Acta PRdiatr Scand 80: 194-1 98, 1991
Decreased Renal Clearance of Sodium in Cystic Fibrosis 'P. STENVINKEL,' L. HJELTE,2 G . ALVANY3A. HEDMAN,3 E. HULTMAN4 and B. STRANDV1K'From the Departments of'Nephrology, 'Pediatrics, 'Clinical Pharmacology, and 'Clinical Chemistry, Karolinska Institute, Huddinge University Hospital, Huddinge, Sweden
ABSTRACT. Stenvinkel, P., Hjelte, L., Alvan, G., Hedman, A., Hultman, E. and Strandvik, B. (Departments of Nephrology, Pediatrics, Clinical Pharmacology, and Clinical Chemistry, Karolinska Institute, Huddinge University Hospital, Huddinge, Sweden). Decreased renal clearance of sodium in cystic fibrosis. Acta Paediatr Scand 80: 194, 1991. In 10 patients with cystic fibrosis (CF) and 10 controls of similar age quantitative segmental handling of sodium was estimated by lithium clearance. In the CF group, there was a tendency for an increased glomerular filtration rate (GFR) and increased absolute proximal sodium reabsorption. The fractional distal sodium reabsorptionwas significantly (p=0.015) increased and sodium clearance was significantly (p< 0.01) decreased in CF. Key words: cystic fibrosis, sodium handling, lithium clearance.
Increased concentrations of sodium and chloride in sweat are nearly pathognomonic for the inherited disease cystic fibrosis (CF) (1). It is now generally accepted that a decreased permeability for the chloride ion in the duct of the sweat gland is the cause of this disturbance (2). The sweat is initially produced as an isotonic solution in the secretory coil of the gland and then normally loses most of its electrolyte content during passage through the duct. The decreased chloride permeability is also manifested as an increased transepithelial voltage in the airways and secondary changes in water content and quality of the mucus follow (3). Berg et al. found that an acute load of NaCl was markedly less well excreted in CF patients than in controls (4). The kidney has been subject to few studies in this systemic disease mainly expressed in secretory epithelia. Quantitative segmental tubular handling of sodium can be measured by lithium clearance (C,J which has been shown to be a safe tool for clinical investigation of water and sodium handling in the nephron (5-6). This is based on the assumption that lithium is reabsorbed in the proximal tubule in proportion to sodium and water and that no lithium is reabsorbed beyond this segment. We have utilized this method to investigate the tubular handling of sodium in CF patients. SUBJECTS AND METHODS Subjects. Ten patients with cystic fibrosis (2 males, 8 females) and 10 healthy staff-members of similar age (2 males, 8 females) agreed to participate in the study which was consistently
Cystic fibrosis = CF, glomerular filtration rate = GFR, lithium clearance = CLi,serum lithium conc = S-Li, serum sodium conc = S-Na, urine lithium conc = U-Li, urine sodium conc = U-Na, clearance = C, urine concentration of electrolyte = U, urine flow = V, serum concentration of electrolyte = S, absolute proximal sodium reabsorption = APR, fractional proximal (sodium) reabsorption = FPR, absolute distal (sodium) reabsorption = ADR, fractional distal (sodium) reabsorption = FDR, filtered load of sodium = FLN,, fractional excretion of sodium = FEN,.
Acta Paediatr S a n d 80
Sodium clearance in cystic fibrosis 195
performed in one laboratory. The study was approved by the Ethics Committee of the Karolinska Institute. The diagnosis was ascertained by pathological sweat test (chloride in sweat > 80 mmol/l) and the presence of typical pulmonary and gastrointestinal symptoms. The age of the CF patients ranged from 21 to 33 years with a mean of 25.6?3.9 years. Mean Brocas index was 1.09 (range 0.96-1.23). The clinical condition varied from moderate to excellent as expressed by Shwachman scores (7) from 55 to 95 (mean 81). All but one had full time occupations working or studying. The blood pressure was normal in all CF patients. The mean serum albumin concentration was 38.9 g/l (range 33-45 g/l) and the mean serum sodium concentration was 139.3 mmol/l (range 136-143 mmol/l). The clinical program did not contain any dietary restrictions and all patients were on pancreatic enzyme supplementation. None had received any antibiotics, NSAIDs or diuretics during at least 2 weeks before the study. No extra salt was given. The controls were all healthy staff members with an age ranging from 20 to 36 years with a mean of 29.4 ? 4.9 years. All had normal blood pressures and no one received any medication. Their routine blood chemistry tests were normal and their mean serum sodium concentration was 139.7 mmol/l. Twelve hours before the investigation each participant was given a dose of lithium carbonate (16.2 mmol). No drinks containing methylxanthines were allowed during 12 h prior to or during the investigation. The participants were not fasting. On the day of the investigation an estimation of the glomerular filtration rate (GFR) with "Cr-EDTA clearance was started at about 9 a.m. At the same time a venous blood sample was taken for serum lithium and sodium measurements (S-Li, S-Na). During the clearance period (6 h) urine was collected for lithium and sodium measurements (U-Li, U-Na). At the end of the "Cr-EDTA clearance determination another venous blood sample for S-Li was collected. During the study all subjects were in the supine position (except while voiding) and 200 ml of tap-water was given by mouth every hour to ensure an adequate urine volume. Methods. Clearance (C) of sodium and lithium was calculated according to the standard formula C=U.V/S where V is urine flow, U urine concentration of the electrolyte and S its serum concentration. Serum and urinary concentrations of lithium were measured by atomic absorption. Sodium concentrations were measured by flame photometry. The segmental tubular sodium handling was estimated using lithium clearance (CLJ according to Thomsen (5). By knowing the GFR, the clearance of sodium (CNa)and lithium (CLl),the absolute and fractional reabsorptions of sodium in the proximal and distal tubules can be calculated. Absolute proximal sodium reabsorption (APR) was calculated as GFR-CL,(ml/min), fractional proximal reabsorption as (FPR) =(1 -CL,/GFR)*100 (Yo), the absolute distal reabsorption as (ADR) =GFR-APR-CN, (ml/min) and the fractional distal reabsorption as (FDR)=(I-CN,. /CLI).loo(%). Filtered load of sodium was calculated as (FLN,)=GFR*S-Na/lOOO mmol/min and fractional excretion of sodium as (FEN,)=(CN,/GFR). 100 (Yo). All flow measurements were adjusted to a body surface area of 1.73 m2. Statistical methods. Mann-Whitney's U-test was used for comparisons between CF patients and control subjects. Differences between means were considered significant at the 0.05 level.
RESULTS Individual values for some of the measurements are given in Table 1 . Mean baseline values for GFR were slightly higher (1 10t 19 vs. 99 t 10 ml/min/l.73 m2,p=0.065) in the CF patients than in the normal subjects, whereas CLidid not differ between the two groups. FLN, averaged 15.3 mmol/min in the CF group and 13.8 mmol/min in the control group. APR and FPR tended to be higher in the CF patients. For all subjects investigated there was a linear correlation between GFR and APR (p
Decreased Renal Clearance of Sodium in Cystic Fibrosis 'P. STENVINKEL,' L. HJELTE,2 G . ALVANY3A. HEDMAN,3 E. HULTMAN4 and B. STRANDV1K'From the Departments of'Nephrology, 'Pediatrics, 'Clinical Pharmacology, and 'Clinical Chemistry, Karolinska Institute, Huddinge University Hospital, Huddinge, Sweden
ABSTRACT. Stenvinkel, P., Hjelte, L., Alvan, G., Hedman, A., Hultman, E. and Strandvik, B. (Departments of Nephrology, Pediatrics, Clinical Pharmacology, and Clinical Chemistry, Karolinska Institute, Huddinge University Hospital, Huddinge, Sweden). Decreased renal clearance of sodium in cystic fibrosis. Acta Paediatr Scand 80: 194, 1991. In 10 patients with cystic fibrosis (CF) and 10 controls of similar age quantitative segmental handling of sodium was estimated by lithium clearance. In the CF group, there was a tendency for an increased glomerular filtration rate (GFR) and increased absolute proximal sodium reabsorption. The fractional distal sodium reabsorptionwas significantly (p=0.015) increased and sodium clearance was significantly (p< 0.01) decreased in CF. Key words: cystic fibrosis, sodium handling, lithium clearance.
Increased concentrations of sodium and chloride in sweat are nearly pathognomonic for the inherited disease cystic fibrosis (CF) (1). It is now generally accepted that a decreased permeability for the chloride ion in the duct of the sweat gland is the cause of this disturbance (2). The sweat is initially produced as an isotonic solution in the secretory coil of the gland and then normally loses most of its electrolyte content during passage through the duct. The decreased chloride permeability is also manifested as an increased transepithelial voltage in the airways and secondary changes in water content and quality of the mucus follow (3). Berg et al. found that an acute load of NaCl was markedly less well excreted in CF patients than in controls (4). The kidney has been subject to few studies in this systemic disease mainly expressed in secretory epithelia. Quantitative segmental tubular handling of sodium can be measured by lithium clearance (C,J which has been shown to be a safe tool for clinical investigation of water and sodium handling in the nephron (5-6). This is based on the assumption that lithium is reabsorbed in the proximal tubule in proportion to sodium and water and that no lithium is reabsorbed beyond this segment. We have utilized this method to investigate the tubular handling of sodium in CF patients. SUBJECTS AND METHODS Subjects. Ten patients with cystic fibrosis (2 males, 8 females) and 10 healthy staff-members of similar age (2 males, 8 females) agreed to participate in the study which was consistently
Cystic fibrosis = CF, glomerular filtration rate = GFR, lithium clearance = CLi,serum lithium conc = S-Li, serum sodium conc = S-Na, urine lithium conc = U-Li, urine sodium conc = U-Na, clearance = C, urine concentration of electrolyte = U, urine flow = V, serum concentration of electrolyte = S, absolute proximal sodium reabsorption = APR, fractional proximal (sodium) reabsorption = FPR, absolute distal (sodium) reabsorption = ADR, fractional distal (sodium) reabsorption = FDR, filtered load of sodium = FLN,, fractional excretion of sodium = FEN,.
Acta Paediatr S a n d 80
Sodium clearance in cystic fibrosis 195
performed in one laboratory. The study was approved by the Ethics Committee of the Karolinska Institute. The diagnosis was ascertained by pathological sweat test (chloride in sweat > 80 mmol/l) and the presence of typical pulmonary and gastrointestinal symptoms. The age of the CF patients ranged from 21 to 33 years with a mean of 25.6?3.9 years. Mean Brocas index was 1.09 (range 0.96-1.23). The clinical condition varied from moderate to excellent as expressed by Shwachman scores (7) from 55 to 95 (mean 81). All but one had full time occupations working or studying. The blood pressure was normal in all CF patients. The mean serum albumin concentration was 38.9 g/l (range 33-45 g/l) and the mean serum sodium concentration was 139.3 mmol/l (range 136-143 mmol/l). The clinical program did not contain any dietary restrictions and all patients were on pancreatic enzyme supplementation. None had received any antibiotics, NSAIDs or diuretics during at least 2 weeks before the study. No extra salt was given. The controls were all healthy staff members with an age ranging from 20 to 36 years with a mean of 29.4 ? 4.9 years. All had normal blood pressures and no one received any medication. Their routine blood chemistry tests were normal and their mean serum sodium concentration was 139.7 mmol/l. Twelve hours before the investigation each participant was given a dose of lithium carbonate (16.2 mmol). No drinks containing methylxanthines were allowed during 12 h prior to or during the investigation. The participants were not fasting. On the day of the investigation an estimation of the glomerular filtration rate (GFR) with "Cr-EDTA clearance was started at about 9 a.m. At the same time a venous blood sample was taken for serum lithium and sodium measurements (S-Li, S-Na). During the clearance period (6 h) urine was collected for lithium and sodium measurements (U-Li, U-Na). At the end of the "Cr-EDTA clearance determination another venous blood sample for S-Li was collected. During the study all subjects were in the supine position (except while voiding) and 200 ml of tap-water was given by mouth every hour to ensure an adequate urine volume. Methods. Clearance (C) of sodium and lithium was calculated according to the standard formula C=U.V/S where V is urine flow, U urine concentration of the electrolyte and S its serum concentration. Serum and urinary concentrations of lithium were measured by atomic absorption. Sodium concentrations were measured by flame photometry. The segmental tubular sodium handling was estimated using lithium clearance (CLJ according to Thomsen (5). By knowing the GFR, the clearance of sodium (CNa)and lithium (CLl),the absolute and fractional reabsorptions of sodium in the proximal and distal tubules can be calculated. Absolute proximal sodium reabsorption (APR) was calculated as GFR-CL,(ml/min), fractional proximal reabsorption as (FPR) =(1 -CL,/GFR)*100 (Yo), the absolute distal reabsorption as (ADR) =GFR-APR-CN, (ml/min) and the fractional distal reabsorption as (FDR)=(I-CN,. /CLI).loo(%). Filtered load of sodium was calculated as (FLN,)=GFR*S-Na/lOOO mmol/min and fractional excretion of sodium as (FEN,)=(CN,/GFR). 100 (Yo). All flow measurements were adjusted to a body surface area of 1.73 m2. Statistical methods. Mann-Whitney's U-test was used for comparisons between CF patients and control subjects. Differences between means were considered significant at the 0.05 level.
RESULTS Individual values for some of the measurements are given in Table 1 . Mean baseline values for GFR were slightly higher (1 10t 19 vs. 99 t 10 ml/min/l.73 m2,p=0.065) in the CF patients than in the normal subjects, whereas CLidid not differ between the two groups. FLN, averaged 15.3 mmol/min in the CF group and 13.8 mmol/min in the control group. APR and FPR tended to be higher in the CF patients. For all subjects investigated there was a linear correlation between GFR and APR (p
