitamin D ingestion. There were no symptoms of peptic ulcer. cemia and hypophosphatemia. Renal tubular acidosis was sus The patient had been on 1-thyroxine, 0.2 mg. daily, fof rioh-tdxie pected because of the persistently low, though occasionally goitre which was diagnosed in 1965. She had undergone total borderline, venous C02 content and the modestly elevated hysterectomy for procidentia in April 1969. The rest df the plasma chloride levels. Studies of urinary acidification were history was unremarkable and the family history Was also carried out as described below and are shown in Table II and Fig. non-contributory. 1. Parathyroid exploration was undertaken on May 2,1969 and a The patient was obese, weighing 172 lbs., her height being 5 ft. parathyroid adenoma was removed which measured 1.5 by 0.8 2 in. B.P. was 134/90. The thyroid gland was normal in size and by 0.3 cm. and was composed of chief cells. Two other normal consistence. The rest of the physical examination was ribrrnal. parathyroid glands were identified. Urinalysis was negative although there were numerous calcium Postoperatively the patient did well with return of serum oxalate crystals in the sediment. Urine cultiires were: sterije. calcium and phosphorus levels to normal. After six months she Hemoglobin was 14.5 g./100 ml., leukocyte count 53b0/cu.mrii;; noted the onset of fatigue and was found to be hypocalcemic ESR 12 mm./hr. Serum protein electrophoresis and thyroid (serum calcium 7.8 mg.%, phosphorus 3.3 mg.%). Oral calcium function tests were normal. Thyroid antibodies were not detect supplements were begun with considerable symptomatic im- ed. Serum electrolytes were: sodium 140 mEq;, potassium 4.0 provement. These were discontinued four months later (10 mEq., chloride 108 mEq. and C02 content 22 mEq./l. thfe months postoperatively) and she continued to feel well and to remainder ofthe laboratory data are shown in Table I. Skeletal show normal serum calcium and phosphorus levels. Serum x-ray films revealed no evidence of osteitis fibrosa. An intrave chloride was 105 and C02 content 22 mEq./l. 24 months after nous pyelogram was normal. A presumptive diagnosis of primary hyperparathyroidism was parathyroidectomy. made by exclusion of other causes of hypercalcemia. Renal tubular acidosis was suspected because of hyperchloremia and persistently low plasma C02 content. Studies of urine acidifica tion are described below and the results are shown in Table II and Table I Fig. 1. Parathyroid exploration was carried out and a chief cell adenoma measuring 1 cm. in diameter was removexi* three other Clinical biochemistry results normal glands being identified. Postoperatively the patient did Case 1 Case 2 well with return of serum calcium and phosphorus levels to normal and with no recurrence of renal colic. However, hyperPrePostPrePost-

operative operative operative operative

Table II Acid-base and electrolyte results

operative operative operative operative

Case 1 Pre-

Case 2
Post-

Pre-

Post-

fNormal range: Serum calcium 8.8-10.3, Uf calcium 4.9-5.8, Phos. * Mean of two to four values. 2.8-4.5 mg.%, Urine calcium < 250 mg., OHpro- fMaximum excretion rate of titratable acid, ammonia, and total line 9-24, C phos. 6-16, %TRP 82-96.15 hydrogen ion. C.M.A. JOURNAL/MARCH 18, 1972/VOL. 106 655

?All values are the average of two

or more

determinations.

chloremia and slightly decreased plasma C02 persisted up to 12 months postoperatively.

content have

1. Ammonium chloride load test. The short test proce dure described by Wrong and Davies2 was used, voided urine being collected under mineral oil at two-hour inter vals from 8 a.m. to 8 p.m. and urine pH, titratable acidity, ammonium, bicarbonate, and creatinine determined on each sample. Ammonium chloride, 0.1 g./kg. body weight, was given orally as non-enteric-coated capsules over a period of 60 minutes from 10 a.m. to 11 a.m. "Arterialized" capillary blood pH, Pco2, and bicarbonate were measured before and one and three hours after ammonium chloride administration. The long (three-day) ammonium chloride load test was used only in Case 2 and the procedure described by Elkinton et al.16 was employed. 2. Bicarbonate reabsorption studies. This test was car ried out in the morning after giving ammonium chloride, 0.05 g./kg. body weight, on the previous evening. The patients were fasting and comfortably recumbent in bed with an adequate diuresis ensured by oral hydration prior to and throughout the test. Standard clearance procedures were used, inulin being administered intravenously in 0.45 N. saline at a rate of 3 ml./min. by an infusion pump. Urine was collected at 15 to 20 minute intervals by means of an indwelling catheter which emptied under a layer of mineral oil. Arterial blood samples were drawn from the brachidl artery through a Cournand needle at the begin ning and end of each clearance period. Plasma bicarbon ate was gradually increased by the intravenous infusion of 5% sodium bicarbonate. Results were plotted by the Bicarbonate reabsorption studies (Fig. 1) methods described by Pitts, Ayer and Schiess.17 Standard In Case 1 the tubular maximum for bicarbonate (TmHC03) was 2.4 mlvi./lOO ml. GFR, which is approxi chemical methods were used. mately 8 to 20% less than the normal values of 2.6 to 3.0 ml. GFR.17 The threshold for bicarbonate mM./lOO Results excretion was approximately 22 mM./l. (Fig. 1). During The two patients described in this report presented with this study the plasma bicarbonate rose from 19.5 to 32 renal calculi and were found to have hypercalcemia, the plasma potassium concentration decreased mM./l., hypophosphatemia and hypercalciuria (Table I). Tubular from 4.0 to 3.3 mEq./l., Pco2 increased from 34 to 38 mm. reabsorption of phosphate was normal in Case 1 and Hg., and inulin clearance ranged from 124 to 143 ml./min. in reduced Neither Case 2. ofthe two patients had Fractional excretion slightly of sodium, an index ofthe degree of aminoaciduria, proteinuria, or increased uric volume expansion, increased glucosuria, from 1.4 to 7.1%. acid clearance. Glomerular filtratiori rate, as judged by inulin clearance, was normal in both patients. Case 2 demonstrated a mild defect in urine concentrating capaci ty. Skeletal x-rays were normal in both cases, but urinary hydroxyproline excretion was increased in Case 1, sug o gesting increased bone turnover. Radiographic studies of o the kidneys showed no evidence of medullary nephrocal cinosis. In the absence of any other cause for hypercal cemia a parathyroid exploration was carried out and a < solitary adenoma removed in each case. The unusual z clinical feature which attracted our attention preopera- o tively in both patients was the presence of mild hyper chloremic acidosis similar to that observed in renal tubu lar acidosis (Table II). Both patients had plasma bicar bonate levels which were slightly decreased. Plasma chlo ride levels were consistently elevated in both patients, 40 36 24 28 32 16 20 ranging from 103-107 mEq./l. in Case 1 and from 108-114 in Case 2. "Arterialized" capillary blood pH mEq./l. PLASMA HC03-(mM/l) values were within normal limits, indicating respiratory FIG. 1.Rates of of metabolic acidosis. filtration, reabsorption and excretion of bicarbonate compensation during bicarbonate infusion. The normal range is indicated by the hatched areas.17 Two patients with primary hyperparathyroidism and Acid excretion studies (Table II) hyperchloremia (Cases 1 and 2) are compared with two "control" Studies of urine acidification were carried out in an patients, one with classic distal RTA and one with primary attempt to clarify the mechanism responsible for hyper- hyperparathyroidism but no hyperchloremia. 656 C.M.A. JOURNAL/MARCH 18, 1972/VOL. 106

Urinary acidification studies

chloremic acidosis. In Case 1, urine pH was 5.52 when the plasma bicarbonate level was 22 mEq./l., and after the administration of ammonium chloride the urine pH fell to 5.06 while the urinary excretion of titratable acid, ammon ium and total hydrogen ion reached normal maximum values.2 These results indicate that the excretion of acid, as well as the capacity to establish a hydrogen ion gradient, were normal. In Case 2, urine pH was 6.34 when plasma bicarbonate was 22 mEq./l. suggesting the possibility of impaired ability to establish a hydrogen ion gradient in the distal nephron.2 The urine pH, however, fell to a minimum of 5.15 after administration of ammonium chloride and the excretion rates of titratable acid, ammonium and total hydrogen ion reached normal maximum values. In Case 2 acid excretion was also studied after a long (three day) ammonium chloride load test.16 The 24-hour urine collect ed on the third day of this test had a pH of 5.30 (normal upper limit 5.33).16 The excretion rates of titratable acid and ammonium were 34.1 and 74; 1 /xEq./min., values within the normal range. "Arterialized" capillary blood pH was 7.34 and HCOs concentration was 19 mEq./l. at the end of the collection period. A second short ammoni um chloride load test was carried out in this patient on the day following the three-day test to provide a stronger stimulus for acid excretion. The minimum urine pH was 4.85 indicating unimpaired capacity to establish a H + ion gradient. The maximum excretory rates for titratable acid and ammonium at this titne were 46 and 119 /*Eq./min.; the blood pH was 7.25 and bicarbonate level 15.6 mEq./l.

normal. It is possible, of course, for defects of both the proximal and distal type to be present in the same patient. Primary hyperparathyroidism has been associated with a significant incidence of hyperchloremia and defective urine acidification.1"5 Previous studies have suggested that the renal tubular acidosis associated with hyperpara thyroidism is of the distal type and it has been classified accordingly.8,9 However, studies of bicarbonate reabsorp tion have not been previously reported and systemic acidosis of sufficient severity to maximaljy stimulate the production ofa hydrogen ion gradient has not always been present. The two patients with primary hyperparathyroi dism described in this report appear to have renal tubular acidosis of the proximal type. Both patients were able to lower their urine pH below 5.3 when systemic acidosis was increased after the administration of an ammonium chlo ride load, while the results of bicarbonate loading studies showed that the tubular maximum for bicarbonate (TmHC03) was approximately 8 to 20% lower than reported normal values.6,717 Such a defect in bicarbonate reabsorption could be related to excessive volume expansion during the test procedure,18*19 but the fractional excretion rates of sodium in the two patients with hyper chloremic primary hyperparathyroidism were similar to those of two "control" subjects, one with classic distal RTA and one with normochloremic primary hyperpara thyroidism, both of the latter patients having normal TmHC08 values. Although the magnitude of the reduc tion in tubular reabsorption of bicarbonate was not great in either patient, the decrease in TmHC03 and the unimpaired ability of the distal nephron to generate a hydrogen ion gradient, indicate a defect in bicarbonate reabsorption of the proximal (or rate-limited) type. Morris9 has logically argued that such a defect could be located Discussion The clinical finding of hyperchloremic acidosis is fre anatomically in the cortical distal nephron where 10 to quently an indication of defective urinary excretion of 15% of bicarbonate reabsorption occurs, as well as in the ion. Until recently the term renal tubular acido proximal tubule, and it is certainly possible that the hydrogen sis (RTA) has been used to refer to an abnormality in functional defect could exist in either or both nephron urinary acidification, without glomerular insufficiency, in segments. which the characteristic defect is an inability to establish a The proximal type of RTA was described as an isolated normal hydrogen ion gradient between blood and tubular defect by Rodriguez-Soriano, Boichis and Edelmann6 in fluid in the distal tubule under the stimulus of spontaneous four children who showed no other evidence of tubular systemic acidosis or acidosis induced by ammonium dysfunction and none ofthe clinical features ofdistal RTA chloride loading. Hyperchloremic acidosis, however, also with the exception of retarded growth. York and Yendt20 occurs due to a decrease in bicarbonate reabsorption in the have reported an adult with the proximal type of urinary proximal tubule, presumably caused by a defect in the rate bicarbonate-wasting, osteomalacia and possible vitamin of tubular hydrogen ion secretion.6,7 Recently, therefore, D deficiency. A defect in bicarbonate reabsorption also it has been suggested that renal tubular acidosis should be occurs in association with phosphaturia, glucosuria, amiclassified into two pathophysiologic types: (a) the "distal" noaciduria, and other tubular defects in the Fanconi (classic or gradient-limited) type, and (b) the "proximal" syndrome of children and adults which may be produced (bicarbonate-wasting or rate-limited) type.8,9 Important by a variety of toxic or metabolic disorders that interfere distinguishing features between the two types are that, with proximal tubule function.8,9 The etiology of the while patients with distal RTA are unable to lower urine defective tubular bicarbonate reabsorption in the two pH below 5.3 in the presence of systemic acidosis and have patients described in this report has not been established, diminished rates of excretion of titratable acid as well as but it is probable that the abnormality is related to the ammonium, (though appropriate for urine pH), patients effects of hyperparathyroidism. No other abnormality of with the proximal type of RTA, though unable to reabsorb tubular function was detected in our patients and glomeru bicarbonate completely owing to a defect in the proximal lar filtration rate was entirely normal thus excluding a tubule, are able to lower their urine pH normally and to reduction in nephron mass as a factor in the decreased excrete adequate amounts of titratable acid and ammoni bicarbonate reabsorption. Hyperparathyroidism could um when their serum bicarbonate level is below the cause defective urinary acidification: (1) by a direct bicarbonate threshold. A reduced tubular maximum for hormonal effect on the kidney; (2) by the direct effect of bicarbonate reabsorption and diminished threshold for hypercalcemia on renal function; (3) by either 1) or 2) bicarbonate excretion, therefore, characterize the defect causing structural renal damage; or (4) by a combination in proximal RTA, while in distal RTA the renal threshold of these mechanisms. It has been shown that the adminis and tubular maximum for bicarbonate reabsorption are tration of parathyroid extracts to animals or maft is
C.M.A. JOURNAL/MARCH 18,

The maximum tubular capacity for bicarbonate reab sorption (TmHCOs) in Case 2 was also 2.4 mM./lOO ml. GFR with the threshold for bicarbonate excretion being approximately 23 mM./l. (Fig. 1). During this study the plasma bicarbonate concentration rose from 21 to 30 mM./l., the plasma potassium concentration fell from 4.1 to 3.2 mEq./l., the blood Pco2 increased from 37 to 42 mm. Hg. and the inulin clearance ranged from 98 to 117 ml./min. Fractional excretion of sodium increased from 1.8 to 6.1% during bicarbonate loading. For comparison, the results of bicarbonate reabsorp tion studies in two other patients are shown in Fig. 1, a patient with classic familial distal renal tubular acidosis who was unable to lower urine pH below 6.1 despite severe systemic acidosis, and a patient with primary hyperpara thyroidism without hyperchloremia or systemic acidosis. Similar techniques were used, both subjects had normal renal function and both demonstrated similar changes in electrolyte parameters, including fractional excretion of sodium, during the bicarbonate titration study. In both patients the renal threshold for bicarbonate excretion was 26 to 27 mM./l. and the tubular maximum for bicarbon ate reabsorption was 2.8 to 3.0 mM/100 ml. GFR, values within the normal range.17 Post-operative results Following surgical removal ofa single parathyroid adeno ma both patients demonstrated return of calcium metabolism to normal, although Case 1 developed transient hypoparathyroidism. However, the abnormalities in se rum electrolytes suggestive of renal tubular acidosis have persisted for 24 months (Case 1) and for 12 months (Case 2) after correction of hyperparathyroidism.

1972/VOL. 106

657

followed by a marked increase in urine pH and bicarbonate excretiopn'0' 13 which is independent of changes in the filtered load of bicarbonate."2 Recent micropuncture results have clearly shown an inhibitory effect of parathyroid' hormone on sodium and phosphate reabsorption in the proximal tubule of the dog2" and it is probable that bicarbonate reabsorption in this segment of the nephron is similarly affected.'8 In contrast to the effect of parathyroid hormone, hypercalcemia induced by the administration of calcium salts causes urine pH to fall, rather than rise,-and results in increased hydrogen ion excretion.22-24 Moreover, hypercalcemic states not related to primary hyperparathyroidism are often associated with alkalosis ra tber thhan acidosis.2 The failure of renal tubular acidosis to disappear after removal of' parathyroid adenomas in the two patients described suggests that the tubular defect was not simply due''to increased circulating parathyroid hormone levels but was'-als'o related to structural damage to the renal tubules. The experimental nephrocalcinosis produced by par,atlormone injections may be related to a hormonal effect on the ground substance of connective tissue26 or on renal tubular' epithelium,27 since simply increasing the serum calcium level by the administration of calcium does not produce similar changes.27 Histologic study of the effects of parathyroid hormone-induced hypercalcemia on renal ultrastructure in the rat and dog indicates that the principal and earliest effects may be seen in the proximal tubule.2Y8`3 However, the distal nephron has also been im;plicated as the primary site of damage in experimental hyperparathyroidism3' so that the question of the most significa'nt site of renal tubular injury cannot be considered settled. Similarly it appears that both the proximal and distal fufi"tional'types of renal tubular acidosis may be observed in Fyperparathyroidism. At least one previous description of distal RTA in hyperparathyroidism was associated with the presence of medullary nephrocalcinosis,5 while in the prefsent two cases with an isolated defect in bicarbonate reabsorptiop (proximal RTA) there was no apparent renal at the time of the study. This observacqlcification present ton suggests that the appearance of distal RTA may be a kI'r development than the proximal type of defect in the course of parathyroid hormone-induced renal damage and 4t'is possible that the appearance of medullary nephrocalcinosis may be related to the more alkaline pH of tubular fliuid induced by the proximal inhibition of bicarbonate reabsorption by parathormone. In the original report of hereditary- fructose intolerance with renal tubular acidosis''a'ai milar sequence of events may be suspected since thjs meta'bolic defect is known to induce an abnormality in prpximal -tubule function (proximal RTA) without nephroc.alcinosis, but if medullary nephrocalcinosis develops then an inability to lower urine pH (distal RTA) may al$' be found, as described by Mass, Smith and Walsh.32 In'the presence of a distal defect it may be difficult to detect a m'ild defect in bicarbonate reabsorption, particularly if the glom'erular filtration rate is reduced. This fact m4y account for the lack of previous reports of proximal RTA in primary hyperparathyroidism. Also, when plasm4 electrolytes are drawn in conditions of venous stasis, the CQ2 content may be artifactually elevated to the normal range- and mild acidosis may be overlooked although.'hyperchloremia is observed. Considering the physiological ef.fects of parathyroid hormone on the proximal tubule it is probable that urinary bicarbonate loss with
658 C.M.A. JOURNAL/MARCH 18, 1972/VOL. 106

reciprocal increase in tubular chloride reabsorption accounts for most cases of hyperchloremia with primary hyperparathyroidism. Secondary hyperparathyroidism may also be implicated as an etiological factor in renal tubular acidosis of either distal or proximal type. In York and Yendt's patient with the proximal type bicarbonate-wasting and osteomalacia, secondary hyperparathyroidism is very likely to have been present.20 Muldowney, Freaney and McGenney' have also described renal tubular acidosis associated with osteomalacia, and provided some evidence that the acidification defect may be due to secondary hyperparathyroidism, although vitamin D deficiency could also be an important factor. In addition, Morris et al. 4 have recently suggested that secondary hyperparathyroidism may play an important role in aggravating the bicarbonate-wasting, phosphaturia, and aminoaciduria found in the Fanconi syndrome. Finally it is possible to speculate that secondary hyperparathyroidism may contribute to the defect in bicarbonate reabsorption observed in some patients with chronic renal failure33 and after renal transplantation.34' Recent preliminary evidence36 ' lends support to these suggestions and further studies of the relationship between parathormone and the mechanisms of urinary acidification will be awaited with interest.
We are indebted to Miss Norma Huber, Mrs. Eleanor Bennett and Mrs. Paula Clayman for technical assistance, and to the nursing staff of the Farquharson Investigation Unit, Toronto General Hospital. Dr. Siddiqui was supported by a Medical Research Council of Canada Research Fellowship, 1968-70.

Resume

Hyperparathyroidieprimaire et acidose renale au niveau

du tube proximal: presentation de deux cas Selon les auteurs, deux cas d'hyperparathyroldie primaire causee par des adenomes simples des parathyroides, presentaient en outre une acidose hyperchlor6mique. L'anomalie de l'acidification urinaire n'appartenait pas au type distal ou a gradient limite, eftant donne que les deux malades pouvaient abaisser le pH urinaire de fagon suffisante. On trouvait cependant un trouble dans la reabsorption du bicarbonate, anomalie consideree comme etant du type proximal de l'acidose renale. Les auteurs estiment que ce trouble a comme cause une exageration de l'effet physiologique de la parathormone sur la reabsorption du bicarbonate qui peut etre invoquee souvent dans la decouverte frequente d'hyperchloremie contemporaine d'une hyperparathyroidie primaire et egalement dans l'elimination urinaire de bicarbonate accompagnant des cas tres varies d'hyperparathyroidie secondaire.
References
1. WILLS MR, McGOWAN GK: Plasma chloride levels in hyperparathyroidism and other hypercalcemic states. Br Med J ii: 1153-1156, 1964 2. WRONG 0, DAVIES HEF: The excretion of acid in renal disease. Q J Med 28: 259-313, 1959 3. FOURMAN P, MCCONKEY B, SMITH JWG: Defects of water reabsorption and of hydrogen ion excretion by the renal tubules in hyperparathyroidism. Lancet 1: 619-623, 1960
4. MULDOWNEY FP, FREANEY R, MCGENNEY D: Renal tubular

acidosis and amino aciduria in osteomalacia of dietary or intesti-

nal origin. QJMed 37: 517-539, 1968

5. REYNOLDS TB, BETHUNE JE: Renal tubular acidosis secondary to hyperparathyroidism. Clin Res 17: 169, 1969 (abstract) 6. RODRIGUEZ-SORIANO J, BoICHIs H, EDELMANN CM JR: Bicarbonate reabsorption and hydrogen ion excretion in children with renal tubular acidosis. J Pediair 71: 802-813, 1967 7. MORRis RC JR: An experimental renal acidification defect in patients with hereditary fructose intolerance. II. Its distinction from classic renal tubular acidosis; its resemblance to the renal acidification defect associated with the Fanconi syndrome of children with cystinosis. J Clin Invest 47: 1648-1663, 1968 8. RODRIGUEZ-SORIANO J, EDELMANN CM JR: Renal tubular acidosis. Ann Rev Med 20: 363-383, 1969 9. MORRIS RC JR: Renal tubular acidosis. N Engi J Med 281: 1405-1413, 1969 10. ELLSWORTH R, NICHOLSON WM: Further observations upon changes in the electrolytes of urine following the injection of parathyroid extract. J Clin Invest 14: 823-827, 1935 11. NORDIN BEC: The effect of intravenous parathyroid extract on urinary pH and electrolyte excretion. Clin Sci 19: 311-319, 1960 12. HELLMAN DE, Au WYW, BARTrER FC: Evidence for a direct effect of parathyroid hormone on urinary acidification. Am J Physiol 209: 643-650, 1964 13. PUSCHETT JB, GOLDBERG M: The relationship between the renal handling of phosphate and bicarbonate in man. J Lab Clin Med 73: 956-969, 1969 14. MORRIS RC JR., MCSHERRY E, SHERWOOD LM et al: Evidence of a pathogenetic role of hyperparathyroidism in renal tubular dysfunction of patients with Fanconi's syndrome. J Clin Invest 49: 68a, 1970 (abstract) 15. YENDT ER, GAGNE RJA: Detection of primary hyperparathyroidism, with special reference to its occurrence in hypercalciuric females with "normal" or borderline serum calcium. Can Med Assoc J 98: 331-336, 1968 16. ELKINTON JR, HUTH EJ, WEBSTER GD JR., et al: The renal excretion of hydrogen ion in renal tubular acidosis. Am J Med 29: 554-575, 1960 17. PITTs RF, AYER JL, SCHIESS WA: The renal regulation of acid base balance in man. III. The reabsorption and excretion of bicarbonate. J Clin Invest 28: 35-44, 1949 18. SLATOPOLSKY E, HOFFSTEN P, PURKERSON M, et al: On the influence of extracellular fluid volume expansion and of uremia on bicarbonate reabsorption in man. J Clin Invest 49: 586-595, 1970 19. KURTZMAN NA: Regulation of renal bicarbonate reabsorption by extracellular volume. Ibid pp 586-595 20. YORK SE, YENDT ER: Osteomalacia associated with renal bicarbonate loss. Can Med Assoc J94: 1329-1342, 1966 21. PUSCHETT JB, AGUS ZS, SENESKY DJ, et al: Mechanism of action of

parathyroid hormone phosphate transport in the dog proximal tubule. J Clin Invest 49: 77a, 1970 (abstract) 22. WALLACH S, CARTER AC: Metabolic and renal effects of acute hypercalcemia in dogs. Am J Physiol 200: 359-366, 1961 23. VERBANCK M, KAHN RJ: Effets de I'hypercalcemie aigue sur la concentration sanguine et l'excretion urinaire des electrolytes chez le chien. Rev Franc Etud Clin et Biol 7: 722-731, 1962 24. AMIEL C, ARDIALLOU R, LECESTRE M, et al: Acidification de l'urine apres injection intraveineuse de gluconate de calcium chez l'homme. III. Etude de l'excretion des ions HCO3. Rev Franc Etud Clin et Biol 8: 647-652, 1963 25. HEINEMANN HO: Metabolic alkalosis in patients with hypercalcemia. Metabolism 14: 1137-1152, 1965 26. BAKER R, REAVEN G, SAWYER G: Ground substance and calcification produced by parathyroid extract or calcium gluconate. Endocrinology 67: 733-743, 1960 27. SCHNEIDER AF, REAVEN EP, REAVEN G: A comparison of renal calcification produced by parathyroid extract or calcium gluconate. Endocrinology 67: 733-743, 1960 28. ENGFELDT B, GARDELL S, HELLSTROM J, et al: Effect of experimentally induced hyperparathyroidism on renal function and structure. Acta Endocrinol 29: 15-26, 1958 29. YANO H, SONODA T, OHKAWA T: An electron microscopic study on the kidney in experimentally induced hyperparathyroidism. Urol Int 20: 319-335, 1965 30. BERRY JP: Nephrocalcinose experimental par injection de parathormone. Etude microanalyseur a sonde electronique. Nephron 7: 97-116, 1970 31. CARONE FA, EPSTEIN FH, BECK D, et al: The effects upon the kidney of transient hypercalcemia induced by parathyroid extract. Am J Pathol 36: 77-103, 1960 32. MASS RE, SMITH WR, WALSH JR: The association of hereditary fructose intolerance and renal tubular acidosis. Am J Med Sci 251: 516-523, 1966 33. SCHWARTZ WB, HALL PW III, HAYS RM, et al: On the mechanism of acidosis in chronic renal failure. J Clin Invest 38: 39-52, 1959 34. MASSRY SG, PREUSS HG, MAHER JE, et al: Renal tubular acidosis after cadaver kidney homotransplantation. Am J Med 42: 284-292, 1967 35. MCIVER MA, RUSSELL PS, THIER SO: "Proximal" renal tubular acidosis in transplant recipients. Clin Res 17: 440, 1969 (abstract) 36. MULDOWNEY FP, DONOHOE JF, CARROLL DV, et al: Reversible renal bicarbonate wastage in primary and secondary hyperparathyroidism. Clin Res 19: 378, 1971 (abstract) 37. MORRIS RC JR., MCSHERRY E, SEBASTIAN A: Parathyroid hormone modulation of renal acidification. J Clin Invest 50: 67a, 1971 (abstract)

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