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Home , Acidosis, Albuminuria, Bicarbonate, Calcinosis, Hemoglobinuria, Hydronephrosis

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Renal Tubular James C.M. Chan, MD,*† The infant’s paternal grandfather Jon I. Scheinman, MD,‡ died at age 61 from and Karl S. Roth, MD*† heavy smoking. The 60-year-old pa- ternal grandmother was healthy and well. There was no family member Objectives After completing of short stature. The 38-year-old this article, readers should be able mother (162.6 cm) and the 46-year- to: old father (175.3 cm) both were in good health. The maternal grandfa- 1. Describe the important presenting ther, age 72, had a history of renal characteristics of renal tubular stones. The 67-year-old maternal acidosis (RTA). grandmother (157.5 cm) had a his- 2. Delineate the mechanisms of the tory of gallstones. No one in the growth failure commonly family was on or had encountered in RTA. diseases except for the maternal grandfather’s renal stones. 3. Characterize the various types of At 2 months of age, the infant had primary RTA. persistent failure to thrive and a 4. Describe diagnostic tests and 1-day history of irritability and vom- treatment modalities available for iting and was readmitted for diagnos- RTA. tic evaluation. 5. Delineate the conditions giving level was 12 mEq/L (12 mmol/L), rise to secondary distal and and she was tachypneic, with a respi- ratory rate of 60 breaths/min and proximal RTA. intercostal retraction. Her height was 48.5 cm (Ͻ5th percentile) and her weight was 3.45 kg (Ͻ5th percen- Case Presentation tile). pressure was 81/48 mm A 2-month-old Caucasian female Hg. She was alert and calm, with presented for failure to thrive. She normal skin turgor. Chest showed was born at 33 weeks’ gestation via equal expansion and clear breath primary cesarean section for preg- sounds, with no rales or wheezes. nancy-induced to a 38- There were distinct heart sounds, a year-old G1P0 mother. Her birth- regular rhythm, and no murmur. weight was 1,430 g, making her The abdomen was soft and non- small for gestational age. Apgar tender, had normally active bowel scores were 7 and 9 at 1 and 5 min- sounds, and had no masses or utes, respectively. Newborn meta- hepatosplenomegaly. Pulses were full bolic screen results were negative. At and equal. She had good muscle tone 3 weeks of age, with good oral intake and spontaneous movement of all of formula, alternating with breast- extremities. feeding, the infant was discharged Laboratory values on admission from the hospital. were: blood pH, 7.28; serum so- dium, 138 mEq/L (138 mmol/L); From the Department of * and the , 5.2 mEq/L (5.2 mmol/ Department of Biochemistry Molecular Biophysics†, L); , 113 mEq/L (113 Virginia Commonwealth University, Richmond, VA, and the Department of Pediatrics at the University mmol/L); bicarbonate, 12 mEq/L of Kansas‡, Kansas City, KS. (12 mmol/L); nitrogen, 3

Pediatrics in Review Vol.22 No.8 August 2001 277 consultation with the specialist

mg/dL (1.07 mcmol/L); and creat- Table 1. Normal Indices of Urinary Excretion of inine, 0.2 mg/dL (17.7 mcmol/L). Urinalysis showed: pH, 7; specific Citrate and Other Variables gravity, 1.003; and no or Index Measurement Normal Values . Diagnostic evaluation for was negative, and ceftriax- <4 mg/kg per 24 h one was discontinued on the sixth Urinary calcium/ ratio: <0.21 mg/mg (adults) hospital day. <0.41 mg/mg (19 mo to 6 y) Ultrasonography of the kidneys <0.60 mg/mg (7 to 18 mo) showed diffuse nephrocalcinosis bi- <0.86 mg/mg (<7 mo) laterally. The right kidney was 5.1 cm Oxalate <50 mg/1.73 m2 per 24 h (<2 mg/kg per 24 h) 2 and the left kidney 4.8 cm. They Uric <815 mg/1.73 m per 24 h (35 mg/kg per 24 h) Cystine <75 mg/g creatinine appeared normal for age, exhibited Citrate >180 mg/g creatinine normal echogenicity and normal Creatinine Newborns: 8 to 10 mg/kg per 24 h preservation of parenchyma, and had Children: 12 to 10 mg/kg per 24 h no or hydroureters. Adults: F 12 to 15 mg/kg per 24 h The alkaline pH consistently M 15 to 20 mg/kg per 24 h above 5.5 in the presence of meta- From Laufer J, Biochis H. Urolithiasis in children: current medical management. Pediatr Nephrol. 1989;3:317–331; Sargent JD, Stukel TA, Kresal J, Klein RZ. Normal values for random urinary bolic acidosis and the presence of calcium to creatinine ratios in infancy. J Pediatr. 1993;123:393–397; and Manz F, Kehrt R, Lausen without a history of B, Merkel A. Urinary calcium excretion in healthy children and adolescents. Pediatr Nephrol. having been used suggested 1999;13:894–899. the diagnosis of (RTA). The urinary calcium-to-creatinine ratio was 0.73 mg. The urinary ci- was discharged from the hospital on about 0.08 mg/mg. The bilateral trate was 80 mg/g creatinine (nor- the eighth day. nephrocalcinosis was followed with mal, Ͼ180 mg/g creatinine, Table She was evaluated every month ultrasonography of the kidneys at 13 1). Urinary oxalate was 1.1 mg/kg for the first 5 months, during which months, 20 months, 2 years, 4 years, per day (normal, Ͻ2 mg/kg per day, Bicitra (1 mLϭ1 mEq) was increased and 5 years of age. The kidneys con- Table 1). to 8 mL tid. At 10 months of age, the tinued to grow, but the nephrocalci- After intravenous infusion of dose was adjusted to 12 mL qid and nosis in the medullary pyramids per- 4 mEq/kg per day of bicar- at age 13 months was modified to a sisted. At 5 years of age, the right bonate, the was daily divided dosage of 12 mL, 12 kidney was 7.23 cm and the left kid- corrected and the re- mL, and 24 mL, with the larger dose ney 8 cm, which was within normal solved. The diagnosis of RTA was at bedtime. The rationale was that values. The urine pH was 8 and spe- confirmed when the urine minus growth hormone secretion is highest cific gravity was 1.001, and the urine blood partial pressure of CO2 was at night and she would benefit from was negative for blood and protein. found to be less than 17 mm Hg better correction of metabolic acido- The Bicitra was modified initially and 10.7 mm Hg on repeat sis with a larger dose at bedtime. At at 5 years of age to 24 mL in the measurement (normal, Ͼ20 mm Hg, 20 months of age, her height was morning, 12 mL at noon, and 36 mL Fig. 1). The child was started on 79 cm (10th percentile) and her at night (total, 5 mEq/kg per day). Bicitra brand of sodium citrate and weight was 9.23 kg (5th percentile). The corresponding pattern citric acid oral 5 mL (5 The average dose of alkali therapy was sodium, 139 mEq/L (139 mmol/ mEq) qid. was 5 to 6 mEq/kg per day. She L); potassium, 4.3 mEq/L (4.3 mmol/ During the admission, the infant subsequently was followed every 3 L); chloride, 105 mEq/L (105 mmol/ alternately breastfed and was given months for the third year of life and L), CO2, 23 mEq/L (23 mmol/L); 45 mL of -fortified forumla every 6 months thereafter. serum urea nitrogen, 11 mg/dL (20 kcal/oz) every 3 to 4 hours. On Urine calcium-to-creatinine ratio (3.9 mmol/L); and creatinine, the fourth hospital day, a soy-based was monitored at each follow-up visit 0.5 mg/dL (44.2 mcmol/L). formula was substituted. She toler- and was documented at normal val- The last ultrasonography was ob- ated Bicitra added to the formula and ues of less than 0.20 mg/mg, usually tained at 6 years of age. Bilateral

278 Pediatrics in Review Vol.22 No.8 August 2001 consultation with the specialist

Case Discussion The initial growth retardation of the child described in the case is related to the 33-week gestation, but the RTA also plays a significant role. Even with the increased therapeutic dose of Bicitra at 5 mEq/kg per day, growth did not increase significantly until the second year, when a double dose began to be administered be- fore bedtime. The presence of severe metabolic acidosis with serum bicarbonate less than 12 mEq/L (12 mmol/L) clini- cally associated with tachypnea illus- trates the logical steps to pursue the diagnosis of RTA (Table 2). In many patients, RTA may present with poly- uria, constipation, and failure to thrive. The of RTA is in- duced partly by the , but the chronic from potassium wasting (vide infra) also contributes to the lack of urine con- centrating ability. Damage to the pa- pillae and their collecting systems caused by interstitial of chronic hypokalemia also may con- tribute. The urine specific gravity of this child was consistently low and at Figure 1. A. Minimum urine pH versus fractional excretion of the latest follow-up was 1.000. The bicarbonate (%). Closed squares and closed circles represent constipation seen in patients who healthy individuals and patients who have proximal, type 2 RTA, have RTA is due to the muscle weak- respectively. Open circles represent rate-dependent distal RTA. All three groups have minimum urine pH of less than 5.5. Patients ness associated with chronic hypoka- who have classic, type 1 distal RTA, represented by open squares, lemia (the is a have minimum urine pH values in excess of 5.5. B. Urine minus long muscular tract).

blood PCO2 (change in mm Hg) versus fractional excretion of The differential diagnosis of fail- bicarbonate. Healthy individuals (open circles) and patients who ure to thrive and constipation in in- have proximal, type 2 RTA (closed circles) have values above fancy must include congenital hypo- 20 mm Hg. In patients who have distal classic, type 1 RTA (open thyroidism (Table 3). Results of squares) and rate-dependent distal RTA (closed squares), values were normal in are less than 20 mm Hg. Reprinted with permission from Strife CF, this child. The classic symptoms of Clardy CW, Varade WS, Prada AL, Waldo FB. Urine-to-blood hypothyroidism typically are seen in dioxide tension gradiant and maximal depression of urinary infancy, especially with screening pH to distinguish rate-dependent from classic distal renal tubular acidosis in children. J Pediatr. 1993;122:60–65. tests, diagnosis, and treatment in the neonatal period. Today, subclinical hypothyroidism in infancy may nephrocalcinosis persisted, but the showed a pH of 8.5, specific gravity present only with failure to thrive. kidney size was normal, with the of 1.000, trace protein, and no The hyperchloremic metabolic aci- right kidney at 7.23 cm and the left blood. The next scheduled follow-up dosis with normal docu- kidney at 8 cm. The last urinalysis visit is in 9 months. mented in this child also could be

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Table 2. Diagnostic Evaluation for RTA Table 3. Differential Studies Interpretation Diagnosis of (1) Fresh, spot urine pH Type 1 RTA, urine pH consistently >5.5. Type 2 RTA, urine pH <5.5. Neonatal Failure (2) Serum electrolytes Metabolic acidosis with serum total CO2 to Thrive and <17.5 mEq/L (17.5 mmol/L) for all types of RTA, usually associated with Normal Anion Gap and normal anion gap. Normal serum urea nitrogen, Metabolic Acidosis creatinine, and creatinine . (3) 24-h urine for calcium, Hypercalciuria, hypocitraturia, and ● Distal renal tubular acidosis citrate, potassium, and potassium wasting are associated with ● Congenital hypothyroidism oxalate type 1 RTA. Rule out . ● Obstructive uropathy (4) Ultrasonography of the Nephrocalcinosis in undiagnosed, ● Early uremic acidosis kidneys untreated, or inadequately treated RTA. ● Bicarbonate loss —Proximal renal tubular (5) Urine minus blood PCO2 Normal values, >20 mm Hg Proximal, type 2 RTA, >20 mm Hg acidosis Distal, type 1 RTA, <20 mm Hg —Diarrhea (6) Tubular reabsorption of Bicarbonate wasting or TRB >15% in —Intestinal fistula bicarbonate (TRB) type 2 RTA and <5% in type 1 RTA at —Ureterosigmoidostomy —Medications: cholestyramine, normalized serum total CO2. (7) Tubular of TRP <60% filtered load of phosphate in magnesium , calcium (TRP) and other proximal chloride tubular defects in reabsorption of ● Acid loading phosphate. If Fanconi syndrome is — chloride suspected, 24-h urine collection is — hydrochloride needed to confirm the and potassium wasting. (8) Renal acidification studies If metabolic acidosis is clearly present,

with total CO2 <17.5 mEq/L (17.5 dosis. The calcium released in ex- mmol/L), there is no need for further change for the obli- acidification. If the metabolic acidosis gates the kidney to increase calcium is unclear, the renal ability to acidify can be tested maximally after excretion to maintain calcium ho- ammonium chloride or arginine meostasis. Thus, hypercalciuria often hydrochloride acid loading. The net accompanies RTA. The hypocitratu- acid excretion of <70 mcEq/min per 2 ria seen in this child, coupled with 1.73m confirms a distal tubular her high normal urine calcium excre- acidification defect. tion, increases the risk of nephro- Steps (1) to (5) are conducted by the generalist. Steps (6) to (8) usually are recommended by the , which is characteristic of pediatric nephrologist. undiagnosed and untreated RTA. In- deed, if untreated or treated inade- quately due to medical noncompli- ance, the nephrocalcinosis may due to obstructive uropathy. Thus, ; intestinal fistula; uretero- worsen and ultimately destroy the ultrasonography of the kidneys is ap- sigmoidostomy; or ingestion of cal- kidneys, resulting in end-stage renal propriate to rule out hydronephrosis cium chloride, magnesium sulfate, or disease (Fig. 2). However, the and hydroureters of obstructive cholestyramine. There was no history nephrocalcinosis in RTA usually is uropathy. Other causes of metabolic of acid loading (eg, ammonium chlo- unresolved, even with aggressive al- acidosis with normal anion gap ride or arginine hydrochloride). kali therapy, in distinct contrast to (Table 3) include early uremic acido- After the extracellular bicarbonate diuretic-induced nephrocalcinosis in sis, which was unlikely in this child and nonbicarbonate buffering sys- infancy, which resolves after cessa- because of the normal serum urea tems are exhausted, calcium salts in tion of the diuretic therapy. nitrogen and creatinine. The history the skeletal system become the next In the past, some research labora- excluded bicarbonate losses from line of defense against metabolic aci- tories offered the determination of

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urine does not injure the membrane of the blood gas electrode any more than does blood.

Clinical Findings of RTA Clinically, RTA is characterized by failure to thrive, polyuria, and consti- pation. Biochemically, it is character- ized by hypokalemic, hyperchlor- emic metabolic acidosis. The basic defect in type 1 or classic RTA lies in a failure of the distal tubular sodium hydrogen ion exchange, resulting in sodium being wasted by the kidneys in association with bicarbonate wast- ing. The ensuing contraction of the extracellular volume gives rise to hy- peraldosteronism and consequent potassium wasting. The resulting hy- pokalemia is manifested symptomat- ically as (including constipation) and lack of renal con- centrating ability (polyuria). Occa- sionally, hyperparathyroidism may be encountered. in the adult and in the child may be seen. Finally, the hyperchloremic metabolic acidosis gives rise to hy- percalciuria and hypocitraturia, Figure 2. Severe nephrocalcinosis in a 4-year-old child who had unrecognized and leading to nephrocalcinosis and untreated RTA and presented from 1 to 4 years of age with failure to thrive and nephrolithiasis as a of microscopic hematuria before end-stage renal disease. showed almost complete obliteration of tubules from the massive nephrocalcinosis, glomerulosclero- unrecognized and untreated RTA. sis, and thickening of the Bowman capsules. Reprinted from Chan JCM. Acid-, The hypercalciuria further contrib- calcium, potassium and in renal tubular acidosis. . utes to the polyuria. Chronic meta- 1979;23:153–159. By permission S Karger AG. bolic acidosis obligates the skeletal buffering of the extra hydrogen ion. In addition, acidosis stimulates mito- chondrial citrate oxidation, resulting urinary pH by glass electrode and Hg (Fig. 1). The value in a child who in a reduction in the renal excretion urinary net excretion by automatic has distal, type 1 RTA, as seen in this of citrate, which is a physiologic cal- titrator. These net acid determina- child, is less than 20 mm Hg. This cium chelater that acts to increase tions are time-consuming to cali- diagnostic test also can be used to calcium . Thus, the hyper- brate and not cost-effective for rou- confirm the diagnosis of the gradient calciuria coupled with hypocitraturia tine chemistry laboratories. Today, a defect distal RTA. Because blood gas make supersaturation probable and useful diagnostic confirmation is the machines are widely available, the nephrocalcinosis likely. urinary minus blood partial pressures partial pressure of CO2 determina- The urine calcium-to-creatinine of , as used in this tion in both urine and blood can be ratio of 0.73 mg/mg reported for child. For healthy individuals and performed easily. A common mis- the child in the case was on the high those who have proximal RTA, the conception is that urine is injurious side of normal for a 2-month-old measurement is more than 20 mm to the blood glass electrodes, but (Table 1). The nephrocalcinosis was

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with the in type 1, distal RTA. The conditions that may cause secondary distal RTA are listed in Table 4.

Type 2, Proximal RTA Type 2 RTA is characterized by bi- wasting with a resetting of the threshold for proximal tubular bicarbonate reabsorption. Instead of the normal bicarbonate reabsorption threshold of 26 mEq/L (26 mmol/ L), it is reset to a much lower rate in type 2 RTA. For example, if the bi- carbonate reabsorption threshold is set at 15 mEq/L (15 mmol/L), bi- carbonate wasting begins when this threshold is exceeded and, thus, the plasma bicarbonate is set corre- Figure 3. Potassium wasting in patients who have RTA (closed pyramids, circles, and squares) versus potassium excretion in spondingly at 15 mEq/L (15 mmol/ healthy individuals from different publications (open circles and L). One of the best schematic presen- crosses). Reprinted from Sebastian A, McSherry E, Morris RC Jr. tations of urine bicarbonate leakage Renal potassium wasting in renal tubular acidosis (RTA). J Clin in proximal RTA is illustrated in Fig- Invest. 1971;50:667–678. By permission Society of Clinical ure 4. In normal subjects, whose Investigation. plasma bicarbonate are 26 mEq/L (26 mmol/L), 85% of the filtered load of bicarbonate is re- absorbed in the proximal tubules and already present, and there is a possi- remic metabolic acidosis and hypo- 15% in the distal tubule in exchange bility that even more severe hypercal- kalemia. The urinary pH is always in with hydrogen . This leaves no ciuria and hypocitraturia already was excess of 5.5, with net acid excretion bicarbonate in the final urine, and the present. The earliest case of nephro- of less than 70 mcEq/min per 1.73 acidic urine pH of 5.5 is maintained. 2 calcinosis in RTA was seen in a m . When metabolic acidosis is cor- Patients who have proximal type 2 3-week-old infant who had distal rected by base therapy, less than 3% RTA, however, have a lower-than- RTA. Nephrocalcinosis is encoun- of the filtered load of bicarbonate is normal set point for bicarbonate re- tered more frequently in type 1 RTA excreted in the final urine output. absorption threshold (eg, at a serum and uncommonly in type 2 RTA. The severe potassium wasting of bicarbonate of 15 mEq/l [15 mmol/ The retention of hydrogen ion in RTA is illustrated in Figure 3. When L]). In this case, the proximal tubular type 1 RTA obligates the hypercalci- healthy individuals sustain hypo- reabsorption of bicarbonate at 60% uria and increases the risk of nephro- kalemia of less than 3.8 mEq/L coupled with the distal tubule of bi- calcinosis. In contrast, type 2 RTA is (3.8 mmol/L), the kidneys respond carbonate reabsorption of 15% is still more difficult to treat because of the by conserving potassium, and urinary sufficient to absorb all the filtered frequent and massive doses of Bicitra potassium excretion falls below load of bicarbonate, and the urinary needed to counteract the massive bi- 40 mEq/d. However, in patients pH remains at 5.5. However, with carbonate wastings. who have distal RTA, the degree of progressive bicarbonate correction of potassium wasting continues irre- the serum bicarbonate to normal spective of the severity of hypokale- concentrations, the 60% proximal tu- Type 1 Distal RTA mia. This remarkable potassium bular bicarbonate reabsorption and Type 1 RTA (also known as classic wasting is believed to be a reflection 15% distal reabsorption is insufficient RTA) is characterized by hyperchlo- of the hyperaldosteronism associated to reabsorb all the filtered load of

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Table 4. Clinical Spectrum of Secondary Type 1, Distal RTA

● Tubulointerstitial renal disorders —Obstructive uropathy —Medullary sponge kidney —Renal transplantation —Nephrocalcinosis induced by metabolic and endocrine disorders ● Vitamin D intoxication ● Hyperparathyroidism ● Idiopathic hypercalicuria ● Wilson disease ● Hyperthyroidism ● Genetically transmitted systemic diseases —Ehlers-Danlos syndrome —Marfan syndrome Figure 4. Nephron in a normal individual (diagram to left) showing plasma bicarbon- — with associated ate of 26 mEq/L (26 mmol/L) and reabsorption of the filtered load of bicarbonate in nerve deafness the proximal tubules (85%) and in the distal tubule (15%). In contrast is the acidotic —Sickle anemia patient who has proximal, type 2 RTA with a plasma bicarbonate of 15 mEq/L —Elliptocytosis (15 mmol/L) (diagram to extreme right) and after correction of metabolic acidosis — deficiency with bicarbonate therapy. The filtered load of bicarbonate exceeds the proximal —Hereditary fructose intolerance tubule’s ability to absorb bicarbonate (only at 60%) and at the distal tubule (15%). —Fabry disease With correction of acidosis, the massive bicarbonate leak causes an alkaline urine pH ● Autoimmune disease of 7.8. From Morris RC, Sebastian A, McSherry E. Renal acidosis. Kidney Int. —Sjo¨gren syndrome 1972;1:322–340. By permission International Society of . —Hypergammaglobulinemic disorders —Systemic lupus erythematosus Aldosterone deficiency may result —Chronic active hepatitis Type 3 RTA —Thyroiditis Infants who have mild, distal renal from congenital adrenogenital syn- ● Toxin- or drug-induced tubular acidification defect com- drome, and aldosterone resistance —Amphotericin B bined with mild proximal bicarbon- may follow relief of posterior urethral —Lithium ate reabsorption defect were classi- valve obstruction or prostatic hyper- —Analgesics fied previously as having type 3 RTA. trophy. —Cyclamate —Toluene This has been reclassified as a subtype ● Hyponatriuric states of type 1 RTA that occurs primarily — in preterm infants. The More Common Type —Hepatic cirrhosis Previously, type 1 RTA was consid- From Hanna JD, Santos F, Chan JCM. Re- Type 4 RTA ered the most common type of RTA nal tubular acidosis. In: Clinical Pediatric Type 4 RTA is due to either aldoste- followed by type 4 RTA, but with Nephrology. New York, NY: McGraw-Hill, Inc; 1992:665–698. rone deficiency or aldosterone resis- more awareness of type 4 RTA fol- tance that results in an inability to lowing obstructive uropathy, it now excrete hydrogen and potassium is regarded as the most common ions. Retention of these ions gives type. Elderly men who have obstruc- bicarbonate, resulting in an alkaline rise to systemic metabolic acidosis tive uropathy from prostatic hyper- urine pH of 7.8. and . The latter features trophy and infants who have congen- The conditions that may cause distinguish type 4 RTA from the hy- ital adrenogenital syndrome give rise secondary proximal RTA are listed in pokalemia, which commonly charac- to more type 4 RTA than all the Table 5. terizes the first two types of RTA. other types.

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RTA to elaborate the minimum Table 5. Clinical Spectrum of Type 2, urine pH of less than 5.5. Thus, us- Proximal RTA ing the minimum urinary pH, the rate-dependent distal RTA may be ● Isolated RTA misdiagnosed. The ability to arrive at —Primary (sporadic or familial) the correct diagnosis of rate- —Carbonic anhydrase inhibition dependent distal RTA requires calcu- ● lation of the urine minus blood par- ● Mafenide (sulfamylon) tial pressure CO . ● Carbonic anhydrase deficiency 2 ● Osteopetrosis with carbonic anhydrase II deficiency ● Generalized Mechanism of Growth Failure —Primary (sporadic or familial) In an abstract presented in 1979, —Inborn error of metabolism McSherry reported the blunting of ● growth hormone release in children ● Lowe syndrome ● Hereditary fructose intolerance who have RTA (see Suggested Read- ● Tyrosinemia ing). To determine how metabolic ● Galactosemia acidosis affects growth hormone se- ● Wilson disease cretion and expression, Challa and ● Pyruvate carboxylase deficiency associates recently demonstrated that ● Metachromatic leukodystrophy ● Glycogen storage disease acidosis inhibits the growth hor- —Dysproteinemic states mone pulse amplitude, pulse area, ● Multiple myeloma and total growth hormone secretion ● Light chain disease in acidotic animals compared with ● Monoclonal gammopathy that of control and pair-fed animals ● Amyloidosis —Vitamin D deficiency, dependence, or resistance (see Suggested Reading). They also —Interstitial renal disease demonstrated that serum insulin-like ● Sjo¨gren syndrome growth factor (IGF), hepatic IGF-1 ● Medullary cystic disease mRNA, hepatic growth hormone re- ● Renal transplantation rejection (early) ceptor mRNA, and gene expression ● Balkan nephropathy ● Chronic renal vein thrombosis of IGF at the growth plate of the —Toxins long all are suppressed in the ● Outdated tetracyclines presence of metabolic acidosis. Thus, ● it appears that acidosis interferes ● Mercury with major aspects of the growth ● ● Cadmium hormone-IGF axis, although re- ● Maleic acid duced nutrition from acidosis- ● Coumarin induced anorexia may contribute to ● Streptozocin decreased growth hormone secre- —Miscellaneous tion. However, metabolic acidosis ● Nephrotic syndrome ● Paroxysmal nocturnal appeared to inhibit IGF-1 mRNA ex- ● Malignancy pression in the growth plate of the ● Congenital heart disease long bone and in the hepatic growth From Hanna JD, Santos F, Chan JCM. Renal tubular acidosis. In: Clinical Pediatric Nephrology. New hormone receptor mRNA specifi- York, NY: McGraw-Hill, Inc; 1992:665–698. cally. These animal experiments showed that metabolic acidosis di- rectly inhibited growth hormone se- Rate-dependent Distal RTA to thrive, coexisting disorders, and cretion and gene expression at target For children, type 1 RTA is difficult the incidence of nephrocalcinosis are sites, anomalies that contribute to to differentiate clinically from rate- indistinguishable between the two the growth failure of metabolic aci- dependent distal RTA. The age of types. The confounding variable is dosis. presentation, the incidence of failure the ability of rate-dependent distal Data from the 1950s and 1960s

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showed impaired intestinal calcium tio is higher. However, such “nor- distal RTA (see Suggested Reading). absorption in young children who mal” values for infants have been Their data suggested that a mean had RTA. The pathogenesis of this confirmed by the total 24-hour cal- dose of 3.5 mEq/kg per day was lack of absorption was not eluci- cium excretion. needed. They also demonstrated a dated. Studies of acidotic animals in Urinary citrate has been shown to very large spectrum of therapeutic the 1970s showed that ammonium be lowered significantly in RTA and ranges for alkali therapy from 1 to chloride-induced metabolic acidosis is one of the contributing factors to 7 mEq/kg per day. There was no interfered with 1-alpha-hydroxylase the nephrocalcinosis. Normal urine difference in dose requirements be- activation of the vitamin D system. citrate excretion is in excess of tween infants and children on a body By inference, the impaired absorp- 180 mg/g of creatinine. Other use- weight basis. Their data also sug- tion of calcium in children who have ful indices of urinary excretion are gested a significant increase in per- RTA is likely the result of interfer- summarized in Table 1. centile weight and height in many ence with 1-alpha-hydroxylase activ- Ultrasonography of the kidneys treated children. Nonetheless, the ity in the presence of metabolic aci- can evaluate their anatomic size and large spectrum of variability likely re- dosis. However, data from Chesney echogenicity; rule out dysplastic kid- flects medical noncompliance. Type and associates (see Suggested Read- neys, obstructive uropathies, and cys- 2 RTA requires larger and more fre- ing) showed no abnormalities in se- tic kidneys; and detect nephrocalci- quent doses of Bicitra (as high as rum 1,25-dihydroxyvitamin D con- nosis. Any nephrocalcinosis should 14 mEq/kg per day). centrations among children who had be monitored by ultrasonography at Type 4 RTA may require treat- RTA, although the serum bicarbon- intervals of every 12 months and if ment with fludrocortisone 0.1 to ate concentrations of 18 mEq/L stable, every 2 to 3 years. 0.3 mg/d (0.05 to 0.15 mg/m2 per (18 mmol/L) suggested that the ac- When metabolic acidosis is cor- day). To reverse the hyperkalemia idosis was mild and may account for rected with sufficient alkali therapy, that characterizes the metabolic aci- the lack of interference of 1-alpha- the urine minus blood partial pres- dosis of type 4 RTA, dietary potas- hydroxylase activity. sure of CO2 can help differentiate sium restriction and orally adminis- distal from proximal RTA (Table 2). tered potassium binders may be Diagnostic Evaluation At this point, the generalist will needed. Finally, to increase renal ex- If RTA is suspected, the diagnostic have completed all appropriate eval- cretion of potassium, chlorothiazide evaluation delineated in Table 2 uations. The next step is referral to and furosemide may be required to should be followed. The fresh early the pediatric nephrologist for deter- correct hyperkalemia. To neutralize morning urine pH should be tested mination of tubular reabsorption of the metabolic acidosis, bicarbonate by dipstick. Although a urine pH de- bicarbonate and phosphate or renal therapy of 1.5 to 2.0 mEq/kg per termined by the glass electrode is acidification tests (Table 2). day has been advocated. more accurate, this is available only at specialized laboratories. An alkaline Treatment Long-term Follow-up of RTA urine pH in excess of 5.5 in the pres- The treatment of type 1 and type 2 The effects of therapy should be ence of systemic metabolic acidosis RTA is relatively simple, requiring monitored (Table 6) every month for (serum bicarbonate Ͻ17.5 mEq/L the use of or the the first 6 months. Close monitoring [17.5 mmol/L] and blood pH slightly more palatable compound of serum bicarbonate , Ͻ7.4) is suggestive of type 1 RTA. Shohl solution (or Bicitra), which urinary calcium/creatinine ratio, and Because of the association with contains citric acid and sodium ci- linear growth allow better adjust- hypercalciuria in the presence of met- trate, providing 1 mEq/mL of alkali. ments of medication to maintain se- abolic acidosis, the urinary calcium- Polycitra K contain potas- rum bicarbonate to more than to-creatinine excretion ratio should sium citrate to provide 2 mEq/mL of 22 mEq/L (22 mmol/L) and to re- be obtained. Normal values are less alkali and 2 mEq/mL of potassium, verse hypercalciuria. Annual ultra- than 0.21 (mg/mg). A notable ex- designed to correct both the acidosis sonographic imaging of the kidneys ception to this value is seen in the first and hypokalemia. is used to monitor the nephrocalci- few years of life (Table 1), with the Santos et al studied the dosage of nosis. In type 1 RTA, the base smaller body muscle mass resulting alkali therapy to maintain a stabilized needed to neutralize the endogenous in a lower urine creatinine value. correction of metabolic acidosis in hydrogen ion production is much With a smaller denominator, the ra- infants and children who had type 1, less than in type 2 RTA, where there

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long-term following of 28 patients. Table 6. Follow-up of RTA J Pediatr. 1992;121:233–241 Studies Interpretation Challa A, Chan W, Krieg RJ Jr, et al. Effect of metabolic acidosis on the expression

Serum total CO2 Adequate base therapy to maintain serum total CO2 of insulin-like growth factor and growth >22 mEq/L (22 mmol/L). hormone receptor. Kidney Int. 1993; Spot urine calcium/ Adequate base therapy to maintain urine calcium/ 44:1224–1227 creatinine ratio creatinine ratio to <0.20 mg/mg. Challa A, Krieg RJ Jr, Thabet MA, Veldhuis Ultrasonography of Monitor nephrocalcinosis. JD, Chan JCM. Metabolic acidosis in- the kidneys hibits growth hormone secretion in rats: mechanism of growth retardation. Am J Physiol. 1993;265:E547–E553 Chesney RW, Kaplan BS, Phelps M, De- is massive bicarbonate wasting. Ac- indicated a variable rate of response Luca HF. Renal tubular acidosis does cordingly, type 1 RTA is easier to to therapy, with accelerated growth not alter circulating values of calcitriol. J Pediatr. 1984;104:51–55 treat because of the lower alkali re- in some after a few months of therapy Manz F, Kehrt R, Lausen B, Merkel A. quirement (Bicitra 3 to 4 mEq/kg and others requiring 1 or more years Urinary calcium excretion in healthy per day) to maintain acid-base equi- of therapy before achieving 3rd per- children and adolescents. Pediatr Neph- librium. The large bicarbonate wast- centile linear growth curve. Further, rol. 1999;13:894–899 ing of type 2 RTA may require up to the threshold for bicarbonate reab- McSherry E, Weberman J, Kaplan S, Grum- 14 mEq/kg per day. The larger dose sorption matured with age in type 2, bach MM. The effects of acidosis on human growth hormone (hGH) release and frequency of dosing makes com- proximal RTA, and in some index in children with non-azotemic renal tu- pliance a problem. patients, this reverted to normal by 8 bular acidosis (RTA) [abstract]. Clin We advocate a larger dose of years of age. Bicarbonate therapy can Res. 1980;28:535A Bicitra at bedtime for type 1 RTA be discontinued when metabolic aci- Nash MA, Torrado AD, Greifer A, Spitzer based on the rationale that growth dosis resolves. No data are available A, Edelmann CM Jr. Renal tubular aci- hormone secretion is maximal during on the long-term outcome of type 4 dosis in infants and children. J Pediatr. 1972;80:738–748 sleep and that the optimal correction RTA because the prognosis is so vari- Norman ME, Feldman NI, Cohn RM, of metabolic acidosis during this pe- able and entirely dependent on the Roth KS, McCurdy DK. Urinary citrate riod will have a significant beneficial underlying causes. excretion in the diagnosis of distal renal effect. Probably all types of RTA can tubular acidosis. J Pediatr. 1978;92: 394–400 benefit from this strategy, not only in ACKNOWLEDGMENTS terms of better growth, but to Rodriguez-Soriano J. New insights into the Supported by N.I.H. grants pathogenesis of renal tubular acidosis achieve a degree of compliance once DK50419, DK07761, and M01 —from functional to molecular studies. or twice a day. RR00065. The authors thank Betty Pediatr Nephrol. 2000;14:1121–1136 One long-term follow-up of 28 Timozek for secretarial assistance. Santos F, Chan JCM. Renal tubular acidosis primary type 1, distal RTA patients in children: diagnosis, treatment and showed that those who had rickets at prognosis. Am J Nephrol. 1986;6: the time of presentation responded 289–295 Suggested Reading Sargent JD, Stukel TA, Kresal J, Klein RZ. poorly to therapy, with inferior Cardas A, Broyer M, Dechaux M, Normal values for random urinary cal- growth compared with those who Kleinknecht C. Primary distal tubular cium to creatinine ratios in infancy. did not have rickets. Earlier studies acidosis in childhood: clinical study and J Pediatr. 1993;123:393–397

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PIR Quiz Quiz also available online at www.pedsinreview.org.

11. A 9-month-old boy presents with a 2-day history of and diarrhea. The mother states that the boy has had 8 to 10 loose stools per day and has been vomiting most of his feedings. shows a dehydrated child who has a rectal temperature of 98°F (36.6°C), respirations of 28 breaths/min, of 140 beats/min, and of 86/58 mm Hg. Mucous membranes and conjunctivae are dry. Skin turgor is diminished, and refill time is 3 seconds. Laboratory examination shows serum sodium, 132 mEq/L (132 mmol/L); potassium, 4.2 mEq/L (4.2 mmol/L); chloride, 104 mEq/L (104 mmol/L); and bicarbonate, 12 mEq/L (12 mmol/L). Capillary blood gas shows a pH of 7.18 and PCO2 of 24 torr. Urine volume is 0.5 mL/kg per hour, and urine pH is 4.5. Which one of the following best explains his acidosis? A. Accumulation of organic . B. Aldosterone deficiency. C. Bicarbonate loss in the distal tubule. D. Bicarbonate loss in the gastrointestinal tract. E. Bicarbonate loss in the .

12. A 10-month-old girl presents with poor feeding, constipation, irritability, and failure to gain weight. Physical examination reveals length at the 10th percentile, weight below the 3rd percentile, respirations of 26 breaths/min, heart rate of 98 beats/min, and blood pressure of 86/54 mm Hg. Muscle mass and subcutaneous fat are diminished. Laboratory findings include serum sodium, 134 mEq/L (134 mmol/L); potassium, 3.1 mEq/L (3.1 mmol/L); chloride, 110 mEq/L (110 mmol/L); and bicarbonate, 12 mEq/L (12 mmol/L). is 4 mg/dL (1.43 mmol/L) and serum creatinine is 0.2 mg/dL (17.7 mcmol/L). Capillary blood gas shows a pH of 7.18 and PCO2 of 24 torr. Urine pH is 7, PCO2 is 5 torr, and specific gravity is 1.004. shows bilateral nephrocalcinosis. Which of the following is the most likely diagnosis? A. . B. Type 1 renal tubular acidosis. C. Type 2 renal tubular acidosis. D. Type 3 renal tubular acidosis. E. Type 4 renal tubular acidosis.

13. An 11-month-old boy presents with poor weight gain. He was born at term via a normal vaginal delivery. Physical examination reveals weight below the 3rd percentile and length at the 10th percentile. There is poor subcutaneous fat over the abdomen and thighs. Urinalysis shows a pH of 6.0 and specific gravity of 1008. Capillary blood gas reveals pH of 7.28, PCO2 of 28 torr, and bicarbonate of 14 mEq/L (14 mmol/L). Which of the following findings is most consistent with the diagnosis of proximal renal tubular acidosis? A. Hyperkalemia. B. Inability to acidify urine pH below 5.5. C. Lack of renal concentrating ability. D. Nephrocalcinosis. ؊ E. Urine blood PCO2 gradient above 20 mm Hg.

14. Which of the following statements regarding distal renal tubular acidosis is true? A. Net renal hydrogen ion excretion is decreased. B. Renal bicarbonate reabsorption is completed at a lower level. C. Renal tubules are less responsive to aldosterone. D. Serum anion gap is increased. E. Urinary pH below 5.5 can be achieved when serum bicarbonate decreases.

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