Renal tubular function in children and adolescents with Gitelman's syndrome, the hypocalciuric variant of Bartter's syndrome

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1 Nephrl Dial Transplant (1995) 10: riginal Article Nephrlgy Dialysis Transplantatin Renal tubular functin in children and adlescents with Gitelman's syndrme, the hypcalciuric variant f Bartter's syndrme N. Peters 1, A. Bettinelli 2,1. Spicher 1, E. Basilic 2, M. G. Metta 2 and M. G. Bianchetti 1. 'Divisin f Pediatric Nephrlgy, University f Beme, Berne, Switzerland; and 2 Department f Pediatrics II, University f Milan, Italy Abstract. Renal tubular functin was studied in 14 patients with Gitelman's syndrme and 14 cntrl subjects. Apart frm the bichemical hallmarks f Gitelman's syndrme, namely alkalaemia, hyperbicarbnataemia, hypkalaemia, hypmagnesaemia (with increased magnesium ver creatinine rati), increased urinary chlride ver creatinine rati, and lw urinary calcium ver creatinine, the patients were fund t have hyperprteinaemia, hypchlraemia, high ttal plasma calcium cncentratin, reduced plasma inized calcium cncentratin, and high urinary sdium excretin. A statistically significant negative linear relatinship between plasma magnesium cncentratin and magnesium excretin crrected fr glmerular filtratin was bserved in patients. The fractinal calcium clearance and the urinary excretin f calcium crrected fr glmerular filtratin was significantly decreased in patients. In patients the urinary smlality after vernight water deprivatin ranged frm 526 t 1067 mml/kg. Glucsuria and aminaciduria were similar in patients and cntrls. The results f the study demnstrate the renal rigin f hypmagnesaemia and hypcalciuria in Gitelman's syndrme. The failure t demnstrate hyperaminaciduria, hyperglucsuria, hyperphsphaturia, hyperuricsuria, and severely impaired urinary cncentrating ability prvide evidence fr a defect residing in the distal cnvluted tubule. Key wrds: Bartter's syndrme; distal cnvluted tubule; Gitelman's syndrme; hypcalciuria; hypmagnesaemia; metablic alkalsis Intrductin Hypmagnesaemia, hypcalciuria, hypkalaemic alkalsis, and hyperchlriduria characterize Gitelman's syndrme, a variant f Bartter's syndrme [1-8]. Crrespndence and ffprint requests t: Dr M. G. Bianchetti, Abteilung fur Nephrlgie, Universitatskinderklinik, Inselspital, CH 3010-Bem, Switzerland. Patients with this tubulpathy, which is inherited in bth dminant and recessive fashins [9], are ften asymptmatic, with the exceptin f muscular weakness and transient episdes f tetany that are smetimes accmpanied by abdminal pain, vmiting and fever [1-9]. Since the need fr distinguishing between classic Bartter's syndrme and Gitelman's syndrme has been challenged until recently [3-9], infrmatin n renal tubular functin in this particular disrder is scanty and based n anecdtal reprts [1,2,4-8] and a retrspective multicentric inquiry [3]. T address this issue, simple renal tubular functin studies were perfrmed in 14 patients with Gitelman's syndrme n fllw-up at ur centres f Pediatric Nephrlgy. Subjects and methds Furteen patients with Gitelman's syndrme (7 females and 7 males, aged years) entered the study. They had histry f frequent tetanic episdes («= 3), muscular weakness («= 7), r bth (n = 3). Bld pressure, plasma creatinine, urinalysis, and renal ultrasund were nrmal. Diagnsis f Gitelman's syndrme was based n the presence [3] f nrmal bld pressure, venus bld ph>7.38, plasma bicarbnate > 28.0 mml/1, plasma ptassium <3.5mml/l, plasma magnesium <0.75 mml/1 (by clrimetric assay), mlar rati f urinary calcium ver creatinine < 0.100, urinary chlride ver creatinine >8.42 [10], urinary magnesium ver creatinine > and negative urinary screen fr diuretics. The Z scres fr height (frm 1.8 t 1.3) and bdy weight (frm 1.7 t 1.4) were nrmal. The 14 patients, wh had been withut any medicatin r electrlyte supplementatin fr at least 5 weeks prir t investigatin, attended the utpatient clinic after vernight fasting between and a.m. They had been instructed t bring a 3-day fd recrd. The patients received a 1.21 tap water lading. After viding the bladder, a 2-h urine specimen was cllected and mid-pint bld was taken with minimal stasis and withut mvement f the frearm. Packed-cell vlume, bld hydrgen in cncentratin, bld carbn dixide tensin and plasma inized calcium cncentratin were measured in duplicate immediately after bld cllectin. The remaining samples were immediately stred at 40 C fr later determinatin f creatinine, Dwnladed frm at Pennsylvania State University n April 8, 2016 > 1995 Eurpean Dialysis and Transplant Assciatin-Eurpean Renal Assciatin

2 1314 N. Peters et al. sdium, ptassium, chlride, inrganic phsphrus, uric acid, ttal calcium and magnesium cncentratin in plasma and urine, and ttal prtein cncentratin in plasma. The patients were subsequently asked t prvide a prtin f a first mrning urine after vernight water deprivatin fr determinatin f smlality, glucse, prtein and amin acids. The afrementined prtcl was applied in a cntrl grup f 14 healthy vlunteers (8 females and 6 males, aged 12 t 20 years). The study had been apprved by the Ethical Cmmittees f the participant centres and infrmed cnsent was btained. The intake f sdium, calcium and magnesium was assessed frm the 3-day fd recrd using dietary charts. Packed-cell vlume was assessed by means f a micrhaematcrit centrifuge. Bld hydrgen in cncentratin, bld carbn dixide pressure, and plasma inized calcium cncentratin were measured using in-selective electrdes. The bld bicarbnate cncentratin was calculated using the Hendersn-Hasselbalch equatin with an acidity expnent f 6.10 and a carbn dixide slubility cefficient f The plasma inized calcium cncentratin was nt crrected fr bld hydrgen in cncentratin. Ttal prtein, creatinine, ptassium, chlride, sdium, inrganic phsphrus, uric acid, ttal calcium, magnesium, and glucse cncentratin were measured with an autanalyser using either in-selective electrdes r clrimetric assays. The urinary cncentratin f amin acids was evaluated by clumn chrmathgraphy. Plasma r urinary electrlytes (P x, U x ) and creatinine (P Cr, U Cr ) were used t calculate the crrespnding fractinal clearance (1) and the urinary excretin crrected fr ne liter f glmerular filtratin rate (GFR) (2) using the fllwing frmulae [11]: u x (1) PxU Cr U,Pr (2) u Cr The fractinal clearance f calcium was calculated bth frm ttal plasma calcium cncentratin (apparent fractinal calcium clearance) as well as frm plasma inized calcium cncentratin (true fractinal calcium clearance). Urinary excretin f electrlytes, amin acids and ttal prtein was als expressed as rati ver creatinine [11]. The tubular threshld fr inrganic phsphrus (3) was calculated frm plasma phsphrus cncentratin (P p ) and its fractinal excretin (FE p ) using the fllwing frmula [12]: P P -(1-FE P ) (3) The tw-tailed Mann-Whitney U test and simple regressins with the rank crrelatin cefficient (r s ) were used fr statistical analysis. Values were expressed either as individual data r as 25th percentile, median and 75th percentile. A P<0.05 was regarded as statistical significant [13,14]. alkalaemia, hyperbicarbnataemia, hypkalaemia, hypmagnesaemia, increased urinary chlride ver creatinine rati, increased urinary magnesium ver creatinine rati, and lw urinary calcium ver creatinine rati, the patients were fund t have hyperprteinaemia, hypchlraemia (and high fractinal chlride excretin), high ttal plasma calcium cncentratin, reduced plasma inized calcium cncentratin, and high urinary sdium excretin (Table 1 and Figure 1). The bdy weight tended t be reduced in patients. In Gitelman's patients the increased urinary magnesium ver creatinine rati was assciated with an increased fractinal magnesium clearance and with an increased magnesium excretin crrected fr GFR. The reduced urinary calcium ver creatinine rati was assciated with lw apparent fractinal calcium clearance, lw true fractinal calcium clearance and lw calcium excretin crrected fr GFR. The reduced urinary calcium ver creatinine rati was assciated with lw apparent fractinal calcium clearance, lw true fractinal calcium clearance and lw calcium excretin crrected fr GFR (Table 1 and Figure 1). The urinary smlality after vernight water deprivatin (Table 2) was slightly but significantly lwer in patients (ranges mml/kg) than in cntrls (ranges mml/kg). Ttal prtein excretin, glucsuria, and aminaciduria were almst identical in patients and cntrls (Table 2). In Gitelman's patients a statistically significant relatinship (Figure 2, panel 1) was bserved between plasma magnesium, taken as independent variable, and magnesium excretin crrected fr GFR, taken as dependent variable (j = x; r s = 0.79; P<0.01). In cntrl subjects the tw parameters did nt crrelate. N significant crrelatin was fund between circulating magnesium r urinary magnesium excretin crrected fr GFR and urinary calcium r ptassium excretin crrected fr GFR in patients and cntrls (Figure 2, panels 1-3). In bth study grups n significant crrelatin was bserved between bld ph r plasma bicarbnate and urinary magnesium, calcium r ptassium excretin crrected fr GFR (Figure 2, panels 5-7, 9-11). Finally, in bth grups n significant crrelatin was fund between urinary magnesium and urinary ptassium excretin crrected fr GFR (Figure 2, panel 8) r between urinary sdium and urinary calcium excretin crrected fr GFR (Figure 2, panel 12). Dwnladed frm at Pennsylvania State University n April 8, 2016 Results The 14 Gitelman's patients and the 14 cntrl subjects did nt significantly differ with respect t height, dietary intake f sdium, calcium r magnesium, bld pressure and heart rate, packed cell vlume, plasma creatinine and sdium, plasma and urinary uric acid, as well as plasma inrganic phsphrus and tubular phsphrus threshld (Table 1). Apart frm the bichemical hallmarks f Gitelman's syndrme, namely Discussin The present investigatin was perfrmed in children and adlescents with Gitelman's syndrme, the hypcalciurica variant f Bartter's syndrme [1-9]. The study prvides infrmatin n three phenmena, ne dealing with the mechanisms underlying magnesium deficiency, ne dealing with the mechanisms underlying hypcalciuria, and ne dealing with the site f the renal tubular dysfunctin.

3 Tubular functin in Gitelman's Syndrme 1315 Table 1. Clinical and bichemical findings in 14 patients with Gitelman's syndrme (aged years) and 14 cntrl subjects (aged years); data as 25th percentile, median, and 75th percentile Patients with Gitelman syndrme Cntrl subjects Bdy weight (kg) Height (m) Supine bld pressure (mmhg) Supine heart rate (beats/min) Packed cell vlume Plasma creatinine (uml/1) Ttal plasma prtein (g/1) Bld ph Plasma bicarbnate (mml/1) Inrganic phsphrus plasma cncentratin (mml/1) tubular threshld (mml/1) Uric acid ttal plasma cncentratin (uml/1) fractinal clearance (10~ 2 ) excretin (uml/1 GFR) Ptassium plasma cncentratin (mml/1) urinary ptassium ver creatinine fractinal clearance (10~ 2 ) excretin (uml/1 GFR) Chlride plasma cncentratin (mml/1) urinary chlride ver creatinine fractinal clearance (10~ 2 ) excretin (uml/1 GFR) Sdium dietary intake (mml/day), urinary sdium ver creatinine plasma cncentratin (mml/1) fractinal clearance (10~ 2 ) excretin (uml/1 GFR) Magnesium dietary intake (mml/day) ttal plasma cncentratin (mml/1) urinary magnesium ver creatinine fractinal clearance (10~ 2 ) excretin (uml/1 GFR) Calcium dietary intake (mml/day) ttal plasma cncentratin (mml/1) inized plasma cncentratin (mml/1) urinary calcium ver creatinine apparent fractinal clearance (10~ 2 ) true fractinal clearance (10~ 2 ) excretin (uml/1 GFR) * / * f T f * H ' U t * * * * f t H H * * t r U ^ / t Patients and cntrls were nt cmpared with respect t this parameter (a statistically significant difference is predictable as the parameter had t be abnrmal fr the subjects t be included in the grup f patients). */ > <0.05 and 1J/ > <0.01 versus cntrl grup. Dwnladed frm at Pennsylvania State University n April 8, 2016 Mechanisms underlying hypmagnesaemia When magnesium intake is restricted r when its intestinal absrptin is altered, the kidney avidly retains magnesium [15-17]. In ur patients with hypmagnesaemia the urinary magnesium excretin was higher than in healthy cntrls. This fact, tgether with the bserved crrelatin between plasma magnesium and urinary magnesium excretin crrected fr GFR, demnstrates the renal rigin f magnesium wasting. Bld ph and plasma bicarbnate may mdulate the urinary magnesium excretin [15-17], but in this study n crrelatin was fund between bld hydrgen in level r plasma bicarbnate and urinary magnesium excretin crrected fr GFR. Dietary magnesium was similar in Gitelman's patients and in cntrls. n the cntrary, the urinary magnesium excretin was higher in Gitelman's patients than in cntrls. Taken tgether these data pint t high intestinal magnesium absrptin as a cmpensatin fr renal lss f magnesium in Gitelman's patients. Mechanisms underlying hycalciuria High ttal plasma calcium cncentratin but lw inized plasma calcium cncentratin were bserved in ur patients with Gitelman's syndrme. Calcium in bdy fluids exists in three frms, namely the frm

4 1316 N. Peters el al. Ttal Plasma Inized Plasma Calcium' t" 7 Apparent Fractinal True Fractinal Calciuria Crrected Calcium, mml/l Calcium, mml/l Creatinine Calcium Clearance Calcium Clearance fr GFR, nml/l GFR " n 0.6 i " J 1.4 " 1.3 " J 0.5 " 0.4 " 0.3 " 0.2 " 0.1 " 0.0 J Fig. 1. Ttal plasma calcium, plasma inized calcium, mlar urinary calcium ver creatinine, apparent fractinal calcium clearance, true fractinal calcium clearance, and calcium excretin crrected fr GFR in 14 patients with Gitelman's syndrme (black symbls) and 14 cntrl subjects (pen symbls). Table 2. Urinary smlality, prteinuria, glucsuria, and aminaciduria in 14 patients with Gitelman's syndrme aged years, and 14 cntrl subjects aged years; data as 25th percentile, median, and 75th percentile, Urinary smlality (mml/kg) Prtein ver creatinine (mg/mml) Glucse (mml/l) Alanine ver creatinine (10~ 3 ) Arginine ver creatinine (10~ 3 ) 1/2 Cystine ver creatinine (10~ 3 ) Glutamic acid ver creatinine (10~ 3 ) Glycine ver creatinine (10~ 3 ) Histidine ver creatinine (10~ 3 ) Isleucine ver creatinine (10~ 3 ) Leucine ver creatinine (10~ 3 ) Lysine ver creatinine (10~ 3 ) Methinine ver creatinine (10~ 3 ) rnithine ver creatinine (10~ 3 ) Phenylalanine ver creatinine (10~ 3 ) Prline ver creatinine (10~ 3 ) Serine ver creatinine (10~ 3 ) Taurine ver creatinine (10~ 3 ) Threnine ver creatinine (10~ 3 ) Tyrsine ver creatinine (10~ 3 ) Valine ver creatinine (10~ 3 ) " 0.0 V. Patients with Gitelman syndrme l^* " 1.0 " 0.0 J 8 40 " " 10 " 0 J Cntrl subjects bicarbnate increases with a decline in hydrgen in cncentratin and with an increase in plasma bicarbnate r prteins: these facts accunt fr the discrepancy between high ttal and lw inized calcium cncentratin in ur grup f Gitelman's patients presenting with hyperbicarbnataemia, alkalaemia, and hyper- Dwnladed frm at Pennsylvania State University n April 8, 2016 %P<0.05 versus cntrl grup. The aminaciduria is given as mlar rati ver creatinine. bund t prteins, the frm cmplexed with lwmlecular-weight anins such as bicarbnate, and the free r inized frm, the nly frm bilgically active [18]. Plasma inized calcium cncentratin appears therefre dependent n several factrs. The amunt f circulating calcium bund t prteins r cmplexed t

5 Tubular functin in Gitelman's Syndrme c > Plasma Magnesium, mml/l 5 60" I E 4 «20" S s 3 0 "1 ' 7.3 B *> 0* a * * t Bld ph 601 c g Plasma Bicarbnate, mml/l I " c DC u ' 500 ' 40 I" y Plasma Magnesium, mml/l Plasma Magnesium, mml/l : « Urinary Magnesium, uml/l GFR IT U c u _ 500 ' Bld ph * <» " 5001 Bld ph Urinary Magnesium, uml/l GFR CC u. E I E ' S 40 " 20 S t Plasma Bicarbnate, mml/l Plasma Bicarbnate, mml/l Urinary Sdium, uml/l GFF Dwnladed frm at Pennsylvania State University n April 8, 2016 Fig. 2. Relatinship between plasma magnesium and urinary magnesium excretin crrected fr GFR (panel I), between plasma magnesium and urinary calcium excretin crrected fr GFR (panel 2), between plasma magnesium and urinary ptassium excretin crrected fr GFR (panel 3), between urinary magnesium excretin crrected fr GFR and urinary calcium excretin crrected fr GFR (panel 4), between bld ph and urinary magnesium excretin crrected fr GFR (panel 5), between bld ph and urinary calcium excretin crrected fr GFR (panel 6), between bld ph and urinary ptassium excretin crrected fr GFR (panel 7), between urinary magnesium excretin crrected fr GFR and urinary ptassium excretin crrected fr GFR (panel 8), between plasma bicarbnate and urinary magnesium excretin crrected fr GFR (panel 9), between plasma bicarbnate and urinary calcium excretin crrected fr GFR (panel 10), between plasma bicarbnate and urinary ptassium excretin crrected fr GFR (panel 11), between urinary sdium excretin crrected fr GFR and urinary calcium excretin crrected fr GFR (panel 12) in 14 patients with Gitelman's syndrme (black symbls) and 14 cntrl subjects (pen symbls). In patients a significant (/ > <0.05) relatinship was bserved between circulating and urinary magnesium (y = JC; r, = 0.79; P<0.0\; panel 1).

6 1318 prteinaemia. The tendency twards hypcalcaemia bserved in ur patients with Gitelman's syndrme is prbably the cnsequence f a blunted secretin f parathyrid hrmne induced by hypmagnesaemia [15-17,19]. Severe hypcalciuria, expressed either as calcium ver creatinine rati, as apparent r true fractinal calcium clearance, r as calcium excretin crrected fr GFR, is the mst striking feature in Gitelman's syndrme. The results f dietary recrds indicate that in ur patients hypcalciuria des nt result frm lw dietary calcium intake. Dietary sdium intake mdulates the urinary calcium excretin but in this study we fund a similar dietary salt intake in patients and cntrls withut any crrelatin between excretin f calcium and sdium. Finally, in Gitelman's syndrme hypcalciuria may be related nly in part t mild cncmitant hypcalcaemia, since bth the true fractinal calcium clearance and the calcium excretin crrected fr GFR were lw, indicating avid tubular reabsrptin. Hypmagnesaemia prmtes tubular calcium reabsrptin [15-17]. Fr that reasn it has been suggested that hypcalciuria in Gitelman's syndrme may be secndary t hypmagnesaemia, but in ur patients n crrelatin was fund between urinary calcium excretin crrected fr GFR and urinary magnesium excretin crrected fr GFR r plasma magnesium. Data frm the literature indicate that in Gitelman's syndrme urinary calcium excretin remains lw even after crrectin f magnesium deficiency [4]. This fact and ur bservatins suggest that in Gitelman's syndrme hypmagnesaemia is nt the cause f hypcalciuria. Whatever the underlying mechanisms, increased tubular reabsrptin f calcium appears a diagnstic sine qua nn fr this variant f Bartter's syndrme [1-9]. Site f the tubular defect in Gitelman's syndrme The present study prvides infrmatin n the prximal tubular functin and n the ability t cncentrate urine in Gitelman's syndrme. A prximal tubular defect has been smetimes reprted in patients with Bartter's syndrme [20]. In ur Gitelman's patients the failure t demnstrate excessive urinary excretin f amin acids, glucse, phsphrus, and uric acid suggests a nrmal prximal tubular functin [21-23]. In Gitelman's patients the urinary smlality after vernight fasting was always higher than 526 mml/kg. This fact prvides evidence against a disturbance residing in the lp r in the cllecting tubule [24,25]. The slightly reduced urinary smlality bserved in Gitelman's patients as cmpared with cntrls is prbably related t the cncmitant ptassium depletin [24,25]. The labratry features f Gitelman's syndrme resemble thse induced by thiazides, which bind t and inhibit the luminal sdium-chlride ctransprter in the distal cnvluted tubule [3-5,7]. A blunted respnse t thiazides has been reprted in adult patients with this tubulpathy [4]. Taken tgether, the N. Peters et al. results f the present investigatin and the afrementined bservatins indicate that Gitelman's syndrme appears best explained by a defective sdium-chlride carrier prtein alng the distal cnvluted tubule. Hwever, the primary tubular abnrmality and the events underlying the characteristic bichemical disturbances f Gitelman's syndrme are still incmpletely understd. Mlecular bilgy studies are required t definitely answer this questin. Cnclusin The present study n Gitelman's syndrme demnstrates the renal rigin f magnesium deficiency and hypcalciuria and prvide sme evidence fr a defect residing in the distal cnvluted tubule. References 1. Gitelman HJ, Graham JB, Welt LG. A new familial disrder characterized by hypkalemia and hypmagnesemia. Trans Assc Am Physicians 1966; 79: McCredie DA, Blair-West JR, Scggins BA, Shipman R. Ptassium-lsing nephrpathy f childhd. Med J Austr 1971; 1: Bettinelh A, Bianchetti MG, Girardin E et al. Use f calcium excretin values t distinguish tw frms f primary renal tubular hypkalemic alkalsis: Bartter and Gitelman syndrmes. J Pediatr 1992; 120: Suttn RAL, Mavichak V, Halabe A, Wilkins GE. Bartter's syndrme: evidence suggesting a distal tubular defect in a hypcalciuric variant f the syndrme. Miner Electrlyte Metab 1992; 18: Rdriguez-Srian J, Vall A, Garcia-Fuentes M. Hypmagnesemia f hereditary renal rigin. Pediatr Nephrl 1987; 1: Pistr K, Heemann K, lbing H. Asymptmatische Hypkaliamie und Hypmagnesiamie mit renalem Katinenverlust (Gitelman-Syndrm). Mnatsschr Kinderheilkd 1987; 135: Clussi G, Rmbla G, De Ferrari ME. Distal nephrn functin in familial hypkalemia-hypmagnesemia (Gitelman's syndrme). Nephrn 1994; 66: Seyberth HW. Hw can yu differentiate nenatal Bartter's syndrme frm hyperprstagland (-uria) E 2 syndrme. Pediatr Nephrl 1994; 8: Bettinelli A, Bianchetti MG, Brella P et al. Genetic hetergeneity in tubular hypmagnesemia-hypkalemia with hypcalciuria (Gitelman's syndrme). 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7 Tubular functin in Gitelman's Syndrme 17. Rude RK. Magnesium metablism and deficiency. Endcrinl Metab Clin Nrth Am 1993; 22: Mallette LE. Regulatin f bld calcium in humans. Endcrinl Metab Clin Nrth Am 1989; 8: Bianchetti MG, Bettinelli A, Casez JP et al. Evidence fr disturbed regulatin f calcitrpic hrmne metablism in Gitelman syndrme. J Clin Endcrinl Metab 1995; 80: Rdriguez-Srian J, Vall A, livers R. Banter's syndrme presenting with features resembling renal tubular acidsis. Imprvement f renal tubular defects by indmethacin. Helv Paediatr Ada 1978; 33: Burg MB. The Nephrn in transprt f sdium, amin acids, and glucse. Hsp Pract 1978; 13: Hlmes EW, Kelley WN, Wyngaarden JB. The kidney and uric acid excretin in man. Kidney Int 1972: 2: Cgan MG. Disrders f prximal nephrn functin. Am J Med 1982; 72: Kkk JP. Renal cncentrating and diluting mechanisms. Hsp Pract 1979; 14: Ruffignac C. Physilgical rle f the lp f Henle in urinary cncentratin. Kidney Int 1972; 2: Received fr publicatin: Accepted in revised frm: Dwnladed frm at Pennsylvania State University n April 8, 2016