Kidney International, Vol. 20 (/981), pp.
799—809
Renal tubular acidosis in childhood
Principal discussant: ELISABETH MCSHERRY
LJnirers,tv of California San Francisco, California
The Nephrology Forum is designed to relate the princi-
ples of basic science to clinical problems in nephrology.
Editors
JORDAN J. COHEN
JOHN T. HARRINOTON
JEROME P. KASSIRER
Managing Editor
CHERYI J. ZUSMAN
New England Medical Center
Tufts University School of Medicine
Boston Massachusetts
Case presentation
A female infant, the product ofan uncomplicated full-term pregnancy
in a 26-year-old primipara. was admitted to a local hospital at 26 days of
age because of vomiting. Her weight stabilized at 3.0 kg and a relatively
hyperosinolar formula, Baker's formula5, was prescribed. The baby
continued to vomit, however, and the formula was changed to one
containing evaporated milk. At 2.5 months of age the baby was still
feeding poorly; she was found to be anemic and was given three iron
and vitamin injections. The formula was changed to Enfamil and iron,
which she did not tolerate well.
At age 3 months, I week, she was admitted to another local hospital
because of vomiting and diarrhea. She was severely anemic, acidotic,
and dehydrated, and she was treated with intravenous fluids and
antibiotics. The diarrhea abated after 2 or 3 days, and intravenous
therapy was discontinued after 10 days.
Approximately 12 days after admission, the patient went into shock;
the morning before, serum total carbon dioxide content had been 3.7
mEq/liter. She was treated with bicarbonate and intravenous fluids. In
response to the administration of vasopressin, the urinary specific
gravity failed to increase, and nephrogenic diabetes insipidus" was
diagnosed. A Hickey-Hare test also failed to produce an antidiuresis.
At 4 months of age, hydrochlorothiazide, 5 mg/kg per day, and a low-
sodium diet were prescribed for treatment of nephrogenic diabetes
insipidus. Ten days later she was transferred to the University of
California San Francisco (UCSF) Hospital because the polyuria failed
to respond to therapy.
Physical examination at the time of admission revealed a cachectic,
dwarfed, mildly dehydrated 4-month-old female infant in no acute
distress. Her weight was 3.02 kg (—6 SD), her height was 50 cm (—5
SD), and her head circumference was 37 cm (—2 SD). The mucous
membranes were moist, the skin was doughy feeling, and the fontanelle
was slightly sunken. Deep tendon reflexes were 2+ and equal bilateral-
ly.
Laboratory studies on admission revealed a serum sodium of 141
mEq/liter: potassium, 2.0 mEq/liter; chloride, 77 mEq/liter; and total
carbon dioxide content, 46 mEq/liter. On the following day, serum
sodium was 131 mEq/liter: potassium. 1.5 mEq/liter; chloride. 80 mEq/
799
NEPHROLOGY FORUM
liter; total carbon dioxide content, 48 mEq/liter; and arterial pH. .7l.
Hydrochlorothiazide was discontinued and the child was treated with
potassium chloride. Over the following 2 days, her total carbon dioxide
content fell to 34 mEq/liter. Serum phosphorus and serum calcium were
normal, as were urinary excretion of phosphorus, glucose, and amino
acids. Urine tests for phenylketonuria were negative. An eye examina-
tion revealed no cystine crystals. Radiologic examination of the bones
showed only osteopenia. Urinary cultures on three occasions showed
no growth.
After 6 days of potassium chloride and a low-salt diet, her total
carbon dioxide content had fallen from 34 to 12 mEq/liter, serum
potassium was 3.6 mEq/liter, and the urinary pH was 7.2. A presump-
tive diagnosis of type-I renal tubular acidosis was made, and treatment
with potassium bicarbonate, 2 mEq/kg body weight per day, was
instituted. After 2 days, her total carbon dioxide content rose to 19
mEq/liter. To maintain the total plasma carbon dioxide content at
approximately 23 to 25 mEq/liter and the serum potassium at 3.8 to 4.8
mEq/liter, the following dosage regimen was required: potassium
bicarbonate, 4 mEq/kg/day; sodium bicarbonate, 8 mEq/kg/day; and a
moderately low sodium chloride diet of SMA 26, which provided a
chloride intake of I to 3 mEq/kg/day and a relatively low osmolar load.
After 2 weeks of potassium and alkali replacement therapy and sus-
tained normokalemia. the patient underwent urinary concentration lests
with 2 units of vasopressin (Pitressin) administered intramuscularly.
Urinary osmolality prior to administration of Pitressin5 was 177 mOsm/
kg and fell to 122 mOsm/kg afterward. Urinary osmolalities of 70
mOsm/kg or less were observed repeatedly when free access to ssater
was allowed. It was concluded that the child had no difficulty in urinary
dilution, but at the time her urinary concentrating capacity was restrict-
ed. The pattern of bicarbonate excretion was evaluated on two occa-
sions during sodium bicarbonate infusion over a plasma bicarbonate
range of 15 to 30 mEq/liter. Identical excretion patterns were obtained
on both occasions and demonstrated a 10% to l5% urinary leak of the
filtered load over the entire range of plasma bicarbonate concentration.
At 6 months of age, ingestion of a normal diet including meat for one
week resulted in the reappearance of dehydration; consequently a meat-
free, low-solute diet was reinstituted. During the rest of the hospitaliza-
tion, large quantities of alkali were given, and the infant hsd a
remarkable growth spurt; over a 10-week period (from 4.0 to 6.5 months
of age) her height increased from 50 to 56cm, and her weight rose from
3.0 to 3.85g. She was discharged with three diagnoses: (1) renal tubular
acidosis, infantile renal bicarbonate wasting, type I; (2) polyuria of
chronic potassium depletion; and (3) severe failure to thrive.
The child has been maintained on large doses of alkali, 8 to 12 mEq/
kg/day (50% to 80% as the potassium salt of bicarbonate). She has had
no significant difficulty with polyuria. At her present age of l2 years,
she is 57" tall. By radiologic examination she remains free of nephrccal-
cinosis.
Presentation of the Forum is made possible by grants from Smith
Kline & French Laboratories, CIBA Pharmaceutical Company.
GEIGY Pharmaceuticals, and Boehringer Ingelheim Ltd.
0085-2538/8 l/0020-0799 $02.20
© 1981 by the International Society of Nephrology
800 Nephrologv Forum

Discussion Non-acidosis Acidosis

I Normal
DR. ELISABETH MCSHERRY (Associate Clinical Professor of Plasma subject
bicarbonate —
Pediatrics, University of Califrirnia San Francisco, Cali'ftir- —---24
nia): I plan first to summarize the pathophysiology of renal (mq/L)
tubular acidosis (RTA) [1—28] and then apply this information to
the unusual manifestations of RTA in this patient. Later, I will
classify the major types of RTA into categories, including a new
schema for the five subtypes of type-4 RTA. I will conclude
with a summary of some of our recent experimental findings in
RTA. These include the effects of acidosis on (I) inhibition of
growth; (2) the release of human growth hormone; (3) collagen
metabolism; and (4) the urinary excretion of pseudoephedrine
(Sudafed®).

Normal renal acidification and its assessment Urine pH - 5.5 7.8 6.5 5.5
The proximal convoluted tubule reabsorbs the bulk of the Fig. I. Schematic representation (f the nephron in normals (left) and
filtered bicarbonate and sodium [27, 28]. In the adult, approxi- (rig/it) in patients wii/m nonazoternjc rype—2 RTA at various filtered loads
mately 85% of the filtered bicarbonate is reabsorbed by the of bicarbonate. On the second panel from left: at normal plasma
bicarbonate and filtered loads, the RTA-proximal tubule spills unreab-
proximal convoluted tubule at normal plasma bicarbonate con- sorbed bicarbonate and overwhelms the distal tubule's capacity to
centrations, compared to approximately 65% in the infant. 'l'he reabsorb bicarbonate so mild acidosis (third panel from left) occurs.
remainder of the filtered bicarbonate normally is reabsorbed in Then, the load to the proximal tubule is lower, and less bicarbonate is
the distal tubule, in part by an aldosterone-dependent process. spilled distally. On the right panel, during more profound acidosis the
In the collecting duct, the luminal fluid is essentially free of filtered load of bicarbonate is so small that the proximal tubule's
capacity to reabsorb 85% of it is sufficient, and therefore the distal
bicarbonate and its pH is approximately 6.2. The filtrate is tubule's capacity is no longer overwhelmed by a massive proximal
acidified further in the collecting duct by the establishment of a bicarbonate spill. Since the distal tubule now can completely reabsorb
lumen-peritubular hydrogen ion gradient. Hydrogen ions are its load(15% of that filtered), it presents an intraluminal fluid with a pH
excreted with two major buffers: ammonia, a freely diffusible of 6.2 to the collecting duct, so a normally low urinary pH is generated.
gas, is trapped in the lumen as ammonium ions; and phosphate
buffers are titrated to their hydrogen-rich form. Buffered phos-
phate makes up the major part of titratable acid in the urine. normal plasma bicarbonate concentration never exceeds 15% in
adults or 25% in infants.
Proximal bicarbonate reabsorption
Reabsorption of bicarbonate in the proximal tubule is Distal bicarbonate reabsorption and acidification
achieved by a hydrogen secretory process that is regulated by The distal nephron, especially the cortical collecting tubules,
several factors: carbonic anhydrase activity, extracellular vol- reahsorbs sodium in part by an aldosterone-dependent process.
ume, carbon dioxide tension, and body potassium stores. A fall Secretion of hydrogen and potassium ions also may be under
in extracellular volume or body potassium, or a rise in PCO2 direct, as well as indirect, aldosterone control. Thus, aldoster-
increases proximal tubular reabsorption of bicarbonate; a rise in one deficiency or renal tubular resistance to aldosterone would
extracellular volume or body potassium, or a fall in PCO2 be expected to result in inappropriate urinary bicarbonate
inhibits proximal bicarbonate reabsorption. In certain circum- excretion, at least at normal plasma bicarbonate concentra-
stances, other factors such as parathyroid hormone, serum tions. In addition, hyperkalemia, consequent to the aldosterone
calcium, and serum phosphorus also affect proximal tubular deficiency, also affects renal acidification by impairing the renal
bicarbonate reabsorption. For example, in normal persons, synthesis of ammonia, thereby reducing net acid excretion in
acute infusions of parathyroid hormone can increase urinary the distal tubule and collecting duct [28J.
losses of bicarbonate; in patients with Fanconi's syndrome and "Distalmost" tubular acidifying ability is assessed by the
defective proximal bicarbonate reabsorption, inhibition of para- measurement of pH, ammonia, and titratable acid during spon-
thyroid hormone by an infusion of sufficient calcium to maintain taneous acidosis or ammonium chloride-induced acidosis. If
normocalcemia ameliorates the proximal acidification defect urinary pH does not fall to or below 5.5, and if ammonia and
[29]. titratable acid excretion do not increase to at least 35 Eq/min/
One can indirectly assess acidification in the proximal tubule 1.73M2 and 25 pEq/min!1.73M2, respectively, defective acidifi-
by measuring urinary bicarbonate excretion when plasma bicar- cation by the distal collecting duct is probably present.
bonate is stable at a normal or slightly reduced level. Under To summarize, normal renal acidification occurs if (I) the
these conditions, if there is a proximal tubular defect, bicarbon- proximal tubule reabsorhs an appropriate amount of filtered
ate escapes reabsorption and spills into the urine (see Fig. I): a bicarbonate; (2) sufficient aldosterone is available, and the
fractional bicarbonate excretion greater than 15% in the adult or distal tubule responds to it; (3) the collecting tubule's intrinsic
greater than 25% in the child suggests a defect in proximal capacity to secrete hydrogen ions against a steep gradient is
tubular acidification, In contrast, if there is an isolated distal intact and is not overwhelmed by excessive amounts of bicar-
tubular defect, less bicarbonate escapes into the urine: in bonate that escape proximal reabsorption; (4) adequate
patients with distal RTA, fractional bicarbonate excretion at a amounts of sodium and urinary buffer are available to maintain
 Renal tubular acidosis in childhood 801

hydrogen ion secretion; and (5) ammoniagenesis is not im- more, were required to sustain correction of acidosis; and (2) at
paired. the same time, the urinary pH rose rapidly to 7.8 or higher.
This patient illustrates that in children with profound renal
bicarbonate wasting, ammonium chloride loading is unneces-
Clinical case discussion sary (and potentially harmful) because profound acidosis can
Before discussing RTA in general, I would like to discuss the occur rapidly when alkali therapy is withheld. Alkali therapy
infant presented today. The first notable finding in this patient was given to match the estimated maintenance requirement of
was failure to thrive. From the age of I month she was 10 mEq/kg/day in this patient. This requirement was estimated
hospitalized several times with an erroneous diagnosis of "milk assuming a value for endogenous acid production in growing
intolerance," and treatment consisted only of many formula children of 2 to 3 mEq/kg/day and from the measured renal
changes. More than 4 months passed before the diagnosis of bicarbonate wasting of 5 to 7 mEq/kg/day. Serum calcium,
renal tubular acidosis was made. In retrospect, most of the phosphorus, and magnesium also were monitored carefully
characteristic physical signs and symptoms of RTA were pres- during alkali therapy.
ent long before. These included: (I) stunted height and weight With sustained correction of acidosis, the infant grew at
( 2.5 SD below the mean for age- and sex-matched normals); threefold her prior rate, and for a few months her growth was
(2) proximal muscle wasting and muscle weakness; (3) listless- equivalent to a rate of 60 cm/year! Her color returned to a
ness; (4) anorexia, vomiting, constipation, and dehydration: (5) healthy pink; anorexia, vomiting, and constipation disappeared;
gray pallor and superficial venospasm during phlebotomy; and and her muscle mass, tone, and strength improved. Within 6
(6) polyuria. Although many of these physical findings also months, she was of average size and seemed normal in all other
occur in infants with nephrogenic diabetes insipidus, the bio- ways as well.
chemical findings in this latter disorder are quite different. A
vasopressin test was found to be abnormal in this patient, but Classification of R TA
careful examination of blood electrolytes, blood gases, and Renal tubular acidosis is a biochemical syndrome character-
urinary pH was not carried out. As a result, nephrogenie ized by minimal or absent azotemia and hyperchloremic acido-
diabetes insipidus was erroneously diagnosed and chlorothia- sis.
zide was prescribed.
The patient was referred to UCSF after one week of thiazide Type-I renal tubular acidosis ("classic," 'distal," "RTA-l ")
therapy. On admission she had an elevated plasma bicarbonate, Prototypic type-I RTA is the only type of RTA in which
was severely alkalemic, and was approximately 5% to 10% urinary pH is high at all times (usually > 6.2), even du:ring
dehydrated. Chlorothiazide was discontinued and therapy with severe metabolic acidosis [1—li]. Failure to thrive is the most
potassium chloride was started. Within 6 days, the plasma common presentation in infants and children [1—22]. In older
bicarbonate fell to 12 mEq/liter, the serum potassium was 3.6 children, renal stones and nephrocalcinosis occur as well.
mEq/liter, and the simultaneous urinary pH was 7.2; during this Type-I RTA presents as a metabolic emergency in less than
period the child remained profoundly ill. 25% of patients; manifestations include acute hypokalemic
Renal tubular acidosis with renal bicarbonate wasting was paralysis, metabolic coma, or shock and, in extreme instances,
suspected during the patient's first week of hospitalization at death [22]. In infants and children with type-I RTA, minimal
UCSF. Renal bicarbonate wasting is defined as a urinary urinary pH often exceeds 6.5, and bicarbonaturia persists even
excretion of greater than 3 mEq of bicarbonate per kg body during profound systemic acidosis. The magnitude and persis-
weight per day at any time when the plasma bicarbonate level is tence of the bicarbonaturia (3—12 mEq/kg/24 hours) can result in
normal or below. I should add that although renal bicarbonate life-threatening acidosis (bicarbonate 3 mEq/liter) if treat-
wasting is rare in adults with type-I ("classic," "distal") RTA, ment is not given [13—22]. The magnitude of the renal bicarbon-
it is characteristic in infants and children with this disorder [12— ate wasting is the major determinant of the amount of alkali
17, 20—22]. therapy required to correct systemic acidosis in children with
What were the clues that renal bicarbonate wasting was type-I RTA; the alkali dose required is calculated, as described
present in this infant? First, the rapid onset of profound and above, by adding the measured urinary bicarbonate excretion to
progressive acidosis in less than one week (as potassium was the estimated endogenous production of nonvolatile acid (Table
replenished) strongly suggested renal bicarbonate wasting. In I).
patients with renal tubular acidosis and bicarbonate wasting. In contrast to the importance of renal bicarbonate wasting in
acidosis occurs rapidly when alkali is withheld, and loading children, endogenous production of acid ( 1 mEq/kg/day) is
with ammonium chloride rarely is required to make the diagno- the major determinant of therapy in virtually all adults with
sis. Second, a urinary pH consistently greater than 7 despite type-l RTA. Sebastian et al at UCSF, however, have studied 2
appreciable hypobicarbonatemia (bicarbonate, 12 mEq/liter), adults with hereditary type-I RTA with renal bicarbonate
suggested that abnormally large amounts of bicarbonate were wasting similar to that in children (unpublished observations).
being excreted in the urine. Third, urinary bicarbonate wasting In infants and children, type-I RTA usually is inherited as a
was 3% to 10% of the filtered load, measured when the plasma Mendelian dominant trait, sometimes occurring in association
bicarbonate concentration was 12 mEq/liter. with other diseases such as elliptocytosis and the Ehlers-Darilos
Two additional clues suggested renal bicarbonate wasting syndrome, but occasionally appearing spontaneously (Table 2).
during the subsequent sustained correction of acidosis with In the past, stunted growth has been a characteristic finding in
alkali therapy: (I) large amounts of alkali, 5 mEq/kg/day or infants and children with type-I RTA and chronic acidosis. But
802 Nephrology Forum

Table I. Determinants of alkali therapy in RTA Table 3. Causes of type-2 RTA ("proximal")
Magnitude of acid input I. With Fanconi's syndrome
I. Normal net acid production A. As inborn error of metabolism (Mendelian recessive)
Adults: 0.5—1.5 mEq/kg/day Cystinosis HFI (receiving fructose)
Children: 1—3 mEq/kg/day Lowe's syndrome Galactosemia (receiving galactose
2. Increased net acid production Tyrosinosis Pyruvate carboxylase deficiency
Increased bone mineralization (with B. As metabolic consequence
rapid growth and/or remineralization) Chronic hypocalcemia and secondary hyperparathyroidism
Gastrointestinal losses of alkali Sprue Nutritional vit. D deficiency (stage 3, 4)
Magnitude of acid/alkali excreted Gut-bypass Vitamin D dependency syndromes
1. Urinary excretion of ammonium and titratable acid Drug or toxin-induced
2. Urinary loss of bicarbonate Lead
Streptozotocin
Outdated tetracycline
Diacromone
Table 2. Causes of type-I RTA ("distal') Rubella syndrome
C. After renal injury
Isolated primary_defect Medullary cystic disease
Mendelian dominant heredity Nephrotic syndrome
Spontaneous Postrcnal transplant
Associated with other disorders Multiple myeloma
Autoimmune II. As isolated proximal tubule defect of bicarbonate reabsorption
Sjogren's syndrome Carbonic anhydrase deficiency
Lupoid hepatitis Secondary to drugs
Diamox
Systemic lupus erythematosus
Genetically transmitted diseases Sulfanilamide
Sickle cell anemia Genetically transmitted (Russell)
Elliptocytosis Idiopathic (Donkerwolke)
Carbonic anhydrase-B deficiency Idiopathic
Ehlers—Danlos syndrome York-Yendt
Marf'an's syndrome Transient (infants)
Other renal diseases
Renal transplantation
Obstructive uropathy
Pyelonephritis thy, polyuria, and listlessness [22]. Sodium bicarbonate is the
Postrubella preferred choice of alkali; it is inexpensive, easy to prepare, and
Disorders causing riephrocalcinosis directly usable in the body without being metabolized by the
Idiopathic hypercalciuria (genetic or sporadic) liver. For children less than 4 years old, alkali is formulated as a
Primary hyperparathyroidism
Medullary sponge kidney
1 mEq/ml solution: an 8-oz box of Arm and Hammer® baking
Wilson's disease soda is dissolved in 2.88 liters of distilled water. The solution is
Hyperthyroidism administered either undiluted or mixed with a small amount of
Drug or toxin-induced nephropathy milk or formula. If alkali is mixed with certain dehydrated
Amphotericin B
Lithium "juice crystals," such as Tang®, alkali potency per mixed dose
Cyclamates appears to fall by at least 40% (unpublished observations). The
Analgesics mechanism for this phenomenon has not been delineated.
Type-2 renal tubular acidosis ("proximal," "RTA-2")
we now know that ifacidosis is corrected for a sustained period, Type-2 RTA is characterized by a defect in proximal bicar-
such children can attain normal stature. In 1978, we reported bonate reabsorption. Typically, manifestations of Fanconi's
that 10 children with type-I RTA attained normal stature when syndrome coexist, including reduced proximal tubular reab-
correction of acidosis was sustained by treatment with high- sorption of amino acids, phosphate, calcium, glucose, urate,
dose alkali therapy (5—15 mEq/kg/day). The study included 6 lysozyme, light-chain immunoglobulins, and citrate. In chil-
children whose heights were more than 2.5 SD below the mean dren, type-2 RTA leads to rickets, delayed bone maturation,
for age- and sex-matched controls [12, 13, 20, 21]. It is and stunted growth [22, 27, 28]. In untreated patients with type-
interesting that if acidosis is only partially corrected by using no 2 RTA, urinary pH is 6.0 or less; during sustained correction of
more than 3 mEq of bicarbonate/kg/day, nephrocalcinosis oc- acidosis, urinary pH rises due to marked bicarbonaturia, which
curs by the time the patient is 4 years of age [9, II, 15, 16, 20, often exceeds 15% to 20% of the filtered load. As discussed
30]. In our experience, however, none of 7 children with type-I earlier, this degree of bicarbonaturia indicates that an acidifica-
RTA treated from infancy with high-dose alkali therapy has tion defect of the proximal nephron exists (see Fig. I).
developed nephrocalcinosis during a 10- to 20-year follow-up Type-2 RTA with Fanconi's syndrome occurs as a permanent
period [20, 30]. Hence, conscientious maintenance of normal condition in association with several disorders of Mendelian
plasma bicarbonate and serum potassium levels confers long- recessive inheritance including cystinosis, Lowe's syndrome,
term advantages on the child with type-l RTA. tyrosinosis, and fructose and galactose intolerances (when the
Other benefits that accrue from adequate treatment of acido- offending sugar is eaten). It also occurs with medullary cystic
sis include resolution of hypokalemia, proximal muscle myopa- disease and with idiopathic complete and partial Fanconi syn-
 Renal tubular neidosis in childhood
Table 4. Pathophysiologic subtypes of type-4 RTA
Subtype
Number Mechanism and designation
Aldosterone deficiency without intrinsic renal disease
I) Primary mineralocorticoid deficiency
(Addison's; congenital adrenal hyperplasia;
isolated hypoaldosteronism)
Aldosterone deficiency with chronic hyporeninemia
2) Primary hyporeninemic secondary hypoaldosteronism
of azotemic adults (diabetes, gout, pyelonephritis
interstitial ne huitw, nephrosclerosis)
3) Adolescent hyperkalemic syndrome ('!Cl-shunt)
Reduced tubular responsiveness to aldosterone
4) Pseudohypoaldosteronism
5) "Early childhood" type-4 RTA
a
BP refers to blood pressure.
NI refers to normal.
dromes. Type-2 RTA sometimes appears transiently after viral
or toxic renal injuries and with long-term vitamin D deficiency
(Table 3). One group has reported that type-2 RTA occurs as a
transient syndrome in infants and young children without
evidence of any other proximal tubular dysfunction [5]. In some
of these patients, fractional bicarbonate excretion was not
sufficiently high to ensure a defect of the proximal nephron
(i.e., <25%), and serum potassium concentrations were consis-
tently high during spontaneous acidosis. The possibility thus
exists that this transient infantile disorder, "pure proximal
type-2 RTA," may represent a variant of subtype 5 of type-4
RTA (see below).
In nonazotemic patients with type-2 RTA, maintenance of
normal levels of serum bicarbonate proves difficult even with
massive doses of alkali because of the equally massive hicar-
bonaturia. Despite alkali therapy, extracellular volume deple-
tion is common and, as a consequence, sustained secondary
hyperaldosteronism is characteristic 127, 28]. Potassium excre-
tion is increased by two phenomena: (I) increased aldosterone
stimulates distal potassium secretion; and (2) bicarbonate,
overflowing from the proximal tubule, acts as a poorly reab-
sorbable anion in the distal tubule, causing an obligate loss of
potassium. For these reasons, at least one-half of the alkali
usually required to sustain correction of acidosis (10 to 25 mEq/
kg/day) should be administered with potassium. In some pa-
tients, such large doses of alkali are poorly tolerated by the
gastrointestinal tract. Dietary salt restriction and chiorothiazide
therapy can be useful adjuncts in patients with severe renal
bicarbonate losses; within several days this regimen inhibits
renal bicarbonate excretion. Potassium supplements always are
required to sustain normokalemia in children with nonazotemic
type-2 RTA. Hypophosphatemia and rickets are effectively
treated with a combination of large doses of dihydrotachysterol
or vitamin D analogs [31, 32] and neutral isotonic sodium
phosphate solution [33, 34].
Type-3 renal tubular acidosis
In 1972 an allegedly new syndrome in infants was designated
type-3 RTA. It was characterized by a high urinary pH (> 6.9)
despite severe acidosis (implicating a defect in the distalmost
803
Clinical finding
Plasma
renin Urinary Blood/ Salt
activity aldosterone plasma BPa volume wasting
1'
1-
11 11
Not Not NP' Low NI
nephron) and by massive bicarbonaturia at all levels of plasma
bicarbonate concentration. As I discussed earlier, we now
know that all infants and children with type-i RTA have
considerable bicarbonaturia. In these patients, massive bicar-
bonate wasting subsides after adolescence or after rapid growth
spurts, but the distalmost acidification defect of classic type-I
RTA does not. Since type-3 RTA is simply the infant and
childhood manifestation of hereditary type-I RTA, most neph-
rologists classify it as the predictable pediatric variant of type-I
RTA rather than as a separate type.
Type-4 renal tubular acidosis
Type-4 RTA, the most common type of RTA in children and
adults, is characterized by hyperchloremic acidosis, hyperkale-
mia, and an acid urinary pH (during acidosis) [22, 35—55].
Currently, it is possible to distinguish five pathophysiologic
subtypes of type-4 RTA; such distinctions provide some useful
insights into the causes of the disorder (Table 4). Subtypes I
and 2 result from a primary hormonal deficiency of renin/
aldosterone and consequent understimulation of the aldoster-
one-sensitive sites in the distal convoluted tubule (Table 2);
subtypes 3 through 5 result from primary renal tubular disor-
ders.
Subtype 1, characterized by decreased urinary aldosterone
levels, increased plasma renin activity, and salt wasting, is
observed in association with Addison's disease, isolated pri-
mary hypoaldosteronism, or congenital adrenal hyperplasia.
The decrease in aldosterone secretion results in acidosis, hyper-
kalemia, and renal sodium chloride wasting.
Subtype 2, also known as hyporeninemic hypoaldosteronism.
and 'type-4 RTA in azotemic adults," is characterized by an
impairment of renal renin production caused by chronic intersti-
tial damage. As a consequence, aldosterone secretion falls and
the circulating aldosterone level is low. Hyperchloremic acido-
sis and hyperkalemia ensue but clinical salt wasting does not
occur, perhaps because of the concomitant azotemia.
Subtype 3 ("adolescent hyperkalemic syndrome." or "renal
chloride shunt") is characterized by hypertension, hypervole-
mia, and hypoaldosteronism [22, 35, 36, 48—531. In this cyn-
drome, for unknown reasons, excessive chloride reabsorption
804 Nephrology Forum

in the distal convoluted tubule apparently leads to hypervole- dispose to renal stone formation. In the urine, citrate complexes
mia and secondary suppression of aldosterone secretion [531. with calcium and increases its solubility, thereby decreasing
Chlorothiazide corrected the hyperkalemia and acidosis in 7 of stone formation. Citrate also inhibits crystal formation and
13 pediatric patients with this syndrome [22, 38, 39, 48—53]. growth in the urine. Presumably during chronic acidosis the
Dietary sodium chloride restriction also corrected the hyperka- mobilization of bone buffers is increased, and in children with
lemia and acidosis [22, 38, 39, 48—53]. type-I and -2 RTA, urinary calcium excretion rises during
Subtype 4 (pseudohypoaldosteronism), characterized by so- acidosis [56—62]. In children with subtype 5 of type-4 RTA,
dium chloride wasting, acidosis, hyperkalemia, and an elevated however, no rise in urinary calcium excretion during chronic
24-hour urinary aldosterone excretion, occurs in infants only acidosis is found; thus, one might suspect that a relative
[54, 55]. It is thought to he due to distal tubular unresponsive- "hyperreabsorption" of calcium is present [35—391. In patients
ness to circulating aldosterone, i.e., an end-organ thilure. This with type-I RTA, all filtered citrate is reabsorbed during
syndrome seemed more prevalent in the past; recently it has acidosis because of the increased metabolic needs. in type-2
been reported only in Belgium (Proesmans W, personal commu- RTA, because of the associated proximal tubular defect, citrate
nication). The defect is transient and disappears after age 2 cannot be fully reabsorbed despite acidosis, and urinary citrate
years if the infant is adequately treated with sodium bicarbonate excretion is high. A similar increase in urinary citrate excretion
and sodium chloride. occurs in subtype 5 of type-4 RTA. Thus, in untreated, chroni-
Subtype 5 ( early childhood" type-4 RTA) is characterized cally acidotic patients with subtype 5 of type-4 RTA, nephrocal-
by hyperchloremic acidosis, hyperkalemia, and aciduria. Clini- cinosis probably does not occur because of calcium hyperreab-
cal salt wasting does not occur and no azotemia or hypertension sorption as well as the persistence of elevated urinary citrate
is present. Unlike subtype 4, this subtype is thought to be due to excretion.
end-organ resistance to only two of the three aldosterone- Before we conclude our review of childhood RTA, I would
dependent functions of the distal tubule: potassium and hydro- like to discuss briefly some of our recent studies on the long-
gen secretion are reduced, but sodium is reabsorbed normally. term effects of renal tubular acidosis.
This is the most common subtype of type-4 RTA and is found
with equal frequency in males and females; occasionally, sever- A /0-year study of radiologic findings
al siblings are affected [22, 35—381. Characteristically, infants A decade of radiographic findings in 92 patients with types-I.
and young children with this subtype are short or stunted, vomit -2 or -4 RTA (56 children and 36 adults) shows that bone disease
frequently, and fail to thrive. is rare in nonazotemic patients with RTA, and then only in
Alkali therapy (4 to 20 mEq/kg/day of sodium bicarbonate) patients with type-2 RTA [63]. Nephrocalcinosis was radiologi-
entirely corrected the abnormalities in 13 children. Plasma cally demonstrable only in patients with type-l RTA but not in
bicarbonate concentration became normal, and serum potassi- children with type-I RTA who received "high-dose" alkali
um fell to 4.8 mEq/liter; growth accelerated and normal therapy since infancy [22, 29, 30, 35, 36]; thus, acidosis and
height was achieved within 6 months of initiating adequate subsequent decreased urinary citrate probably are predisposing
alkali therapy [35—39]. Interestingly, after about 5 years of age, factors for nephrocalcinosis in type-I RTA [63].
alkali therapy was no longer needed. It is not known why
children with both subtype 4 and subtype 5 outgrow their Secondary effrcts of acidosis on growl/i and human growth
clinical manifestations. One can postulate that their initial Iwiiao ne
disorder represents an abnormal number or conformation of the Recent findings indicate that hyperchloremic acidosis alone
aldosterone receptors, possibly due to the short distal nephrons causes reversible, severe short stature and even stunting (height
characteristic of infants. 2.5 SD). in 10 children with nonazotemic type-l RTA,
Patients with subtype 5 provide a unique opportunity to study acidosis caused short stature that was reversed when acidosis
the pathophysiologic characteristics of the type-4 RTA hydro- was corrected with high doses of alkali [12, 13, 21]. Also, in 13
gen ion transport defect in a relatively pristine state: the patient children with subtype 5 of type-4 RTA, short stature (mean
is free from the secondary effects of azotemia, clinical salt —2.4 SD) was corrected in 6 months with high-dose alkali
wasting, and the major hormonal imbalance of subtypes I therapy [35—37, 64]. Because of these findings, we studied the
through 4 [22, 35—381. We found that renal bicarbonate wasting isolated effect of acidosis and its correction by alkali therapy on
occurred during sustained correction of acidosis with high-dose hormonal and metabolic factors related to growth.
alkali therapy in each of 13 children despite consistently normal Human growth hormone (HGH) release was stimulated with
or high values of both plasma renin and 24-hour urinary arginine and L-dopa infusion in 11 children with type-I RTA
aldosterone excretion. Further, in marked contrast to patients and in 4 children with subtype S of type-4 RTA 165]. During
with type-2 RTA, in whom bicarbonaturia is associated with a chronic acidosis (> 6 months, n = 7) and during acute,
marked increase in kaliuria, bicarbonaturia is not associated experimentally induced acidosis (3 to 6 days, n = 15), peak
with significant kaliuria (CK/Clfl 16%) in patients with sub- HGH release was blunted (< 8 ng/ml prepubertal, < 12 ng/ml
type 5 of type-4 RTA. This observation supports the hypothesis pubertal). Conversely, in individual paired studies, HGH re-
that distal tubular potassium secretion as well as hydrogen lease was normal following chronic (n = 15) or acute (n = 7)
secretion is defective in children with this subtype. correction of acidosis [65].
Two factors that affect renal stone formation in patients with The results demonstrate that acidosis reduces peak HGH
subtype 5 of type-4 RTA are worth noting: urinary calcium and release after standard stimulation tests in nonazotemic children
citrate excretion, As is widely known, both increased urinary with types-I or -4 RTA and in normal children [65, 66]. The
calcium excretion and decreased urinary citrate excretion pre- study further suggests that plasma bicarbonate is a critical
 Renal tubular cu idosis in childhood 805

Intracellular
al of alkali therapy for 4 days, LU increased fourfold; LU
activity then fell to unmeasurable levels within 24 hours of
Kription institution of fully corrective alkali therapy [69]. This study
Extracellular
2. Hydroxylatron
1 provided the first demonstration that acidosis directly affects
collagen metabolism.
Pseudoephedrine (Sudafed) excretion
Pseudoephedrine is a decongestant used commonly in the
3.GlycosyIation pediatric population. The administration of pseudoephedrine
4. Procollagen proteolysis
for chronic otitis for 6 weeks in a 6-year-old girl with type-I
5. Oxidative deamination RTA produced a weight loss of 6 pounds, an amphetamine-like
psychosis, and greatly elevated pseudoephedrine blood levels.
Lysyl oxidase We postulated that the drug accumulated because her persist-
ently alkaline urinary pH favored the renal tubular reabsorption
6. Crosslinking of pseudoephedrine, which is a weak base (PKa = 9.4) [64, 71,
72]. The renal determinants of the urinary elimination of
7. Crosslink maturation pseudoephedrine were assessed in 15 studies in 8 subjects: 3
normal adults, 3 normal children, and one adult and one child
each with type-I RTA. The pseudoephedrine (5 mg/kg) was
Fiber
administered orally; blood and urinary levels were measured
LysI oxidase formation serially. Urinary pH was controlled at various levels by the
) &
administration of sodium bicarbonate or ammonium chloride.
crosslinking In all studies, 45% of the administered pseudoephedrine close
CHO
was excreted unaltered, and 6% 1.0% as norpseudofed.
Crosslin
Elimination half-life correlated significantly and directly with
Aldehyde the urinary pH [72]. Another factor determining pseudoephed-
crosslink
precursor
rine excretion in an alkaline urine was urine flow rate [72].
Acid-soluble
collagen \atrion These findings suggest that the elimination of pseudoephedrine
Insoluble
and its metabolite norpseudofed are importantly determined by
r.nllatien both urinary pH and urine flow rate in humans [72].
Fig. 2. Collagen synthesis: A schema (f the major steps (A) and the Questions and answers
final extraiellular enzy,na(ic step (B). The major part of the synthesis of
the collagen molecule is intracellular (A), but the critical final enzymatic DR. JOHN T. HARRINOTON: Could you tell us what the
step that ensures normal strength and structural stability, through an precise pathophysiologic mechanism is for the renal bicarbon-
adequate cross-linkage of the collagen molecule, occurs extracellularly ate wasting in children and infants with type-l, i.e., distal,
(B) with the enzyme lysyl oxidase. The plasma activity of this collagen RTA?
synthetic enzyme, lysyl oxidase, is increased several fold during DR. MCSHERRY: Unfortunately, we don't really know the
hyperchloremic acidosis.
precise proportion of bicarbonate reabsorption in proximal and
distal tubules in rapidly growing human infants and in children
of different ages. The GFR in normal infants (on a surface area
determinant of HGH release in children undergoing standard basis) is only about 50% that of older children and adults. One
HGH stimulation tests [65, 66]. of the speculations is that there is glomerular-tubular imbalance
for bicarbonate reabsorption during early infant development.
Secondary eJfrcts of acidosis on collagen synthesis Ultimately, we are trying to account for the bicarbonate-
The synthesis of collagen has seven major enzymatic steps, wasting phenomenon that occurs in children with type-I RTA
the last of which is catalyzed by the extracellular enzyme lysyl when their growth is two to three times normal, but which Ihen
oxidase (LU) after the partially completed collagen molecule is disappears when their growth rate returns to normal. We
extruded from the fibroblast (see Fig. 2). In rats with experi- frequently observed children with type-I RTA who, with con-
mental hepatic fibrosis, and in chicks with vitamin D deficiency tinued high-dose alkali, grow very rapidly in the first two years
(a syndrome in which acidosis and growth retardation are of life, and then after they attain normal size, lose their renal
chacacteristic), plasma LU activity is elevated. In 10 children bicarbonate wasting. Another natural growth rate peak occurs
(ages 6 months to 18 years: 7 with type-I RTA, 3 with type-4 during normal adolescence, when the growth rate increases to
RTA), mean plasma LU activity was elevated eight- to tenfold about 13 cm/year. We are anxious to see whether renal bicar-
during acidosis. After correction of acidosis with alkali therapy, bonate wasting returns at that time in these now normal-sized
the LU level immediately fell to normal [67—70]. In steady states children with type-l RTA in whom correction of acidosis has
of at least one week duration, plasma LU activity correlated been chronically sustained with alkali therapy.
inversely with plasma bicarbonate concentration over the range DR. HARRINOTON: Have you analyzed bone biopsy speci-
of 15 to 23 mEq/liter (15 studies of 10 patients) [69, 701. In a 3- mens in your patients? I am specifically interested in bone
year-old child with type-4 RTA (subtype 5), activity of LU was carbonate levels.
measurable and was mildly but not markedly increased during DR. MCSHERRY: No, we have not done such studies in these
chronic, partially treated acidosis. But with complete withdraw- children.
806 IVephroioj,'y Ior,ui

DR. JORDAN J. COHEN: It is well recognized, as you pointed DR. MCSHERRY: We don't see conversion of type-I to type-4
out, that the status of extracellular volume exerts an important
RTA (or hyperkalemic, bicarbonate-wasting syndromes) in
influence on proximal bicarbonate reabsorption. '['his prompts these children. However, the time course of renal bicarbonate
me to ask two somewhat related questions. First, how much, if wasting itself is a fascinating phenomenon in children with type-
any, of the bicarbonate wasting you observed during treatment I RTA. In infants growing as fast as 44 cm/year, major changes
with large bicarbonate loads can he ascribed to the associated take place in a few days that can take a year or so to occur in an
expansion in extracellular fluid volume? Second, the practical older child or adult. We have seen children who did not waste
definition of bicarbonate wasting that you use, namely, the bicarbonate when first treated (growing slowly), in whom larger
excretion of 3 mEq/kg/day, must bear some relation to the amounts of alkali therapy were required as time passed and
status of extracellular fluid volume. Does this value differ whose growth rate increased. The time frame in children is
significantly in accordance with the degree of volume expansion much different, however, than in adults. Many children, initial-
induced by the bicarbonate titration protocol employed? ly well controlled on a low dose of alkali, need twice the dose of
DR. MCSHERRY: First, renal bicarbonate wasting occurs in alkali to maintain normal plasma bicarbonate concentration in 6
our children with type-I RTA, even when plasma bicarbonate is weeks or 2 months. Bicarbonate wasting continues in these
slightly or severely subnormal and even when no alkali therapy children until normal height is reached; then it abruptly stops.
is being given. Second, we have measured plasma volume in In children this usually occurs 2 to 3 years after initiation of
several of these patients receiving alkali therapy, and plasma therapy. As I just mentioned, we haven't watched enough
volume never increases beyond normal limits despite the large patients long enough to know whether bicarbonate wasting will
doses of alkali administration. Third. despite the continuous return during normal rapid growth in adolescence, If renal
high-dose alkali in these children, plasma aldosterone levels bicarbonate wasting does return, I would anticipate that it might
tend to remain elevated or normal and plasma renins also stop after the adolescent growth rate falls from 15 cm/year to
remain either high or normal. Therefore, we don't believe there zero.
is any evidence to support the possibility that these large doses DR. KASSIRER: Why do these children still have hyperaldo-
of alkali are suppressing proximal bicarbonate reabsorption and steronism if they are receiving adequate quantities of sodium
inducing iatrogenic bicarbonate wasting by volume expansion. and alkali and are excreting it?
In contrast to our findings in children with type-I RTA, studies DR. MCSHERRY: Most of our children with type-I RTA on
show that when 10 mEq/kg/day of alkali is given to an otherwise chronic high-dose alkali have normal or only slightly elevated
normal human, plasma renin activity and 24-hour urinary levels of renin and aldosterone. We have 2 children (one of
aldosterone excretion are suppressed completely; the suppres- them, the patient presented) who, despite large doses of alkali,
sion occurs immediately and persists as long as the alkali load is continue to have very high aldosterone and renin levels for
continued. reasons not fully understood.
Your second question was why do we define renal bicarbon- DR. KASSIRER: Does renal sodium wasting explain it?
ate wasting as greater than or equal to 3 mEq/kg/day? Winters DR. MCSHERRY: No. We have done sodium balance studies
and Kildeherg found in rapidly growing premature infants that in these patients using potassium bicarbonate as the only source
the maximum rate of endogenous acid production was 3 mEq/ of alkali. 'l'he patients can conserve sodium normally (< 2 mEq/
kg/day. In children, this was due in large part to the rapid laying day excretion in the urine) when dietary sodium intake is
down of new bone. Thus in growing children with RTA, only severely curtailed (' 10 mEq/day). We questioned whether we
when bicarbonaturia exceeds the upper limit of normal endoge- were chronically stimulating aldosterone secretion by continu-
nous acid production (3 mEq/kg/day) does it become the major ously administering potassium to these 2 hyperreninemic chil-
determinant of alkali therapy and thereby qualify for the term dren with type-I RTA who also have recurrent hypokalemia.
"bicarbonate wasting." We therefore have continued to attempt to withdraw potassium
DR. JEROME P. KASSIRER: Do you think that conversion of supplements hut have not been able to do so without causing
type-I to type-4 RTA may be an iatrogenic artifact in some persistent hypokalemia. We have one adult with hereditary
instances? 1 am proposing that chronic ingestion of large type-I renal tubular acidosis—the only bicarbonate wasting
quantities of sodium bicarbonate could expand extracellular adult we have—who maintains a potassium ot' 1.7 mEq/liter
volume and suppress renin and aldosterone. This phenomenon without potassium supplements. Because of the severe hypoka-
is known to occur in normals [73], and it probably occurred in a lemia we have never been able to withdraw her from potassium
patient I have been following for more than 20 years. When I therapy. This adult and our two children with type-I RTA (and
first saw this woman, she had classic type-I R'I'A, and she persistent potassium wasting and hyperaldosteronism) had their
required only modest quantities of alkali to maintain normal disorders for a very long time before adequate alkali therapy
acid-base equilibrium. Some years later her bicarbonate re- was started. We don't know whether the long duration of
quirement increased, and with large alkali supplements, plasma acidosis and volume depletion allowed these patients to develop
bicarbonate remained slightly below normal. Later, without an some sort of secondary autonomous hyperaldosteronism.
alteration in renal function, she became hyperkalemic, and mild DR. HARRTNOTON: You nientioned that despite bicarbonate
hyperkalemia persisted even after we discontinued her potassi- loading and induction of bicarhonaturia in your patients with
um supplements. The discovery that she had a suppressed subtype 5 of type-4 RTA. there was no increase in urinary
plasma aldosterone level at that time seemed to explain the potassium excretion. First, were the serum potassium levels
gradual conversion to a bicarbonate-wasting state. Have you elevated in these patients? Second, what is your speculation as
seen this sequence in children? to why there was no increase in potassium excretion? I would
 Reruil tubular (aithrsis in chi/rilioud 807

have suspected that an increase in distal bicarbonate delivery corrected with sodium bicarbonate. Drs. Portale, Booth, Tsai,
might have caused an increase in urinary potassium excretion. and Morris are investigating the effect of vitamin D metabolites
DR. MCSHERRY: In regard to your first question, serum in children with moderate chronic renal failure, but that work is
potassium levels do come down following the administration of preliminary 1741. With vitamin D deficiency alone, an acidosis
high-dose alkali therapy over a long period. During acute develops that reverses with repletion of vitamin [). The changes
bicarbonate infusion studies in these patients, fractional urinary in acid-base status induced by the vitamin D metabolites alone
potassium excretion does not increase over the range of low to cause problems in the interpretations of studies of growth in
normal plasma bicarbonate concentrations but remains low, azotemia. Nevertheless, these studies on vitamin D are the one
about 16%. Why urinary potassium excretion does not increase area in which growth during azotemic acidosis is currently
during chronic alkali therapy in these patients is not well being investigated.
known. The blood volume increases from low levels before to DR. MARK MOLITCH (Endocrinology Division, NEMC): Is
normal levels after alkali treatment; I assume volume expansion the acidosis that arises in vitamin D delIciency due directly to
may have some role. Further, potassium may be driven intra- the vitamin D deficiency or due to secondary hyperpara-
cellularly with correction of acidosis. Unfortunately, no intra- thyroidism?
cellular potassium data are available in these patients. Finally, DR. MCSHERRY: We have looked at adults with sprue and
during very rapid growth in children receiving constant diets, children with type-2 renal tubular acidosis; both have apparent
more of the ingested sodium and potassium is incorporated in vitamin D deliciency and secondary hyperparathyroidism. in
new tissue and less is excreted in the urine then in the same both, the secondary hyperparathyroidism and acidosis can he
individual on a comparable diet during periods of slow growth. rapidly corrected to some degree by calcium infusions that
DR. COHEN: what is the natural history of this form of RTA? inhibit parathyroid hormone. Chronically in patients with
We don't see adult patients with this condition; I assume that sprue, both normocalcemia and vitamin D replenishment ap-
they get better. pear necessary to reverse the type-2 RTA and Fanconi syn-
DR. MCSHERRY: Children with subtype 4 of type-4 RTA (the drome.
rare Cheek and Perry's disease described in the late l950s and DR. HARRJNGTON: Are the differences in growth hormone
early l960s in Paris and England, and currently in Belgium) that you showed clinically significant, and would they he
have clinical salt wasting but "outgrow" the clinical expression anticipated to lead to changes in linear growth?
of their disease if they survive, and they appear normal in DR. MCSHERRY: Yes, in pituitary dwarfs with either isolated
adulthood. These patients have hyperkalemia, acidosis, and growth hormone deficiency or panhypopituitarism, peak las-
clinical salt wasting; that is, all three distal tubular aldosterone- ma human growth hormone level is usually less than 2 ng/ml.
dependent processes are defective. In our patients with "early Patients with slow growth due to isolated partial growth hor-
childhood," subtype 5 of type-4 RTA. salt wasting is not mone deficiency are called "blunted growth hormone respond-
present. The disease usually is manifested between 6.5 months ers." Peak HGH levels range between 2 and 8 ng/ml in
and 18 months o! age. In patients with other affected siblings, prepubertal patients and from 2 to IS ng/ml in pubertal patients.
we have diagnosed the defect during the first two weeks of life When these slowly growing but otherwise normal patients
but rarely see a spontaneous case that early. Usually these ("blunted responders") are given growth hormone, they grow
patients outgrow their disorder at about 4 years of age if they normally. Thus, the low levels of HGH found in children with
RTA when acidotic certainly are in the clinically significant
have received consistent, fully corrective alkali therapy. At that
time they appear to he completely normal, hut I suspect the range.
carrier state could he recognized in some way, perhaps if we DR. MotlicH: Have you been able to correlate somatomedin
measured their urinary calcium or citrate excretion during levels with growth?
acidosis. The correction of the clinical syndrome of acidosis DR. MCSHLRRY: if we could measure somatomedin with
that occurs in these older children who have grown well may confidence, we could evaluate its role in the growth retardation
occur spontaneously because the proximal nephron takes over of hyperchloremic acidosis. There have been a numbe]r of
more of the bicarbonate reabsorption (as it does in normal problems with somatomedin measurement. With new, more
children as they mature) and thus compensates for any slightly reliable assays, we soon will measure somatomedin-c in sam-
defective function of the distal aldosterone-sensitive nephron. ples we have saved, but we have no data at present.
The other possibility is that maturation in capacity or function DR. KASSIRER: How do ou explain the remarkable elevation
of distal tubule aldosterone receptors occurs. of plasma bicarbonate on admission to UCSF in this patient
DR. HARRING1ors: The studies you have presented concern with type-i RTA with renal bicarbonate wasting? Were you
alterations and stimulation of growth in nonazotemic renal attributing it all to treatment with chlorothiazide?
acidosis and not in azotemic renal acidosis. Given your impres- DR. MCSHERRY: No. Some patients with type-I RTA, espe-
sive results in stimulating growth, it seems appropriate that this cially adults, have severe alkalosis with potassium depletion
notion be extended to azotemic renal acidosis. Admittedly, alone. This patient was not only volume depleted because of
there are probably many other reasons for growth retardation in chlorothiazide therapy, but also had vomiting and severe pctas-
children with azotemic acidosis. Have you tried to fully and sium depletion to account for her alkalosis.
totally correct acidosis in children with chronic renal failure to DR. KASSIRER: I'm not entirely satisfied with that explana-
see whether growth is affected? tion. I wonder whether selective depletion of chloride coupled
DR. MCSHIRRY: lam not aware of studies that have carefully with sodium avidity could be playing a role, at least in maintain-
evaluated growth in azotemic children whose acidosis is fully ing the alkalosis. Why these patients become severely alkalotic
808 Nephro/og' Forum
in the first place is more obscure, but I wouldn't be surprised to
find that the history in many children would disclose that they
had been vomiting. Extremely severe metabolic alkalosis al-
most always results from external loss of hydrochloric acid
from the stomach.
DR. MCSHERRY: Although this child had vomiting through-
out, as I said before, many of our adults with type-I RTA
presenting with alkalosis have only hypokalemia to account for
their alkalosis.
Da. COHEN: In view of the experimental evidence that a
reduction in carbon dioxide tension may have an independent
effect on renal bicarbonate reabsorption and contribute to the
hypobicarbonatemia of chronic metabolic acidosis 175], I am
curious to know whether the level of secondary hypocapnia in
youngsters with RTA is similar to that observed in other forms
of acidosis of comparable severity.
DR. MCSHERRY: I know of no directly comparative study of
that nature in children with RTA. With severe chronic acidosis,
the carbon dioxide tension in children with type-l RTA usually
is 18 to 20 mm Hg. This reduction appears to be comparable to
that in patients with diabetic ketoacidosis, for example.
Acknowledgment
Dr. McSherry gratefully acknowledges the support of National
Institutes of Health grants AM-2177l, RR-00079(PCRC), and National
Foundation 6-198.
Reprint requests to Dr. Elisabeth McSherry, University of California
at San Francisco, 1203 M, San Francisco, Ca/ijbrnia 94143, USA
References
1. Soisio JR, BoicHis H, EDELMANN CM JR: Bicarbonate reab-
sorption and hydrogen ion excretion in children with renal tubular
acidosis. J Pediatr 71:802—813, 1967
2. S0RIAN0 JR, EDELMANN CM JR: Renal tubular acidosis. Anna Rev
Med 20:363—382, 1969
3. EDELMANN CM JR, BARNETT HL: Pediatric nephrology, in Dis-
eases of the Kidne , second edition, edited by STRAUS MB, WELT
LG, Boston, Little, Brown and Company. pp. 1392—1395. 1971
4. EDELMANN CM JR: Renal tubular acidosis, in The Body Fluids in
Pediatrics, edited by WINTERS RW, Boston, Little, Brown, and
Company, 1973, pp. 384—401
5. NASH MA, TORRADO AD, GREIFER 1, SPITZER A, EDELMANN CM
JR: Renal tubular acidosis in infants and children. J Pediatr 80:738—
748, 1972
6. ALBRIGHT F, C0Ns0LAzI0 WV, COOMBS ES, SUIKOWITII HW,
TALBOTT JH: Metabolic studies and therapy in a case of nephrocal-
cinosis with rickets and dwarfism. Bull Johns Hopkins Hosp 66:7,
1940
7. Coo RE, KLEEMAN CR: Distal tubular dysfunction with renal
calcification. Yale J Biol Med 23:199—206, 1960
8. Foss GL, PERRY CB, WOOD RJY: Renal tubular acidosis. Quart J
Med 98:185—200, 1956
9. GREENBERG AJ, MCNAMARA H, McCR0RY WW: Metabolic bal-
ance studies in primary renal tubular acidosis: Effects of acidosis on
external calcium and phosphorus balances, J Pediair 69:610—618,
1966
10. SOBEL E: Preschool and school age child: Growth problem, in
Biological Basis of Pediatric Practice, vol. II, edited by CooKE RF,
LEVIN S, New York, McGraw-Hill, 1968. pp. 1568—1569
11. PALMER RH, CORNFELD D: Primary renal tubular acidosis recog-
nized and treated at three days of age. A case report illustrating the
value of routine post-mortem examination. C/in Pediatr 12: l40—
144, 1973
12. MCSHERRY E, SEBASTIAN A, MORRIS RC JR: Correction of im-
paired growth in children with classic renal tubular acidosis (cRTA)
by sustained correction of acidosis. C/in Re,s 21 :700A. 1973
13. MCSHERRY E, MORRIS RC JR: Attainment of normal stature with
alkali therapy in infants and children with classic renal tubular
acidosis (RTA): Evidence that acidosis is critical to the pathogene-
sis of impaired growth. J C/in invest 61:509—527, 1978
14. MCSHERRY E, SEBASTIAN A, MORRIS RC JR: Renal tubular acidosis
(RTA) in infants: The several kinds, including bicarbonate-wasting,
classic renal tubular acidosis. J C/in Invest 51:499—5 14, 1972
15. RODRIQUEZ-SORIANO J, VALLO A, GARCIA-GENTES M: Distal renal
tubular acidosis in infancy. A bicarbonate-wasting state. J Pediatr
86:524—532, 1975
16. LEUMANN EP, SKINMANN B: Persistent and transient distal renal
tubular acidosis with bicarbonate wasting. Pediatr Res 9:767—773.
1975
17. MCSHERRY E, SEBASTIAN A, MORRIS RC JR: Renal bicarbonate
wasting (RBW) in children: Its predictable occurrence. Proc Am
Soc Nephrol, 1977, p. lISA
18. RANDALL RE JR, IARGGART WL: Familial renal tubular acidosis.
Ann intern Med54:l108—1116, 1961
19. RANDALL RE JR: Familial renal tubular acidosis revisited. Ann
intern Med 66:1024. 1967
20. MORRIS RC JR. SEBASTIAN A, MCSHERRY E: Therapeutic experi-
ence in patients with classic renal tubular acidosis, in Proceedings
of the V//tb international Congress qf Nephro/ogv, 1978, pp. 345—
349
21. MCSHERRY E: Acidosis and growth in chronic non-uremic renal
disease. Kidney mt 14:349—354. 1978
22. MCSHERRY E: Renal tubular disorders of childhood, in Textbook of
Pediatrics, 17th ed,, edited by RUDOLPH AM, BARNETT HL, New
York, Appleton-Century-Crofts, in press
23. ALBERT MS, WINTERS RW: Acid-base equilibrium of blood in
normal infants. Pediatrics 37:728—732, 1966
24. EDELMANN CM JR, Boldills H, RODRIQUEZ-SORIANO J, STARK H:
The renal response of children to acute ammonium chloride acido-
sis. Pediatr Res 1:452—460, 1967
25. FRALEY DS, ADLER S: Isohydric regulation of plasma potassium by
bicarbonate in rat. Kidney mt 9:333—345, 1976
26. SCRIBNER BH, BURNELL JM: Interpretation of the serum potassi-
um concentration. Metabolism 5:468—479, 1956
27. MORRIS RC JR, SEBASTIAN A, MCSHERRY E: Renal acidosis, in
Symposium on regulation of acid-base balance, edited by RECTOR
FC. Kidney mt 1:322—340, 1972
28. SEBASTIAN A, MCSI-IERRY E, MORRIS RC JR: Metabolic acidosis
with special reference to the renal acidosis, in The Kidney, edited
by RECTOR FC, BRENNER BM, Philadelphia, WB Saunders Co.,
1976, pp. 615—660
29. MORRIS RC JR. MCSHERRY E. SEBASTIAN A: The experimental
renal dysfunction of hereditary fructose intolerance; its modulation
by circulating parathyroid hormone. Proc Natl Acad Sci USA
68:132—135, 1971
30. MCSHERRY E, POKROY M: The absence of nephrocalcinosis in
children with type I RTA on high dose alkali therapy since infancy.
C/in Res 26:470A, 1978
31. ETCHES P, PICKERING D, SMITH R: Cystinotic rickets treated with
Vitamin D metabolites. Arch Dis Child 52:661—666. 1977
32. GERTNER JM, BRENTON DP, DENT CE, DOMENICH M: Treatment
of the rickets of cystinosis with l-alpha-hydroxycholecalciferol.
Calcif Tissue Re.c' 22:66—67, 1977
33. MCENERY PT, SILVERMAN FN, WEST CD: Acceleration of growth
with combined Vitamin D-phosphate therapy of hypophosphatemic
resistant rickets. J Pediatr 80:753—774, 1972
34. WILSON DR, YENDT ER: Treatment of the adult Fanconi syndrome
with oral phosphate supplements and alkali—Report of two cases
associated with nephrolithiasis. Am J Med 35:487—S Il, 1963
35. MCSHERRY E: Current issues in renal tubular acidosis, in Proceed-
ings of the Fifth international Congress of Pediatric Nephrologv
(10/10/80), in press
36. MCSHERRY E: Renal tubular acidosis. in Pediatrics Update, 4th
ed., New York, Elsevier, in press
37. MCSHERRY E, PORTAI.E A, GATES J: Non-azotemic, non-hyporen-
inemic type 4 renal tubular acidosis (RTA) of infancy. Proc Am Soc
Nephrol, 1978. p. 135A.
38. MCSHERRY F, GATES J: The predictable occurrence of impaired
growth in infants with type-4 RTA, in Proceedings qf the V//fit
international Congress of Nephrology (6/21/78)
 Reiuil tubular a :idosis in childhood
39. MCSHERRY F, GATES J, PIALAET M: The incidence of nephrocal-
cinosis and the urinary excretion of citrate and calcium in patients
with non-azotemic type 4 renal tubular acidosis, in Urolithiasis:
Clinical and Basic Research. edited by SMITH LH, ROBERTSON
WG, FINLAYSON B. New York, Plenum Press, 1981, pp. 747—755
40. IMAI M. IGARASHI Y, SOKABE H: Plasma renin activity in congeni-
tal virilizing adrenal hyperplasia. Pediatrics 41:897—904. 1968
41. OETLIKER 0. ZURBRUGG RP: Renal tubular acidosis in salt-losing
syndrome of congenital adrenal hyperplasia (CAH). J C/in Endo-
crinol Metab 31:447—450, 1970
42. ROS1ER A, THEODOR R, BoIci-lIs H. GERTY R. ULIcK S ALAGEM
M, TABACHNIK E, COHEN B. RABJNOWITZ D: Metabolic responses
to the administration of Angiotensin Ii. K and ACTH in two salt
wasting syndromes. J C/in Endocrinol Metab 44:292—301. 1977
43. ROSLER A, RABINOWITZ D, Ti-iEoDoR R, RAMIREX LC, UlICK 5:
The nature of the defect in a sale wasting disorder in Jews of Iran, J
C/in Endocrinol Metab 44:297—291. 1977
44. ULICK S: Diagnosis and nomenclature of the disorders of the
terminal portion of the aldoslerone biosynthetic pathway. J C/in
Endocrinol Metab 43:92—96. 1976
45. DAVID R, GOLAN S. DRUCKER W: Familial aldosterone deficiency:
Enzyme defect, diagnosis, and clinical course. Pediatrics 41:403—
412, 1968
46. SCHAMBELAN M, STOCKGIT JR. BIGLIERI EG: isolated hypoaldos-
teronism in adults, a renin deficiency syndrome. N EngI J Med
287:573—578. 1972
47. SCHAMBELAN M, SEBASTIAN A, BIGLIERI EG: Studies of the
prevalence, pathogenesis and functional significance of aldosterone
deficiency in hyperkalemic patients with chronic renal insufficien-
cy. Kidney In! 17:89—101, 1980
48. ARNOI.D JE, HEALY JK: Hyperkalemia. hypertension and systemic
acidosis without renal failure associated with tubular defect in
potassium excretion. Am J Med 47:461—472, 1969
49. GORDON RD, GEDDES RA, PAWSEY CGK. 0HALLORAN MW:
Hypertension and severe hyperkalaemia associated with suppres-
sion of renin and aldosterone and completely reversed by dietary
sodium restriction. Australian Ann Med 19:288—294. 970
50. SPITZER A, EDELMANN CM JR. GOLDBERG LD, HENNEMAN PH:
Short stature, hyperkalemia and acidosis: A defect in renal trans-
port of potassium. Kidney mt 3:251—257, 1978
SI. WEINSTEIN SF, ALLAN DME, MEND0zA SA: Hyperkalemia, aci-
dosis, and short stature associated with a defect in renal potassium
excretion. I Pediatr 85:355—358, 1974
52. BRAUrBAR N, LEVI J, ROSLER A, ILl rE5D0RE E. Djiou II M,
EPSTEIN M. KLEEMAN CR: Familial hyperkalemia, hypertension
and hyporeninemia with normal aldosterone levels: A tubular
defect in potassium handling. Arc/I Intern Med 138:607-610. 1978
53. SCHAMBELAN M, SEBASTIAN A, RECTOR FC JR: Mineralocorticoid
(MC) resistant renal potassium (K) secretory defect: Proposed
distal tubule chloride shunt. C/in Res 26:545A. 1978
54. CHEEK DB, PERRY JW: A salt wasting syndrome in infancy Arch
Dis Child 33:252—256, 958
55. ROSLER A, GAZIT E, THEODOR R, Boicuis H. RABINOWITZ D: Salt
wastage, raised plasma-renin activity, and normal or high plasma-
aldosterone: A form of pseudohypoaldosteronism. I.a,Icet 1:959-
962, 1973
56. NORMAN ME, COHN RM, MCCURDY DK: Urinary citrate excretion
in the diagnosis of distal renal tubular acidosis. I Pediatr 69:6 10—
618, 1966
809
57. MEYER JL, SMITH LH: Growth of calcium oxalate crystals. 11.
Inhibition by natural urinary crystal growth inhibitors. Invest Urol
13:31—35, 1975
58. SMITH LH, MEYER JL. McCall JT: Chemical nature of crystal
inhibitors isolated from human urine, in Urinary Calculi. Recent
Advances in A etiology, Stone Structure and 7eat,nent, edited by
DELATTE CIFUENTES U. RAPADO A, H0DGKIN50N A. et at. New
York, Karger. 1973, p. 318.
59. BISAZ S. FELIX R. NEUMAN WF, et al: Quantitative determination
precipitation in whole urine. Mm
of inhibitors of calcium phosphate
Eleetr Metab 1:74, 1978
60. PETONI E, N0RDI0 S: Relationship between calcium-phosphorus
metabolism, the 'Krebs cycle' and steroid metabolism. Arch Dis
Child 34:37 1—382. 1959
61. MILNE ME), STANBURGY SW, THOMSEN E: Observations on the
Fanconi syndrome in the adult. Quart I Med 21:61—88, 1952
62. CLARKE E. Evans BM. MACINTYRE J, MILNE MD: Acidosis in
experimental electrolyte depletion. C/in Sci 14:42 1—440, 1955
63. BRENNER JB, SPRING D, MCSHERRY E, SEBASTIAN A. GENANT H,
MoRRIs RC, PALUBINSKAS AJ: Radiographic findings in 96 pa'ients
(56 children, 36 adults) with the 3 major types of RTA. Radiology,
in press
64. KURTZMAN RU, TSAI I, BRAND L, MARK LC: The influence of
urinary pH on the plasma half-life of pseudoephedrine in man and
dog and a sensitive assay for its determination in human plasma.
C/in Phar,nacol Ther 12:62—67, 1971
65. MCSHERRY E, WEBERMAN J, GRUMBACH M, KAPLAN S: The effect
of acidosis on human growth hormone (HGHO) release in children
with non-azotemic RTA. C/in Res 28:535A. 1980
66. MATTEINI M, CoTRozzi G. CAPELLI G: Human growth hormone
secretion induced by sodium bicarbonate infusion. Acta Med Au.vo/
8:49—54, 1976
67. SIEGEL RC: Lysyl oxidase. In! Rev Connect Tissue Res 8:73—118.
1979
68. SIEGEL RC, PINNELL SR. MARTIN GR: Crosslinking of collagen
and elastin. Properties of lysyl oxidase. Biochem I 9:4486—4492.
1970
69. GRIGER C, SIEGEL R, MCSHERRY E: The modulation of the plasma
of lysyl oxidase activity by plasma bicarbonate concentration. Proc
Am Soc Nephro/, 1978, p. l8A
70. MCSLIERRY E, MORRIS RC JR, GRIGER C, SIEoEL R: Evidence that
acidosis affects collagen metabolism in children with RTA. C/in Res
27:373A, 1979
71. BECKETT AH, ROWLAND M: Urinary excretion kinetics ofamphet-
amine in man. J Pharm Pharmacol 1:628—639, 1965
72. BRATER DC, KAOJARERN 5, BENET LZ, LIN ET, LOCKWOOD T,
MCSHERRY E, MORRIS RC. MELMON KU: Renal excretion of
pseudoephedrine by man. C/in Res 28:238A. 1980
73. VAN GOIDSENHOVEN GMT, GRAY OV. PRICE AV, SANDELSON
PH: The effect of prolonged administration uf large doses of sodium
bicarbonate in man. C/in Sci 13:383, 1954
74. PORTALE AA, BOOTH BE, TsAI HC. MORRIS RC JR: Reduced
plasma concentration of I ,25(0HUD in children with moderate
renal insufficiency. Proc Am Soc Nephrol, 1979, p. l52A
75. MADIAS NE, SCHWARTZ WB, COHEN JJ: The maladaptive renal
response to secondary hypocapnia during chronic HCI acidosis in
the dog. J C/in I/Ices! 60:1393—1401, 1977