Pediatr Nephrol (1999) 13:315–318
© IPNA 1999
O R I G I NA L A RT I C L E
&roles:Jayanthi Chandar · Carolyn Abitbol · Milan Novak Gastón Zilleruelo · José Strauss
Abnormal urinary acidification in infants with hydronephrosis
&misc:Received: 3 June 1997 / Revised: 7 July 1998 / Accepted: 8 July 1998
&p.1:Abstract Distal renal tubular abnormalities have been observed in patients with dilated urinary tract disorders. The present study was undertaken to look for patterns in urinary acidification in infants with varying degrees of hydronephrosis due to either reflux or obstruction and occurring as unilateral or bilateral disease. Three groups of infants (mean age 3.7±3.8 months) were studied prospectively. Groups IA and IB included patients with hydronephrosis who were acidotic and non-acidotic, respectively. Group II served as controls and consisted of patients with diarrhea and secondary metabolic acidosis with no known renal disease. Serum electrolytes, creatinine, and urine pH were measured in all patients. Urinary titratable acidity, ammonium (NH4), and net acid excretion (NAE) were measured by the titrimetric method. Infants with hydronephrosis demonstrated lower urinary buffering capacity, reflected in low NAE in the face of acidosis. Deficiencies were noted in both titratable acid and NH4 excretion compared with control infants. Acidosis was as common in unilateral as in bilateral disease, regardless of severity score. These data confirm a defect in distal urinary acidification in infants with hydronephrosis, whether unilateral or bilateral. Immaturity and endogenous acid load may play a significant role in the manifestation of metabolic acidosis with unilateral disease. &kwd:Key words Hydronephrosis · Metabolic acidosis · Urinary acidification&bdy:
Introduction Infants with urinary tract dilatation have a propensity to develop abnormal urinary acidification [1, 2]. During reJ. Chandar · C. Abitbol (✉) · M. Novak · G. Zilleruelo · J. Strauss Department of Pediatrics, Division of Pediatric Nephrology, University of Miami School of Medicine/ Jackson Memorial Medical Center, P.O. Box 016960, Miami, FL 33101, USA Tel.: +1-305-585 6726, Fax: +1-305-547 1709&/fn-block:
cent years we have observed at our institution that approximately half of infants with hydronephrosis manifest systemic acidosis with inadequate urinary acidification [3]. This abnormality has been as frequent in unilateral urinary tract dilatation as in bilateral disease. Controlled studies in infants with hydronephrosis have not been performed to assess the nature of the distal tubular acidification defect. We therefore designed a prospective study to evaluate the pattern of urinary acid and ammonium (NH4) excretion in infants with hydronephrosis due to obstruction or reflux.
Patients and methods Patients At the University of Miami/Jackson Memorial Medical Center, during the period between January 1993 and June 1994, 22 infants born at term with congenital hydronephrosis were followed prospectively for assessment of urinary acidification and the development of acidosis. The diagnosis of hydronephrosis was made in the following circumstances: (1) prenatal ultrasonography showing hydronephrosis and confirmed by postnatal imaging studies; (2) investigations following a urinary tract infection. Criteria for inclusion in the study included age <15 months and normal glomerular function for age at the time of initial diagnosis. Patients with an active urinary tract infection were excluded from the study. The diagnosis was established by renal ultrasonography, voiding cystourethrogram, and MAG-3 radionuclide renal scan. An estimate of the severity of hydronephrosis was obtained by ultrasound evaluation of the degree of dilatation of the renal pelvis and scored as follows: mild 1, moderate 2, and severe 3. Measurements were taken of the longest anterior-posterior diameter of the renal pelvis and designated as mild dilatation with 5–10 mm, moderate with 10–15 mm, and severe with ≥15 mm [4]. Vesicoureteral reflux was graded from I to V based on criteria established by the International Reflux Study [5]. For the purposes of comparison, hydronephrosis due to reflux was considered mild if grade I–II, moderate if grade III, and severe if grade IV–V. A control group of 12 patients matched for age without urinary tract disease but admitted for treatment of diarrhea and associated acidosis was also studied. The patients were divided into three study groups as follows: group IA – 13 patients with persistent metabolic acidosis [total plasma carbon dioxide (TCO2) ≤19 mEq/l on 2 or more occasions] associated with hydronephrosis; group IB – 9 patients with hydronephrosis who did not develop acidosis;
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Laboratory methods Included in the laboratory assessment were serum and urine for electrolytes [sodium (Na), potassium (K), chloride, TCO2], creatinine, calcium, phosphorus, blood urea nitrogen (BUN), and glucose. Urine was obtained simultaneously for determination of titratable acidity (TA) and net acid excretion (NAE). Urine and serum chemistry assays were performed in the hospital laboratory on a Beckman multichannel autoanalyzer. Urine osmolality (Uosm) was determined by freeze-point osmometry. Plasma osmolality (Posm) was calculated from the following formula: Posm=2 [Na]+[glucose]/18+BUN/2.8. The titrimetric method described by Chan [6] was followed for the determination of TA, NAE, and NH4. The method required a pH radiometer and titrator. The urine was treated with a fixed volume of acid (0.1 M hydrochloric acid) followed by boiling and titration with alkali (0.1 M sodium hydroxide) to pH 7.4 to measure TA. After addition of 8% formaldehyde, the sample was back-titrated to pH 7.4 to determine NAE. NH4 was the difference between NAE and TA, all in millimoles per liter. Transtubular potassium gradient (TTKG [7] was calculated using the formula: UrineK ÷ [Urine/Plasma Osmolality]/Plasma (normal ≥5.0). All laboratory data obtained at a time when the patients with hydronephrosis were stable with no evidence of acute infection. Creatinine clearance was estimated by using body length and plasma creatinine [9].
tables [8]. The data are presented as the mean value and standard deviation.
Results Patient demographics A demographic comparison of the three study groups is shown in Table 1. The average age of the infants was 3.7±3.8 months. There was a male predominance in each group, with an overall male:female ratio of 4:1. The predominant race was Caucasian, with an overall ratio of 1.3:1 white:black, although the ratio was 2:1 when only the hydronephrotic patient groups (IA and IB) were considered. Average serum creatinine was 0.5±0.2 mg/dl and was not different between groups. Six infants in group IA and 4 infants in group IB had urinary tract dilatation secondary to vesicoureteral reflux. The remainder of the hydronephrotic patients had obstructive urinary tract disease. Figure 1 shows the distribution of acidotic and nonacidotic patients relative to their severity score and laterNon - acidotic
3
2
1
Statistical methods
0
Analysis of data was performed using scientific statistical software (GraphPad InStat and InPlot) with group comparisons performed by one-way analysis of variance. Relative risk by severity score and laterality for presence of acidosis in groups IA and IB was determined by the Fisher’s exact test using chi-squared contingency Table 1 Patient demographics&/tbl.c:&
Acidotic
4
Severity score
group II – 12 patients with metabolic acidosis (TCO2≤19 mEq/l) during transient diarrheal disease. Six patients with hydronephrosis (4 in the acidotic and 2 in non-acidotic group) were fed Similac PM6040. All other infants with hydronephrosis were fed Enfamil with iron and their average consumption of milk was 180 ml/kg per day. One patient in the control group was fed Pregestimil. The other patients in the control group were fed Ricelyte or Pedialyte and were hydrated with intravenous fluids. In the initial hour following institution of intravenous fluids, Ringer’s lactate was given. This was followed by 0.45 normal saline with dextrose for 8 h and then 0.2 normal saline with dextrose for 16 h. The rate of fluid administration varied depending on oral intake and stool losses. Baby food was given to 5 patients with hydronephrosis (4 in the acidotic and 1 in the nonacidotic groups) and 1 patient in the control group.
UUD
BUD
Fig. 1 Distribution of hydronephrotic infants by laterality and severity score. UUD, Unilateral urinary tract dilatation; BUD, bilateral urinary tract dilatation&ig.c:/f
Group (n)
Age (months)
M:F
W:B
PCr (mg/dl)
TCO2 (mEq/l)
M, Male; F, female; W, white; B, black; PCr, plasma creatinine; CCr, creatinine clearance; TCO2, plasma total carbon dioxide * P<0.01&/tbl.:
CCr (ml/min per 1.73 m2)
IA (13) IB (9) II (12) Mean±SD
4.7±5.0 2.2±3.0 4.3±6 3.7±4
6:1 4:1 3:1 4:1
2:1 1.3:1 0:1 1.3:1
0.5±0.2 0.5±0.1 0.4±0.2 0.5±0.2
78±38 58±30 63±25 67±32
17±3 23±3 * 14±4
Table 2 Urine acidification in hydronephrotic infants&/tbl.c:&
Group (n)
TCO2 (mEq/l)
Urine pH
NAE (mmol/l)
TA (mmol/l)
NH4 (mmol/l)
IA (13) IB (9) II (12) ANOVA F P
17±3 23±3 * 14±4 18.4 <0.001
5.8±0.8 6.6±0.8 * 5.2±0.3 11.3 <0.05
13±13 7±16 40±18 ** 14.1 <0.001
3.1±7 0±14 10±7 3.3 0.05
10±7 7±5 29±17 ** 12.6 <0.001
ANOVA, Analysis of variance; NAE, net acid excretion; TA, titratable acidity; NH4, ammonium * P<0.05; ** P<0.01&/tbl.:
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pared with acidotic controls. TA was similarly low in the acidotic hydronephrotic patients, although it did not achieve statistical significance. NH4 excretion increased in the acidotic hydronephrotic group relative to the nonacidotic group, but did not achieve the magnitude of the acidotic control group. Mean serum K was 5.8±1.0, 5.3±1.1, and 5.0±0.9 mmol/l in groups I, II, and III, respectively. Correspondingly, the mean TTKG was 7±4, 6±4, and 5±6, respectively. Although there was no statistical significance, the mean TTKG was lower in the group of infants with diarrhea, possibly associated with hypokalemia in some.
Net acid excretion (mmol / l)
100 Hydronephrotic Acidotic controls
75 50 25 0 - 25 - 50 0
5
10
15
20
25
30
Plasma bicarbonate ( TCO2 ) (mmol / l) 9 Hydronephrotic Acidotic controls
Discussion
Urine pH
8 7 6 5 4 0
5
10
15
20
25
30
Plasma bicarbonate ( TCO2 ) (mmol / l)
Components of urinary acidification (mmol / l)
Fig. 2 Net acid excretion and urine pH against plasma bicarbonate (TCO2) in hydronephrotic and control infants with acidosis. Solid line indicates normal anticipated urine pH curve&ig.c:/f 50
∗
Net acid excretion Titratable acidity
40
Ammonium
∗
30
20
10
0
Group Ia
Group Ib
Group II
Fig. 3 Components of urinary acidification in hydronephrotic and control infants. * P<0.05 vs. other groups&ig.c:/f
ality. The occurrence of acidosis was as likely in unilateral as in bilateral disease. Similarly, acidosis was as frequent in those patients with lower as in those with higher severity scores. Table 2 summarizes the components of urine acidification relative to the metabolic status of each group of patients. Figure 2 depicts NAE and urine pH relative to plasma bicarbonate in each group of patients. Urine pH was similar in the patients with metabolic acidosis from diarrhea and patients with hydronephrosis and acidosis. NAE was low in acidotic hydronephrotic patients com-
In the presence of acidosis, the hydronephrotic infants were unable to substantially increase their NAE compared with control infants. The defect in NH4 excretion was the most-striking abnormality. However, the very low values for TA in acidotic infants with genitourinary abnormalities suggests multiple components to the defect in distal nephron acidification. NAE and TA were low in the non-acidotic hydronephrotic group of infants. However they were not given an exogenous acid load to demonstrate a definite defect in urinary acidification. Limitations in the synthesis of NH4 by the immature kidney have been described in the past [10, 11]. It is probable that, aside from immaturity, there were other contributing factors in the defective generation of NH4 in the acidotic, hydronephrotic infants. The decreased ability to generate more NH4 cannot be explained on the basis of decreased renal mass, as the integrity of the parenchyma was demonstrated by ultrasonography. It is known that hyperkalemia as a result of aldosterone resistance at the distal tubule can be associated with low NH4 generation [10]. A low TTKG in conjunction with hyperkalemia, particularly when confirmed with a mineralocorticoid challenge, has been reported as specific for aldosterone resistance at the distal nephron [type IV distal renal tubular acidosis (dRTA)] [12, 13]. Aldosterone resistance was not a feature in these infants. The urine anion gap as an indirect estimate of NH4 excretion in term infants greater than 3 weeks of age may be useful in the clinical assessment of acidemia [14]. However, NH4 is an “unmeasured” cation excreted with chloride. A falsely positive urine anion gap may be caused by other unmeasured anions such as antibiotics excreted as Na or K salts. This would mimic the positive urine anion gap characteristic of dRTA, making it a lessreliable diagnostic parameter. The acidifying defect observed in these infants with hydronephrosis is from an acquired dRTA and is probably a “rate-dependent defect” in which the urine pH can be ≤5.5 [15]. The equal and high prevalence of abnormal acidification in unilateral as well as bilateral disease is one of the most-intriguing aspects of this problem in infants. All infants with hydronephrosis had MAG-3 renal scans performed. The scan showed prompt uptake and
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normal clearance of radiotracer in the contralateral kidney of patients with unilateral hydronephrosis. This finding makes the possibility of dysplasia unlikely in the contralateral kidney. This phenomenon may be explained on the basis of immature compensatory mechanisms in the contralateral unaffected kidney. Also, increased endogenous acid production in infants, particularly during times of stress, may contribute to the acid burden imposed on the compensating renal units.
References 1. McSherry E (1981) Renal tubular acidosis in childhood. Kidney Int 20:799–809 2. Hutcheon RA, Kaplan BS, Drummond KN (1976) Distal renal tubular acidosis in children with chronic hydronephrosis. Pediatrics 89:372–376 3. Chandar J, Abitbol C, Zilleruelo G, Gosalbez R, Montané B, Strauss J (1996) Renal tubular abnormalities in infants with hydronephrosis. J Urol 155:660–663 4. Blachar A, Blachar Y, Livne PM, Zurkowski L, Pelet D, Mogilner B (1994) Clinical outcome and follow-up of prenatal hydronephrosis. Pediatr Nephrol 8:30–35 5. Lebowith RL, Olbing H, Parkkulainen K, Smellie J, Tamminen-Mobius T (1985) International system of radiographic grading of vesicoureteric reflux. Pediatr Radiol 15:105– 109
6. Chan JCM (1980) In: Duarte CG (ed) Renal function tests – clinical laboratory procedures and diagnosis. Little Brown, Boston, pp 239–268 7. Santos F, Oreas G, Foreman J, Chan JCM (1991) Diagnostic workup of renal disorders. Curr Probl Pediatr 21:48–74 8. Downie NM, Heath RW (1970) Basic statistical methods, 3rd edn. Harper and Row, New York, pp 86–142, 215–240 9. Schwartz GJ, Haycock GB, Edelmann CM Jr, Spitzer A (1976) A simple estimate of glomerular filtration rate in children derived from body length and plasma creatinine. Pediatrics 58:259–263 10. Schwartz GJ (1992) Acid-base homeostasis. In: Edelmann CN Jr (ed) Pediatric kidney disease, vol 1, 2nd edn. Little Brown, Boston, pp 201–230 11. Goldstein L (1970) Renal ammonia and acid excretion in infant rats. Am J Physiol 18:1394–1398 12. West ML, Marsden PA, Richardson RM (1986) New clinical approach to evaluate disorders of potassium excretion. Miner Electrolyte Metab 12:234–239 13. Rodriguez-Soriano J, Ubetagoyena M, Vallo A (1990) Transtubular potassium concentration gradient: a useful test to estimate renal aldosterone bio-activity in infants and children. Pediatr Nephrol 4:105–110 14. Halperin ML, Richardson RMA, Bear RA, Magner PO, Kamel K, Ethier J (1988) Urine ammonium: the key to the diagnosis of distal renal tubular acidosis. Nephron 50:1–4 15. Cohen J, Harrington J, Kassirer J, Madias J (1983) Acquired distal renal tubular acidosis. Kidney Int 24:807–819
L I T E R AT U R E A B S T R A C T S
H. Maxwell · D. Haffner · L. Rees&bdy:
G.B. Fogazzi
Catch-up growth occurs after renal transplantation in children of pubertal age
The description of the renal glomeruli by Marcello Malpighi
&misc:J Pediatr (1998) 133:435–440
&misc:Nephrol Dial Transplant (1997) 12:2191–2192
Objective Assessment of growth after renal transplantation in children of pubertal age by analyzing the annual increment in height standard deviation score (Ht SDS) in all girls >or=10 years and boys >or=11 years of age at the time of transplantation until latest follow-up (minimum 2 years). Patients A total of 59 grafts were placed in 54 recipients (30 boys) between December 1984 and January 1995. Mean (range) age at transplantation was 13.6 years (10.1 to 17.7 years). Fiftyone percent had congenital renal disease, 36% acquired renal disease, and 13% had hereditary nephropathies. Eighty-seven percent were first grafts; of these, 29% were performed pre-emptively, and 23% were from living related donors. Results Mean (SD) Ht SDS at transplantation was −1.8 (0.2) and increased significantly thereafter, such that it was −1.6 (0.2) at 1 year, n=52; −1.5 (0.2) at 2 years, n=47; −1.0 (0.2) at 3 years, n=27; −0.7 (0.3) at 4 years, n=19; and −0.6 (0.3), n=13, at 5 years after transplantation (analysis of variance, P<0.001). The greatest improvement in Ht SDS in the first year was seen in children with the highest glomerular filtration rate (r=0.429, P=0.002) and in those who were shortest at the time of transplantation (r=−0.356, P=0.009). Conclusion Catch-up growth occurs in children receiving renal transplants during the expected time of puberty.
“In all the kidneys I have happened to have in my hands so far, I have always noticed the presence of tiny corpuscles. To see these corpuscles the artery of the kidney has to be injected with a black liquid [and then] one can see the small corpuscles which have turned black ... hanging like apples from the blood vessels which, swollen with the black fluid, look like a beautiful tree.” (Malighi 1666)
