Acta Pzdiatr Scand 64: 671-674. 1975
CASE REPORT
PROXIMAL RENAL TUBULAR ACIDOSIS I N TETRALOGY OF FALLOT J . RODRIGUEZ-SORIANO, A. VALLO, M . CHOLJZA and G . CASTILL0 From the Drpurlment of Paediutrics, Ho>pilal Infuntil de Itr Seguridud Social,
Bilbao, S p i n
ABSTRACT. Rodriguez-Soriano, J., Vallo, A., Chouza, M. and Castillo, G. (Department of Paediatrics, Hospital Infantil de la Seguridad Social, Bilbao, Spain). Proximal renal tubular 9-year-old girl acidosis in tetralogy of Fallot. Acta Paediatr Scand, 64:671, 1975.-A presented with tetralogy of Fallot and moderate metabolic acidosis. Despite a Blalock's fistula there was evidence of chronic hypoxia with cyanosis, clubbing of fingers and toes and very elevated blood hematocrit values. Renal acidification and bicarbonate titration demonstrated the existence of proximal renal tubular acidosis: renal bicarbonate threshold was low (18 mmolesfl) and normal urinary acidification was present at subthreshold serum bicarbonate levels. Following corrective heart surgery, blood acid-base values and renal reabsorption of bicarbonate became normal. A causal relationship between extracellular fluid volume expansion dependent on the high hematocrit and proximal renal tubular acidosis is suggested.
KEY WORDS: Tetralogy of Fallot, proximal renal tubular acidosis, metabolic acidosis, acid-base balance
Metabolic acidosis is a common event in association with congenital cyanotic heart disease (7) and an increased lactacidemia secondary to chronic hypoxemia is generally implicated in its genesis (8, 12). Recent findings, however, indicate that non-lactic acidosis may also be present due to an associated defect in the renal reabsorption of bicarbonate ( I , 2). The present report demonstrates this abnormality in a patient with tetralogy of Fallot and its complete disappearance following total corrective heart surgery.
CASE REPORT A girl, 9"Yl2 years old, was admitted to hospital because of generalized convulsions. She had been diagnosed previously as a case of Fallot's tetralogy and a palliative shunt operation according to Blalock-Taussig had been performed at 5 years of age. Seizures have recurred in-
termittently since 18 month5 of age. On physical examination she was comatous, and outstanding findings were moderate growth retardation (height 120 cm, weight 22.5 kg), generalized cyanosis and marked clubbing of fingers and toes. The clinical diagnosis of Fallot's tetralogy along with the patency of the Blalock's fistula was subsequently confirmed by cardiac catheterization and angiocardioY. At the time of admission, blood hematocrit was elevated (73%) and a moderate metabolic acidosis was present (Fig. I). Following substitution of 200 ml of seroalbumin for the same amount of blood, a marked improvement took place and the level of consciousness became normal. Hematocrit decreased to 60% but the metabolic acidosis persisted. Other :blood laboratory data were normal: sodium 135 mEq/l, potassium 4.8 mEq/l, osmolality 282 mOsm/l, urea 37 mg/100 ml, calcium 9.7 mg/lOO ml, phosphorus 4.2 nig/IOO ml. Neither protein nor reducing substances were present in the urine. Early morning urinary osmolality attained 844 mOsm/l. Tubular reabsorption of phosphorus (TRP) was 88 %. Administration of 60 mEq/day of sodium bicarbonate was followed by complete normalization of acid-base data and that therapy was maintained until the time of cardiac surgery, 3 months later. Withdrawal of therapy during 24 Acra Pediarr Scand 64
672
J . Rodriguez-Soriano et al.
-
. . . .. . ...... VEODY 1
-
2
7.P’
Hcojrrrur
60
(UVday)
Fig. 1 . Clinical course. Biochemical features, as influenced by alkali therapy and corrective heart surgery.
hours, when cardiac catheterization was performed, was immediately followed by reappearance of metabolic acidosis. A complete correction of Fallot’s tetralogy, with ligation of the previous fistula, was performed when the patient was 11/12years old. Postoperatively, cyanosis was absent and a good general condition was maintained with digitalis therapy. Follow-up studies of acid-base balance have been repeatedly normal and no alkali treatment has been required any longer. Special studies Assessment of tubular reabsorption of bicarbonate was performed according to the procedure described by Edelmann et al. (5). Special care was taken to minimize extracellular fluid volume expansion. Glomerular filtration rate (GFR) was estimated by endogenous creatinine clearance. Laboratory determinations were carried out as described by one of us (10).
RESULTS The study of tubular reabsorption of bicarbonate was performed twice, before, and 2
months after complete correction of Fallot’s tetralogy. Pertinent clinical and physiological data at the time of the studies are given in Table 1. Results are set out in Fig. 2. Rates of reabsorption and excretion of bicarbonate are related to 100 ml G F and plotted against serum bicarbonate concentration. Before surgery a low renal bicarbonate threshold of 18 mmolesl litre established the diagnosis of proximal renal tubular acidosis. After surgery a normal threshold of 25 mmoles/litre was reached. In Fig. 3, urine pH is plotted as a function of bicarbonate concentration in serum, both in the condition of induced metabolic acidosis and in alkalosis. The curve represents the average relationship found in normal children (6). Before surgery the points are skewed to the left of the normal line, indicating the lowering of the renal bicarbonate threshold: a normal urinary acidification-with a minimal urinary pH of 4.90-is present but this is only accomplished at serum levels below 16 mmoles/litre. After surgery the points follow the normal line and comparable levels of urinary pH are achieved at higher levels of serum bicarbonate. DISCUSSION This 9-year-old girl presented with moderate metabolic acidosis in association with congenital heart disease due to Fallot’s tetralogy. Despite a Blalock’s fistula there was evidence of chronic hypoxia with cyanosis, clubbing of fingers and toes and very elevated blood hematocrit values. Although serum levels of lactic acid were not determined and some elevation cannot be excluded, there is no doubt that the metabolic acidosis was caused mainly by a defect in the renal reabsorption of
Table 1. Clinical and physiological data at the Ih e of the bicarbonate titration studies Study 1
2
Age (years)
Blood pressure (mmHg)
Hematocrit
P%,
(%)
9 l’/ 12 103/~
115/75 120/80
55 46
Acta Psediatr Scand 64
(mmHg)
Serum potassium (mEq/l)
Creatinine clearance (ml/min/1.73 m?
62 84
4.8 4.4
108
99
Renal tubular acidosis in tetralogy of Fallot
-
3.2
-.
2.8
-
2.4
-
2.0
-
1.6
-
k
[?
2
0
4
3
673
BEFORE SURGERY 0 AFrER SURGERY
REABSORBED
al
r(
0
3 ?
-
1.2
0.8
C1
(moles/liter)
Fig. 2 . Reabsorption and excretion of filtered bicarbonate during continuous bicarbonate infusion. Time and conditions at the time of titration studies are described in Table 1 and in Fig. 1 .
bicarbonate. Renal bicarbonate threshold was low and a normal urinary acidification was achieved at subthreshold bicarbonate levels, thus defining the proximal type of renal tubular acidosis (10, 11). No abnormalities were found in glomerular or other tubular functions. A defect in tubular reabsorption of bicarbonate in patients with tetralogy of Fallot has already been suspected (1, 2), but no studies are available showing its complete disappearance after corrective heart surgery as was demonstrated in our patient, thus demonstrating that the renal abnormality is directly related to the cardiac lesion. We can only speculate about the nature of
the renal disorder. Aperia et al. (1) have emphasized the possible role of low arterial Pcoz values due to hyperventilation found in patients with Fallot’s tetralogy (3,4) as a cause of a secondary depression of renal reabsorption of bicarbonate. In our patient, Pco2levels were not constantly decreased and no obvious relationship was evident between them and the degree of metabolic acidosis. Aperia et al. (1) have also shown that the natriuretic response to an oral sodium load was lower in patients with tetralogy of Fallot than in normal subjects, and that the urinary sodium excretion correlated inversely with the filtration fraction which was markedly elevated in the cardiac
0.4
i2 SERUM
8
41
BICARBONATE
before surgery
.
O a f t e r surgery
7-
6-
X
a
al C
5-
.I.I
5
4-
I
12
14
16
S e r u m
16
20
22
24
H C 0; m m o l e s / l i t e r
26
26
a
30
32
Fig. 3. Relationship of urinary pH to concentration of bicarbonate in serum. The curve represents the average relationship found in normal children (6). Acta Pediatr Scand 64
patienh. They suggested that the diminished REFERENCES urinary sodium excretion was probably caused I . Aperia, A , , Bjarke, B., Broberger, 0. & Thoren, C.: Renal function in Fallot’s tetralogy. Acta Pueditrtr by the high hematocrit and intrarenal physical Scund, 63: 398, 1974. forces. since no hyperdldosteronism was pres2. Callis, L., Castell6. F. & Vallo. A.: Acidosis tubular ent. According to these studies it can be asproximal en las cardiopatias congenitas cianosantes. Proceedings of the 2nd Ir~iernntionalSvmposiutn qf sumed that the extracellular fluid volume is Pediatric Nrpkrologv. Paris, August 25-28, 1971, p. probably expanded in some sub-iects with high 197. hematocrit due to cyanotic heart disease 3. Campbell. I . M. H.. Hunt, G. H. & Poulton, E. P.: On examination of blood gases and respiration in disease through the increased tendency to sodium rewith reference of the cause of breathlessness and tention. When this situation occurs it could cyanosis. J Path Bact, 26: 234, 1923. lead directly to a depression of renal reabsorp- 4. Davies, H . & Gacetopoulos, N.: Dyspnea in cyanotic congenital heart disease. Rr Heurr J , 27: 28, 1965. tion of bicarbonate since there is strong eviEdelmann, C. M . Jr, Rodriguez-Soriano, J . , Boichis, 5 . dence that this reabsorption is dependent on H . . Gruskin, A. B. & Acosta, M. I . : Renal bicarbovariations of extracellular fluid volume (9). nate reabsorption and hydrogen ion excretion in normal infants. J Clin Invest, 46: 1309, 1967. It appears that patients with cyanotic heart 6. Edelmann. C. M., Jr, Boichis, H . , Rodriguez-Soriano. disease may benefit from sodium retention by J. & Stark, H.: The renal response of children to increasing their plasma volume and thereby acute ammonium chloride acidosis. Pediuir Res, 1:452, 1967. preventing the hematocrit from reaching high G. M.: Acidemia of cardiogenic origin in Folger. 7. levels ( I ) . At a certain level of volume expanyoung infants with cyanotic congenital heart sion, however. regulation of extracellular volabnormalities. Clin Pediatr, / I : 573. 1972. 8. Gootman, N. L., Scarpelli, E. M. & Rudolph, A . M.: ume might become preferential and sodium Metabolic acidosis in children with severe congenital bicarbonate escape into the urine. The benefit heart disease. Pediatrics. 31: 251, 1963. of sodium retention is lost and a further eleva9. Martinez-Maldonado. M., Eknoyan, G. & Suki, W. N.: Diuretics in nonedematous states. Physiological tion of hematocrit may be followed by basis for their clinical use. Arch Inirrn M e d , 131: 797, neurological complications, as was the case in 1973, our patient. 10. Rodriguez-Soriano, J . , Boichis, H., Stark, H. & Edelmann, C. M . , Jr: Proximal renal tubular acidosis. If the above hypothesis is correct it may A defect in bicarbonate reabsorption with normal unhave a direct implication on the management nary acidification. Pediatr Res. I : 81. 1967. of the metabolic acidosis. I t should be treated 11. Rodriguez-Soriano, J . : The renal regulation of acid-base balance and the disturbances noted in renal by measures tending to increase the plasma tubular acidosis. Pediatr Clin N A m , 18: 529, 1971. volume such as the administration of sodium 12. Rudolph, A. M.: Metabolic and hemodynamic adbicarbonate. It is known that hydrochlorothjustments to hypoxia in infancy. Bu/l N Y Acad Med. 42: 982, 1966. iazide may be useful in the treatment of proximal renal tubular acidosis through the increased tubular reabsorption of bicarbonate Submitted Oct. 11, 1974 induced by the extracellular fluid volume con- Accepted Nov. 16, 1974 traction caused by the sodium loss (9). In patients with cyanotic heart disease and as- (J. R. S . ) Dept. of Paediatrics sociated metabolic acidosis this therapy might Hospital Infantil de la Seguridad Social “Enrique Sotornayor’’ be potentially dangerous since it could be fol- Cruces lowed by an acute elevation of hematocrit and Bilbao Spain a threatening neurological complication.
Acts Pediatr Scand 64
J f
CASE REPORT
PROXIMAL RENAL TUBULAR ACIDOSIS I N TETRALOGY OF FALLOT J . RODRIGUEZ-SORIANO, A. VALLO, M . CHOLJZA and G . CASTILL0 From the Drpurlment of Paediutrics, Ho>pilal Infuntil de Itr Seguridud Social,
Bilbao, S p i n
ABSTRACT. Rodriguez-Soriano, J., Vallo, A., Chouza, M. and Castillo, G. (Department of Paediatrics, Hospital Infantil de la Seguridad Social, Bilbao, Spain). Proximal renal tubular 9-year-old girl acidosis in tetralogy of Fallot. Acta Paediatr Scand, 64:671, 1975.-A presented with tetralogy of Fallot and moderate metabolic acidosis. Despite a Blalock's fistula there was evidence of chronic hypoxia with cyanosis, clubbing of fingers and toes and very elevated blood hematocrit values. Renal acidification and bicarbonate titration demonstrated the existence of proximal renal tubular acidosis: renal bicarbonate threshold was low (18 mmolesfl) and normal urinary acidification was present at subthreshold serum bicarbonate levels. Following corrective heart surgery, blood acid-base values and renal reabsorption of bicarbonate became normal. A causal relationship between extracellular fluid volume expansion dependent on the high hematocrit and proximal renal tubular acidosis is suggested.
KEY WORDS: Tetralogy of Fallot, proximal renal tubular acidosis, metabolic acidosis, acid-base balance
Metabolic acidosis is a common event in association with congenital cyanotic heart disease (7) and an increased lactacidemia secondary to chronic hypoxemia is generally implicated in its genesis (8, 12). Recent findings, however, indicate that non-lactic acidosis may also be present due to an associated defect in the renal reabsorption of bicarbonate ( I , 2). The present report demonstrates this abnormality in a patient with tetralogy of Fallot and its complete disappearance following total corrective heart surgery.
CASE REPORT A girl, 9"Yl2 years old, was admitted to hospital because of generalized convulsions. She had been diagnosed previously as a case of Fallot's tetralogy and a palliative shunt operation according to Blalock-Taussig had been performed at 5 years of age. Seizures have recurred in-
termittently since 18 month5 of age. On physical examination she was comatous, and outstanding findings were moderate growth retardation (height 120 cm, weight 22.5 kg), generalized cyanosis and marked clubbing of fingers and toes. The clinical diagnosis of Fallot's tetralogy along with the patency of the Blalock's fistula was subsequently confirmed by cardiac catheterization and angiocardioY. At the time of admission, blood hematocrit was elevated (73%) and a moderate metabolic acidosis was present (Fig. I). Following substitution of 200 ml of seroalbumin for the same amount of blood, a marked improvement took place and the level of consciousness became normal. Hematocrit decreased to 60% but the metabolic acidosis persisted. Other :blood laboratory data were normal: sodium 135 mEq/l, potassium 4.8 mEq/l, osmolality 282 mOsm/l, urea 37 mg/100 ml, calcium 9.7 mg/lOO ml, phosphorus 4.2 nig/IOO ml. Neither protein nor reducing substances were present in the urine. Early morning urinary osmolality attained 844 mOsm/l. Tubular reabsorption of phosphorus (TRP) was 88 %. Administration of 60 mEq/day of sodium bicarbonate was followed by complete normalization of acid-base data and that therapy was maintained until the time of cardiac surgery, 3 months later. Withdrawal of therapy during 24 Acra Pediarr Scand 64
672
J . Rodriguez-Soriano et al.
-
. . . .. . ...... VEODY 1
-
2
7.P’
Hcojrrrur
60
(UVday)
Fig. 1 . Clinical course. Biochemical features, as influenced by alkali therapy and corrective heart surgery.
hours, when cardiac catheterization was performed, was immediately followed by reappearance of metabolic acidosis. A complete correction of Fallot’s tetralogy, with ligation of the previous fistula, was performed when the patient was 11/12years old. Postoperatively, cyanosis was absent and a good general condition was maintained with digitalis therapy. Follow-up studies of acid-base balance have been repeatedly normal and no alkali treatment has been required any longer. Special studies Assessment of tubular reabsorption of bicarbonate was performed according to the procedure described by Edelmann et al. (5). Special care was taken to minimize extracellular fluid volume expansion. Glomerular filtration rate (GFR) was estimated by endogenous creatinine clearance. Laboratory determinations were carried out as described by one of us (10).
RESULTS The study of tubular reabsorption of bicarbonate was performed twice, before, and 2
months after complete correction of Fallot’s tetralogy. Pertinent clinical and physiological data at the time of the studies are given in Table 1. Results are set out in Fig. 2. Rates of reabsorption and excretion of bicarbonate are related to 100 ml G F and plotted against serum bicarbonate concentration. Before surgery a low renal bicarbonate threshold of 18 mmolesl litre established the diagnosis of proximal renal tubular acidosis. After surgery a normal threshold of 25 mmoles/litre was reached. In Fig. 3, urine pH is plotted as a function of bicarbonate concentration in serum, both in the condition of induced metabolic acidosis and in alkalosis. The curve represents the average relationship found in normal children (6). Before surgery the points are skewed to the left of the normal line, indicating the lowering of the renal bicarbonate threshold: a normal urinary acidification-with a minimal urinary pH of 4.90-is present but this is only accomplished at serum levels below 16 mmoles/litre. After surgery the points follow the normal line and comparable levels of urinary pH are achieved at higher levels of serum bicarbonate. DISCUSSION This 9-year-old girl presented with moderate metabolic acidosis in association with congenital heart disease due to Fallot’s tetralogy. Despite a Blalock’s fistula there was evidence of chronic hypoxia with cyanosis, clubbing of fingers and toes and very elevated blood hematocrit values. Although serum levels of lactic acid were not determined and some elevation cannot be excluded, there is no doubt that the metabolic acidosis was caused mainly by a defect in the renal reabsorption of
Table 1. Clinical and physiological data at the Ih e of the bicarbonate titration studies Study 1
2
Age (years)
Blood pressure (mmHg)
Hematocrit
P%,
(%)
9 l’/ 12 103/~
115/75 120/80
55 46
Acta Psediatr Scand 64
(mmHg)
Serum potassium (mEq/l)
Creatinine clearance (ml/min/1.73 m?
62 84
4.8 4.4
108
99
Renal tubular acidosis in tetralogy of Fallot
-
3.2
-.
2.8
-
2.4
-
2.0
-
1.6
-
k
[?
2
0
4
3
673
BEFORE SURGERY 0 AFrER SURGERY
REABSORBED
al
r(
0
3 ?
-
1.2
0.8
C1
(moles/liter)
Fig. 2 . Reabsorption and excretion of filtered bicarbonate during continuous bicarbonate infusion. Time and conditions at the time of titration studies are described in Table 1 and in Fig. 1 .
bicarbonate. Renal bicarbonate threshold was low and a normal urinary acidification was achieved at subthreshold bicarbonate levels, thus defining the proximal type of renal tubular acidosis (10, 11). No abnormalities were found in glomerular or other tubular functions. A defect in tubular reabsorption of bicarbonate in patients with tetralogy of Fallot has already been suspected (1, 2), but no studies are available showing its complete disappearance after corrective heart surgery as was demonstrated in our patient, thus demonstrating that the renal abnormality is directly related to the cardiac lesion. We can only speculate about the nature of
the renal disorder. Aperia et al. (1) have emphasized the possible role of low arterial Pcoz values due to hyperventilation found in patients with Fallot’s tetralogy (3,4) as a cause of a secondary depression of renal reabsorption of bicarbonate. In our patient, Pco2levels were not constantly decreased and no obvious relationship was evident between them and the degree of metabolic acidosis. Aperia et al. (1) have also shown that the natriuretic response to an oral sodium load was lower in patients with tetralogy of Fallot than in normal subjects, and that the urinary sodium excretion correlated inversely with the filtration fraction which was markedly elevated in the cardiac
0.4
i2 SERUM
8
41
BICARBONATE
before surgery
.
O a f t e r surgery
7-
6-
X
a
al C
5-
.I.I
5
4-
I
12
14
16
S e r u m
16
20
22
24
H C 0; m m o l e s / l i t e r
26
26
a
30
32
Fig. 3. Relationship of urinary pH to concentration of bicarbonate in serum. The curve represents the average relationship found in normal children (6). Acta Pediatr Scand 64
patienh. They suggested that the diminished REFERENCES urinary sodium excretion was probably caused I . Aperia, A , , Bjarke, B., Broberger, 0. & Thoren, C.: Renal function in Fallot’s tetralogy. Acta Pueditrtr by the high hematocrit and intrarenal physical Scund, 63: 398, 1974. forces. since no hyperdldosteronism was pres2. Callis, L., Castell6. F. & Vallo. A.: Acidosis tubular ent. According to these studies it can be asproximal en las cardiopatias congenitas cianosantes. Proceedings of the 2nd Ir~iernntionalSvmposiutn qf sumed that the extracellular fluid volume is Pediatric Nrpkrologv. Paris, August 25-28, 1971, p. probably expanded in some sub-iects with high 197. hematocrit due to cyanotic heart disease 3. Campbell. I . M. H.. Hunt, G. H. & Poulton, E. P.: On examination of blood gases and respiration in disease through the increased tendency to sodium rewith reference of the cause of breathlessness and tention. When this situation occurs it could cyanosis. J Path Bact, 26: 234, 1923. lead directly to a depression of renal reabsorp- 4. Davies, H . & Gacetopoulos, N.: Dyspnea in cyanotic congenital heart disease. Rr Heurr J , 27: 28, 1965. tion of bicarbonate since there is strong eviEdelmann, C. M . Jr, Rodriguez-Soriano, J . , Boichis, 5 . dence that this reabsorption is dependent on H . . Gruskin, A. B. & Acosta, M. I . : Renal bicarbovariations of extracellular fluid volume (9). nate reabsorption and hydrogen ion excretion in normal infants. J Clin Invest, 46: 1309, 1967. It appears that patients with cyanotic heart 6. Edelmann. C. M., Jr, Boichis, H . , Rodriguez-Soriano. disease may benefit from sodium retention by J. & Stark, H.: The renal response of children to increasing their plasma volume and thereby acute ammonium chloride acidosis. Pediuir Res, 1:452, 1967. preventing the hematocrit from reaching high G. M.: Acidemia of cardiogenic origin in Folger. 7. levels ( I ) . At a certain level of volume expanyoung infants with cyanotic congenital heart sion, however. regulation of extracellular volabnormalities. Clin Pediatr, / I : 573. 1972. 8. Gootman, N. L., Scarpelli, E. M. & Rudolph, A . M.: ume might become preferential and sodium Metabolic acidosis in children with severe congenital bicarbonate escape into the urine. The benefit heart disease. Pediatrics. 31: 251, 1963. of sodium retention is lost and a further eleva9. Martinez-Maldonado. M., Eknoyan, G. & Suki, W. N.: Diuretics in nonedematous states. Physiological tion of hematocrit may be followed by basis for their clinical use. Arch Inirrn M e d , 131: 797, neurological complications, as was the case in 1973, our patient. 10. Rodriguez-Soriano, J . , Boichis, H., Stark, H. & Edelmann, C. M . , Jr: Proximal renal tubular acidosis. If the above hypothesis is correct it may A defect in bicarbonate reabsorption with normal unhave a direct implication on the management nary acidification. Pediatr Res. I : 81. 1967. of the metabolic acidosis. I t should be treated 11. Rodriguez-Soriano, J . : The renal regulation of acid-base balance and the disturbances noted in renal by measures tending to increase the plasma tubular acidosis. Pediatr Clin N A m , 18: 529, 1971. volume such as the administration of sodium 12. Rudolph, A. M.: Metabolic and hemodynamic adbicarbonate. It is known that hydrochlorothjustments to hypoxia in infancy. Bu/l N Y Acad Med. 42: 982, 1966. iazide may be useful in the treatment of proximal renal tubular acidosis through the increased tubular reabsorption of bicarbonate Submitted Oct. 11, 1974 induced by the extracellular fluid volume con- Accepted Nov. 16, 1974 traction caused by the sodium loss (9). In patients with cyanotic heart disease and as- (J. R. S . ) Dept. of Paediatrics sociated metabolic acidosis this therapy might Hospital Infantil de la Seguridad Social “Enrique Sotornayor’’ be potentially dangerous since it could be fol- Cruces lowed by an acute elevation of hematocrit and Bilbao Spain a threatening neurological complication.
Acts Pediatr Scand 64
J f
