Nephrol Dial Transplant (1992) 7: 896-901 %, 1992 European Dialysis and Transplant Association-European Renal Association
Nephrology
Dialysis Transplantation
Original Article Pseudo-Bartter's syndrome from surreptitious diuretic intake: differential diagnosis with true Bartter's syndrome G. Colussi, G. Rombola, C. Airaghi, M. E. De Ferrari and L. Minetti Division of Nephrology and Dialysis, Niguarda-Ca'Granda Hospital, Milan, Italy
Abstract. Five patients with pseudo-Bartter's syndrome from surreptitious diuretic abuse were compared with six patients with true Bartter's syndrome, diagnosed as a normotensive, hyperreninaemic, hypokalaemic metabolic alkalosis with normal urine chloride excretion, low CH2O/(CH2O + CC1) ratio during maximal water diuresis and negative urine screen for diuretics. The latter was positive for frusemide in four and for hydrochlorothiazide in the remaining pseudo-Bartter's patients. The two groups of patients did not differ as for plasma Na + , C r , K + , HCO3", renin, and aldosterone, while uric acid and Mg2 + were greater in pseudo-Bartter's patients. Daily and fasting urine Na + , Cl" and K + excretion were less in pseudo-Bartter's patients; however, there was substantial overlap of values between the two groups. Fractional distal solute reabsorption during maximal water diuresis was low in the six patients with Bartter's syndrome and in two pseudo-Bartter's patients; thus, this parameter could not be taken as a specific diagnostic marker of Bartter's syndrome. Frusemide administration, 40 mg i.v., induced a brisk increase of urine flow (11.7-21.8 ml/min), Uo,m (148186mOsm/kg H2O) and FENo (14.6-24%) in Bartter's syndrome, but not pseudo-Bartter's patients; in all pseudo-Bartter's patients frusemide-induced changes of UQ,,,, (13-97) and FE N . (-0.5 to 10.2) were markedly less than in Bartter's syndrome patients. Frusemide resistance in pseudo-Bartter's patients was most probably related to diuretic-
induced ECF volume contraction and increased proximal tubule solute reabsorption; in fact fractional lithium clearance (FELl, a marker of post-proximal solute delivery) was low in pseudo-Bartter's, but not in Bartter's syndrome patients. Accordingly, fractional uric acid clearance (FEy.) was low in pseudoBartter's, but not Bartter's syndrome patients. Thus, tubular effects of ECF volume contraction (i.e. reduced FELi and FEUa, and renal resistance to frusemide) could be detected in pseudo-Bartter's but not in Bartter's syndrome patients. These biochemical parameters, particularly renal resistance to frusemide, may be of diagnostic value in the evaluation of normotensive, hypokalaemic metabolic alkalosis, if a direct diuretic screen is not routinely available. Key words: Bartter's syndrome; diuretic abuse: frusemide; hypokalaemic metabolic alkalosis
Introduction
"Pseudo'-Bartter's syndrome resulting from concealed, chronic or intermittent diuretic ingestion, as occurs in some people with various emotional and psychiatric disorders, may be difficult to differentiate from Bartter's syndrome in the absence of a thorough search for diuretics in the patient's plasma and/or urine [1-3]. In both conditions the patients may have hyperreninaemic hypokalaemic metabolic alkalosis, normal blood pressure, and 'normal' urine Na and Correspondence and offprint requests to: Dr Giacomo Colussi, Divisione di Nefrologia e Dialisi. Ospedale Niguarda-Ca"Granda. Cl excretion: although rarely measured, urine prostaPiazza Ospedale Maggiore 3, 20162 Milan, Italy. glandin excretion may be equally increased [4]. Addi-
Downloaded from https://academic.oup.com/ndt/article-abstract/7/9/896/1862954 by University of California, Santa Barbara user on 15 April 2018
Pseudo-Banter's syndrome from diuretic abuse
tionally. impairment of maximal urine diluting capacity, which was proposed as a specific diagnostic marker of Bartter's s> ndrome [5], might theoretically occur also in pseudo-Bartter's, since several distalacting diuretics impair free water generation by the distal nephron [6]. We have evaluated plasma and urine electrolyte profiles, as well as tubule function by lithium clearance and free water clearance methodology, in five patients who eventually were shown to have pseudoBartter's and in six patients with Bartter's syndrome. A most distinctive feature was the blunted natriuretic effect of a standard dose of frusemide in pseudoBartter's, which might be of potential diagnostic usefulness.
Subjects and methods Patients with Bartter's syndrome were three males and three females, aged 13-54 years, with chronic hypokalaemia, chloride-resistant metabolic alkalosis, hyperreninaemia, and normal blood pressure; urine screen for diuretics had been negative for all of them, and fractional distal solute reabsorption during maximal water-induced diuresis (i.e. the CHlO (C H l O + C a ) ratio) was reduced in all (from 68.8 to 76.1 %, n.v. 84.4± 5.5, ranges 76 96), as yet reported for five of them [7]. Pseudo-Bartter's patients were five women, aged 29-36 years; they had been sent to our clinic for evaluation of chronic hypokalaemia (lasting for several years in all) and normal blood pressure. Two of them had been diagnosed elsewhere as having Bartter's syndrome, and had long been treated with spironolactone and antiprostaglandin drugs. Diuretics were found in urine specimens of all these patients: frusemide in four, and hydrochlorothiazide in the remaining patient. All of them admitted chronic diuretic abuse after they were informed of the urine screen results. All the patients were studied as outpatients; they performed daily urine collections under mineral oil at home, and came fasting to our outpatient clinic for blood drawings, 'spot' urine collections, and dynamic studies. Multiple evaluations were available for most patients. All the patients underwent a free-water clearance study, which was performed in the morning according to a protocol in use in our laboratory [8 10]: the patients drank 20 ml kg b.w. distilled water in 15 30 min as a starting dose, and thereafter an amount of water equal to each voided specimen every 15 min. When urine osmolality reached minimal and stable levels (usually less than lOOmOsm kg H 2 O), three 15-min clearances were performed for crcatinine clearance (CCr as a marker of GFR), C Hl o a n d Q i evaluations, according to 'classical' free-water clearance methodology [11]; frusemide. 40 mg was then administered as an i.v. bolus, and three additional 10-min clearances were performed. These frusemide clearances were performed for a separate evaluation of distal nephron segments' function (i.e. 'Henles' loop' and 'distal tubule' function), as detailed elsewhere [12, 8 10]. Lithium carbonate, 600 mg p.o., was administered at 9 p.m. the day before the free water clearance study, and lithium clearance was evaluated on a timed urine collection the next morning, before the water load began.
Downloaded from https://academic.oup.com/ndt/article-abstract/7/9/896/1862954 by University of California, Santa Barbara user on 15 April 2018
897
Diuretic screen, performed in a specimen of 24-h urine using thin-la>er chromatography, was directed against frusemide. bumetanidf. piretanide. cthacrynic add. hvdrochlorothiazide. chlorthalidone. spironolactone. and amiloride. In three pseudo-Bartter's and four Bartter's syndrome patients, urine was also screened for frusemide by HPLC methodology [13], which confirmed chromatographic results. Analytical methods in use in our laboratory are reported elsewhere [8 10]. Results are given as median and ranges for biochemical parameters which were not normally distributed, and as mean±SD for clearance results. Statistical analysis was performed by use of the Wilcoxon signed rank test for non parametric data and Student's t test for clearance parameters.
Results Pseudo-Bartter's and Bartter's syndrome patients did not differ as for creatinine clearance, plasma Na + , Cl" and K + levels, degree of metabolic alkalosis, and plasma renin and aldosterone levels; Bartter's syndrome patients had lower plasma Mg 2 + (PMg) and uric acid (Pv,) levels; however, overlap with values in pseudo-Bartter's patients did occur (Table 1). Specifically, three pseudo-Bartter's (and no Bartter's syndrome) patients had hyperuricaemia (P L l > 387 umol 1 or 6.5 mg/dl), and one of five pseudo-Bartter's patients (the patient ingesting hydrochlorothiazide), and four of six Bartter's syndrome had hypomagnesaemia (P M g
Nephrology
Dialysis Transplantation
Original Article Pseudo-Bartter's syndrome from surreptitious diuretic intake: differential diagnosis with true Bartter's syndrome G. Colussi, G. Rombola, C. Airaghi, M. E. De Ferrari and L. Minetti Division of Nephrology and Dialysis, Niguarda-Ca'Granda Hospital, Milan, Italy
Abstract. Five patients with pseudo-Bartter's syndrome from surreptitious diuretic abuse were compared with six patients with true Bartter's syndrome, diagnosed as a normotensive, hyperreninaemic, hypokalaemic metabolic alkalosis with normal urine chloride excretion, low CH2O/(CH2O + CC1) ratio during maximal water diuresis and negative urine screen for diuretics. The latter was positive for frusemide in four and for hydrochlorothiazide in the remaining pseudo-Bartter's patients. The two groups of patients did not differ as for plasma Na + , C r , K + , HCO3", renin, and aldosterone, while uric acid and Mg2 + were greater in pseudo-Bartter's patients. Daily and fasting urine Na + , Cl" and K + excretion were less in pseudo-Bartter's patients; however, there was substantial overlap of values between the two groups. Fractional distal solute reabsorption during maximal water diuresis was low in the six patients with Bartter's syndrome and in two pseudo-Bartter's patients; thus, this parameter could not be taken as a specific diagnostic marker of Bartter's syndrome. Frusemide administration, 40 mg i.v., induced a brisk increase of urine flow (11.7-21.8 ml/min), Uo,m (148186mOsm/kg H2O) and FENo (14.6-24%) in Bartter's syndrome, but not pseudo-Bartter's patients; in all pseudo-Bartter's patients frusemide-induced changes of UQ,,,, (13-97) and FE N . (-0.5 to 10.2) were markedly less than in Bartter's syndrome patients. Frusemide resistance in pseudo-Bartter's patients was most probably related to diuretic-
induced ECF volume contraction and increased proximal tubule solute reabsorption; in fact fractional lithium clearance (FELl, a marker of post-proximal solute delivery) was low in pseudo-Bartter's, but not in Bartter's syndrome patients. Accordingly, fractional uric acid clearance (FEy.) was low in pseudoBartter's, but not Bartter's syndrome patients. Thus, tubular effects of ECF volume contraction (i.e. reduced FELi and FEUa, and renal resistance to frusemide) could be detected in pseudo-Bartter's but not in Bartter's syndrome patients. These biochemical parameters, particularly renal resistance to frusemide, may be of diagnostic value in the evaluation of normotensive, hypokalaemic metabolic alkalosis, if a direct diuretic screen is not routinely available. Key words: Bartter's syndrome; diuretic abuse: frusemide; hypokalaemic metabolic alkalosis
Introduction
"Pseudo'-Bartter's syndrome resulting from concealed, chronic or intermittent diuretic ingestion, as occurs in some people with various emotional and psychiatric disorders, may be difficult to differentiate from Bartter's syndrome in the absence of a thorough search for diuretics in the patient's plasma and/or urine [1-3]. In both conditions the patients may have hyperreninaemic hypokalaemic metabolic alkalosis, normal blood pressure, and 'normal' urine Na and Correspondence and offprint requests to: Dr Giacomo Colussi, Divisione di Nefrologia e Dialisi. Ospedale Niguarda-Ca"Granda. Cl excretion: although rarely measured, urine prostaPiazza Ospedale Maggiore 3, 20162 Milan, Italy. glandin excretion may be equally increased [4]. Addi-
Downloaded from https://academic.oup.com/ndt/article-abstract/7/9/896/1862954 by University of California, Santa Barbara user on 15 April 2018
Pseudo-Banter's syndrome from diuretic abuse
tionally. impairment of maximal urine diluting capacity, which was proposed as a specific diagnostic marker of Bartter's s> ndrome [5], might theoretically occur also in pseudo-Bartter's, since several distalacting diuretics impair free water generation by the distal nephron [6]. We have evaluated plasma and urine electrolyte profiles, as well as tubule function by lithium clearance and free water clearance methodology, in five patients who eventually were shown to have pseudoBartter's and in six patients with Bartter's syndrome. A most distinctive feature was the blunted natriuretic effect of a standard dose of frusemide in pseudoBartter's, which might be of potential diagnostic usefulness.
Subjects and methods Patients with Bartter's syndrome were three males and three females, aged 13-54 years, with chronic hypokalaemia, chloride-resistant metabolic alkalosis, hyperreninaemia, and normal blood pressure; urine screen for diuretics had been negative for all of them, and fractional distal solute reabsorption during maximal water-induced diuresis (i.e. the CHlO (C H l O + C a ) ratio) was reduced in all (from 68.8 to 76.1 %, n.v. 84.4± 5.5, ranges 76 96), as yet reported for five of them [7]. Pseudo-Bartter's patients were five women, aged 29-36 years; they had been sent to our clinic for evaluation of chronic hypokalaemia (lasting for several years in all) and normal blood pressure. Two of them had been diagnosed elsewhere as having Bartter's syndrome, and had long been treated with spironolactone and antiprostaglandin drugs. Diuretics were found in urine specimens of all these patients: frusemide in four, and hydrochlorothiazide in the remaining patient. All of them admitted chronic diuretic abuse after they were informed of the urine screen results. All the patients were studied as outpatients; they performed daily urine collections under mineral oil at home, and came fasting to our outpatient clinic for blood drawings, 'spot' urine collections, and dynamic studies. Multiple evaluations were available for most patients. All the patients underwent a free-water clearance study, which was performed in the morning according to a protocol in use in our laboratory [8 10]: the patients drank 20 ml kg b.w. distilled water in 15 30 min as a starting dose, and thereafter an amount of water equal to each voided specimen every 15 min. When urine osmolality reached minimal and stable levels (usually less than lOOmOsm kg H 2 O), three 15-min clearances were performed for crcatinine clearance (CCr as a marker of GFR), C Hl o a n d Q i evaluations, according to 'classical' free-water clearance methodology [11]; frusemide. 40 mg was then administered as an i.v. bolus, and three additional 10-min clearances were performed. These frusemide clearances were performed for a separate evaluation of distal nephron segments' function (i.e. 'Henles' loop' and 'distal tubule' function), as detailed elsewhere [12, 8 10]. Lithium carbonate, 600 mg p.o., was administered at 9 p.m. the day before the free water clearance study, and lithium clearance was evaluated on a timed urine collection the next morning, before the water load began.
Downloaded from https://academic.oup.com/ndt/article-abstract/7/9/896/1862954 by University of California, Santa Barbara user on 15 April 2018
897
Diuretic screen, performed in a specimen of 24-h urine using thin-la>er chromatography, was directed against frusemide. bumetanidf. piretanide. cthacrynic add. hvdrochlorothiazide. chlorthalidone. spironolactone. and amiloride. In three pseudo-Bartter's and four Bartter's syndrome patients, urine was also screened for frusemide by HPLC methodology [13], which confirmed chromatographic results. Analytical methods in use in our laboratory are reported elsewhere [8 10]. Results are given as median and ranges for biochemical parameters which were not normally distributed, and as mean±SD for clearance results. Statistical analysis was performed by use of the Wilcoxon signed rank test for non parametric data and Student's t test for clearance parameters.
Results Pseudo-Bartter's and Bartter's syndrome patients did not differ as for creatinine clearance, plasma Na + , Cl" and K + levels, degree of metabolic alkalosis, and plasma renin and aldosterone levels; Bartter's syndrome patients had lower plasma Mg 2 + (PMg) and uric acid (Pv,) levels; however, overlap with values in pseudo-Bartter's patients did occur (Table 1). Specifically, three pseudo-Bartter's (and no Bartter's syndrome) patients had hyperuricaemia (P L l > 387 umol 1 or 6.5 mg/dl), and one of five pseudo-Bartter's patients (the patient ingesting hydrochlorothiazide), and four of six Bartter's syndrome had hypomagnesaemia (P M g
