View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by Elsevier - Publisher Connector Kidney International, Vol. 28 (1985), pp. 85—93 NEPHROLOGY FORUM The pathogenetic spectrum of Bartter's syndrome Principal discussant: JAY H. STEIN The University of Texas Health Science Center at San Antonio, San Antonio, Texas fractional distal solute reabsorption. Values of .52, .60, and .57 ( a mean of .56) were obtained at a time when his urinary chloride was below 10 Editors mEq/day and when his plasma chloride was 84—88 mEq/liter. During JORDANJ.COHEN this same admission, he was given I to 4 mg/day of amiloride, a JOHN T. HARRINGTON potassium-sparing agent, for 4 days while ingesting a diet similar to that JEROME P.KASSIRER regularly taken by the patient in his normal environment (sodium chloride, 150 mEq/day, potassium 70 mEq/day). In this 4-day period, NIcoLAosE. MADIAS his serum potassium rose from 2.9 to 3.3 mEq/liter. Three additional days at home on 3 mg/day of amiloride did not increase the serum ManagingEditor potassium. His treatment regimen was restored to spironolactone, 75 CHERYLJ.ZUSMAN mg/day; ibuprofen, 400 mg/day; and potassium chloride, 120 mEq/day; therapy continued unchanged for the next 4 years. At times, the patient has not complied with his treatment program. During the latest admission, he entered the Clinical Research Center Michael Reese Hospital and Medical Center for a short metabolic study to assess the effect of magnesium repletion University of Chicago Pritzker School of Medicine on potassium balance. He discontinued taking all medication except and potassium chloride 10 days before admission. On admission, the New England Medical Center Hospitals laboratory data were as follows: sodium, 138 mEq/liter; potassium, 2.3 mEq/liter; chloride, 91 mEq/liter; and bicarbonate, 35 mEq/liter. The Tufts University School of Medicine BUN was 15 mg/dl; creatinine, 0.8 mg/dl; and glucose, 103 mg/dl. The remainder of the SMA-12 was normal. Plasma magnesium was 1.2 mEq/ liter, with a normal range of 1.8 to 2.2 mEq/liter. The white blood cell count was 10,300 mm3; hemoglobin, 15.8 g/dl; hematocrit, 46%; and Case presentation platelet count, 453,000 mm3. Urinalysis was normal. An 18-year-old white male was admitted to the Clinical Research The patient was given a constant diet containing 100 mEq of sodium, Center of the Audie L. Murphy Memorial Veterans Hospital in San 25 mEq of magnesium, and 75 mEq of potassium per day. An additional Antonio for evaluation of magnesium repletion in Bartter's syndrome. 72 mEq/day of potassium chloride had to be given to maintain his serum The diagnosis had been made at another hospital 5 years earlier when, potassium above 2 mEq/liter. After a control period, an infusion of after being admitted for a urinary tract infection, the patient was found magnesium chloride was given at the rate of 2 mEq/hour for 6 days. to have hypokalemia and metabolic alkalosis with normal blood pres- Based on the dietary and urinary analyses, approximately 100 mEq of sure. Plasma renin activity was elevated (60 nglmllhr), and an angioten- magnesium was retained over the 6-day period. No feces were collect- sin II infusion test failed to increase the diastolic blood pressure by 20 ed, so a complete balance study was not obtained. Plasma magnesium mm Hg until more than 30 to 40 times the normal dose was given. Renal rose from 1.0 to 2.1 mEq/liter. The plasma potassium rose from 2.3 to clearances under conditions of maximal free-water diuresis revealed 2,6 mEq/liter with only a transient retention of 50 mEq of potassium on fractional distal solute reabsorption of .45, .54, and .52 (normal, .85— the first day of infusion. Free-water clearance studies, performed the .98). An open renal biopsy at the time of a ureteral implantation for right day before the start of the magnesium infusions and the morning after vesicoureteral reflux showed marked hyperplasia and increased granu- the end of the infusions, revealed fractional distal solute reabsorption of larity of the juxtaglomerular cells. The patient was given spironolac- .70 and .65 respectively. These data, although not in the normal range, tone, ibuprofen, and potassium chloride; the serum potassium level are higher than his data 4 years previously. rose from 2.2 to 3.1 mEq/liter. The patient was given his previous regimen of spironolactone, Because the patient was adopted at the age of 18 months, the family ibuprofen, and potassium chloride and was discharged when his serum history is not available. He has no limitations on his physical activities. potassium reached 3. 1 mEq/liter. He has a learning impairment and goes to a special school, where he does well. He reports that he feels fine but has symptoms such as Discussion weakness, dizziness, and blurred vision when he forgets to take his medicine. DR. JAY H. STEIN (Chairman, Department of Medicine, and The patient had been admitted to the Clinical Research Center on two Professor, The University of Texas Health Science Center, San previous occasions. On the first admission the effect of chronically administered indomethacin on fractional distal solute reabsorption was Antonio, Texas): Bartter's syndrome, first described in 1962 [1], evaluated. Values of .50 and .51 (not different from his control data) is characterized by hypokalemia, metabolic alkalosis, hyperren- were obtained. Eight months prior to the latest admission, he wasinemia, secondary hyperaldosteronism, and normal blood pres- hospitalized for a study of the effect of a low chloride intake onsure. Resistance to the pressor effects of angiotensin II and norepinephnne also is characteristic. Histopathologic examina- tion reveals hyperplasia of the juxtaglomerular complex. In Presentation of the Forum is made possible by grants from CIBA1976 Fichman [2], Verberckmoes [3], and Gill [4] demonstrated Pharmaceutical Company, Geigy Pharmaceuticals. and Sandoz,increased production of urinary prostaglandin E2 in patients Incorporated. with Bartter's syndrome. Further investigation disclosed that © 1985 by the International Society of Nephrology the potent vasodilator PG!2 was increased in the blood vessels 85 86 Nephrology Forum lncr. Urinary K suggestive of Bartter's syndrome was noted in infants ingesting formulas low in chloride [6, 7]. When chloride deficits were Decr. Plasma restored by administering either the sodium or potassium salt, / K\ however, all the features of the syndrome disappeared [8]. lncr. Renal PGE2 Incr. Vasc. PGI2 Iner. P1. Bradykinin Patients with cystic fibrosis lose excessive quantities of sodium, potassium, and chloride in sweat and, early in their course, I 1 14 Vasodepressor some have been misdiagnosed as having Bartter's syndrome Normal BP ncr. Renin Secr. Vasopressor [9]. These conditions can be differentiated from Bartter's syn- drome and in each the associated potassium deficits can be 'I, ncr. Plasma A II_______ t repaired readily. ncr. NE If we exclude all conditions that resemble Bartter's syn- —e- Incr. P1. Aldo drome, we are left with a large number of patients with hypokalemia, metabolic alkalosis, renal potassium wasting, and the other features of the syndrome, but with dissimilarities in lncr. Renal Kallikrein PL or Renal Kininogen— results obtained from careful studies of renal tubular function. It appears that the basic renal defect(s) that leads to the potassium wasting differs among patients who otherwise fullfill Inhibit —c- all the criteria for having Bartter's syndrome. Fig.1.Aschema to explain the central findings in Banter's syndrome. Early reports indicated that a defect in proximal sodium reabsorption was the fundamental disorder that ultimately accounted for the excessive renal potassium loss [10—13]. In of patients with this syndrome, although measurement only ofrecent years a defect in sodium and chloride reabsorption in the the urinary metabolite 6 keto, PGF1, has been made [5].thick ascending limb of the loop of Henle has been considered Suppression of prostaglandin production with prostaglandinas the "proximate" cause; this possibility was suggested by synthetase inhibitors corrects all the chemical features of theErkelens and Statius Van Eps [14] as well as by Kurtzman [15], syndrome except the urinary potassium loss [4]; the serumbut was demonstrated by Chaimovitz [16], Fujita [17], and Gill potassium usually increases towards but not to normal, reach-and Bartter [18]. Indeed, Dr. Bartter himself incorporated a ing levels of 3.0 to 3.4 mEq/liter, but large quantities ofdefect in sodium and chloride reabsorption in the thick ascend- potassium chloride typically still are required along with theing limb in his own definition of the syndrome, because renal prostaglandin inhibitors. clearance studies demonstrated such a defect in the original If an obligatory renal loss of potassium is considered thepatient and in many subsequently described patients who major abnormality in patients with Bartter's syndrome, thesatisfied all his other criteria [19]. His definition depends on the sequence of events outlined in Figure 1 may serve to explain thedemonstration of a fractional distal solute reabsorption of less various components of the syndrome. According to this view,than 0.65 obtained under conditions of maximal free-water the renal loss of potassium results in a decrease in the plasmadiuresis induced by the intravenous infusion of 5% dextrose in concentration of potassium, which has three further directwater. sequelae—increased production of PGE2 by renal cells, in- A number of investigators, however, have failed to demon- creased production of PGI2 by blood vessels, and decreasedstrate this abnormality in some patients who, on the basis of production of aldosterone by the adrenals. The increase inother findings, seem to have Bartter's syndrome. Moreover, a PGE2 stimulates renin production, which in turn results inrecent preliminary publication has challenged the validity of increased angiotensin II and stimulation of aldosterone produc-tests of renal diluting ability that use intravenous hypotonic tion by the adrenal gland.