The Malnourished Child, edited by Robert

M. Suskind and Leslie Lewinter-Suskind.

Nestle Nutrition Workshop Series, Vol. 19.
Nestec Ltd., Vevey/Raven Press, Ltd.,
New York © 1990.

Renal Function in the Malnourished Child

Gustavo Gordillo-Paniagua* and Silvestre Frenkt

*Department of Nephrological Research, Hospital Infantil de Mexico "Federico Gomez";

and fUnit of Biomedical Research, Centro Medico National, iastituto Mexicano del Seguro
Social, 06720 Mexico, D.F.

The classic aphorism of Homer Smith: "Blood composition results, not from
what we eat but from what our kidneys are able to retain" (1), relates the variables
of body composition, nutrition, growth, and kidney function. This conceptual
framework appears to be of little relevance in the mature, healthy, and well-
nourished human being but becomes of the greatest importance in the newborn
child, in the patient with chronic renal failure, and in severely malnourished sub-
jects (2).
The renal adjustments and the maturation of renal function in the human in the
neonatal period and during rapid growth in childhood are the subject of intense re-
search. Much emphasis has also been placed on the impact of chronic kidney dis-
eases on the nutritional state and on the composition of the internal environment. In
contrast, the changes and adjustments of renal function in chronic malnutrition have
scarcely been explored. The purpose of this chapter is to review some of the studies
that have been carried out in this area.
A good understanding of renal adjustments to malnutrition may be obtained from
an outline of current knowledge about the changes in the body fluids and their elec-
trolyte composition that characterize advanced protein-energy malnutrition (PEM)
in infants and preschool children.
Although there is a wide clinical spectrum, severe or third-degree PEM has two
extreme pictures, which represent different stages of "adaptation" to nutritional and
infective stress. At one end, there is infantile marasmus or "dry" PEM; at the other,
there is the edematous type, mostly occurring in toddlers, which is universally
known as kwashiorkor. However, the majority of cases belong to intermediate, less
clear-cut, clinical pictures (3,4).
Despite their strikingly discrepant appearances and some differences in their epi-
demiologic and nutritional background, these clinical pictures are actually two fac-
ets of the same ailment and thus share several universal functional features (5).

309
310 RENAL FUNCTION IN PEM

WATER ECONOMY

As metabolically active tissues are broken down during nutritional failure, total
body water increases proportionally to the deficit in muscle, fat, and skeletal mass
(6). This excess of body water is one of the universal features of PEM, since it is
found in every type of analytic measurement: total body composition analyses (7,8),
tissue biopsies (9,10), or dilution techniques (11,12). It characterizes all clinical
types of PEM, including nonedematous marasmus (13). Water volume may be sim-
ilar to that of a younger normal child with an equal body mass.
Both extracellular and intracellular compartments are involved in the water ex-
cess (9,12,14). Quantitative data may vary with different analytic procedures; thus,
plasma volume is found to be increased per unit of body weight when determined by
dye dilution procedures (3) but reduced when measured as the red cell dispersion
space (15).

INTRACELLULARIONS

Frenk et al. (9) reported data obtained in a study of the chemical composition of
tissues in malnourished preschool children. In most cases, muscle and skin showed
an increase in the total content of water, sodium, and chloride. These changes were
less striking but still persisted in cases with clinical dehydration. The content of po-
tassium in muscle was slightly to moderately decreased in edematous children.
These patients showed a markedly decreased intracellular concentration of potas-
sium (Fig. 1). Muscle, obtained shortly before death, showed a marked shift of
water and sodium into the intracellular compartment. A low ratio of concentration
of potassium to noncollagenous nitrogen, as compared with normals, was generally
observed.
In two instances, initial and final muscle biopsies were obtained in children who
died and showed contraction of the extracellular compartment and expansion of the

CNa]e CK]c

150
EC IC FIG. 1. Composition of muscle in
1O0J « ' • " r- eVF6ft - infantile malnutrition (per 100 g dry
1
50 J
0J
I «»E«€
L DBATION
fat-free solids). Abscissa from 0 to
OEHYDRATK)N WITH OIARRH •A ORIGINALLY CLINICALLY EOEHATOUS the left indicates extracellular fluid
'50 G p s
volume; from 0 to the right, intracellu-
lOOJ
5oJ lar fluid volume. Ordinates indicate
oJ CLINICALLY *DN EDEMATCMJS
concentration (on the left, sodium; on
150 H BO
the right, potassium). There is initial
expansion of body fluids in all in-
50 ]
oJ 1 stances except in nonedematous pa-
CLINICALL V EDEMATOUS tients. Intracellular potassium is
150
IOOJ
markedly reduced in edematous pa-
50 J tients. (From Frenk et al., ref. 9.)
ol NOR •IAL
250 200 150 100 50 0 50 100 150 200 250 300 350
 RENAL FUNCTION IN PEM 311

GTM <? 2^

INIT AL ( 7 / 1 5 / 5 5 ) WT= 6 94 Kg
150

100
[K]i
[Nali = 33 5 mM/L
mM/L 50 (K)i = 33.3
K/NCN:2.5
0

7/20/55 WT = 6.76 Kg FIG. 2. Recovery from chronic malnutri-

tion and dehydration. Muscle composition
100
[Na]. = 3 7.3 mM/L
(per 100 g dry fat-free solids). Same sym-
50
(K)i =42.9 bols as in Fig. 1. Initial biopsy shows extra-
K/NCN = 2.9 cellular fluid volume contraction, intracellular
0
expansion, and high intracellular sodium
concentration. Second and third biopsies
FINAL (6/6/55) W I . 7.26 Kg
150 show gradual restoration to normal values
(broken lines). DFFS, dry fat-free solids.
100 [Na] i : 11.6 mM/L
(K)i = 37.0
(From Metcoff et al., ref. 19.)
60 K/NCN =3.1

DO 100 (
EXTRACELLULAR INTRACELLULAR
WATER (mL) WATER ( m L )
BALANCE 7/15-20 -8/1 -8/8
Na(mM) +16 +65 -19
Cl +4 +9 +203
K +25 +72 +226

intracellular compartment associated with accumulation of sodium within the cell

and a reduction in intracellular potassium concentration. The reverse was observed
in serial muscle biopsies in a malnourished child suffering from acute dehydration,
secondary to diarrhea, who recovered: The initial contraction of extracellular water
and expansion of intracellular water improved until water distribution was almost
normal in the final biopsy; the intracellular sodium excess and potassium deficit also
reverted toward normal, with nearly normal concentrations in the final biopsy (Fig.
2). These findings have since been confirmed by other investigators (10,14).
Magnesium deficiency, as shown by balance measurements, loading studies, and
muscle biopsies (16-18), is also characteristic of severe PEM. Certain nonspecific
neurologic and electrocardiographic signs have been attributed to this deficit.
Phosphates, both inorganic (Pi) and organic, are markedly reduced in striated
muscle in PEM. With clinical deterioration, Pi increases, apparently because of
breakdown of organic phosphates. Both forms of phosphate increase with recovery
(19).

EXTRACELLULAR IONS

Through measurement of the freezing point, Salge (20), in 1912, found a reduc-
tion in the serum osmolality in four malnourished infants; in two of them who recov-
ered, osmolality values improved until they were almost in the normal range.
Soto et al. (21) studied the serum osmolalities of 211 preschool Mexican children
312 RENAL FUNCTION IN PEM

presenting with different degrees of malnutrition; none of them had any acute water
and electrolyte disturbance. The results showed a reduction in serum osmolality in
direct proportion to the degree of malnutrition (Table 1). These findings have been
confirmed by other workers (14). Extracellular hypotonicity is normally associated
with low serum sodium concentration, which has been regarded as a bad prognostic
sign (22,23).
With regard to plasma electrolyte composition, hyponatremia secondary to dilu-
tion is a common finding. Potassium values are variable, but it is not infrequent
to find severe hypokalemia, particularly after treatment of metabolic acidosis
(14,22,23).
Balance studies carried out by Lopez-Montano (24) in Mexico showed important
potassium deficits in nondehydrated malnourished children. In order to obtain posi-
tive potassium balance, an intake of 6 mmol/kg-day was required. This is twice the
amount established by Darrow (25) as the requirement for well-nourished infants
with acute dehydration.
Serum calcium concentrations are usually low in malnourished children, due to a
reduction in protein-bound calcium (14). Gomez et al. (26) confirmed the findings
of low serum concentrations of calcium, phosphate, and alkaline phosphatase. They
attributed the seizures observed after correction of metabolic acidosis to these
changes. Serum magnesium concentration is variable in malnutrition; however, low
values have been found in malnourished children with acute diarrhea (14).
The presence of metabolic acidosis is infrequent in malnourished children without
complications, but during superimposed acute dehydration secondary to diarrhea,
severe uncompensated acidosis is quite common (14,23,27).
The chloride concentration in the sweat is abnormally high, a fact that needs to be
taken into consideration in the differential diagnosis between PEM and cystic fibro-
sis; however, this may be an artifact due to a low sweat secretion rate in PEM.
Zinc and copper are also deficient in PEM (28-31). Serum zinc concentration is
markedly reduced, particularly in kwashiorkor (32). Dermal and mucosal lesions
seen in acute kwashiorkor may bear a striking resemblance to those of acroderma-
titis enteropathica and could be related to zinc deficiency.

TABLE 1. Serum osmolality in children with different degrees of malnutrition

No. of Osmolality
Nutritional state subjects (mOsm/kg)

Well-nourished 102 289 ± 6.8

1st-degree malnutrition 30 291 ± 10.1 NS
2nd-degree malnutrition 30 285 ± 3.3 p < 0.01
3rd-degree malnutrition 49 275 ± 17.4 p < 0.01

NS, not significant.

From Soto AR, et al., ref. 21.
 RENAL FUNCTION IN PEM 313

INTRACELLULAR ENZYME ACTIVITY

The abnormal sodium, potassium, magnesium, and phosphate concentrations in

the intracellular fluid are functionally related to the glycolytic and common meta-
bolic cycles (6). Among the extensive research on enzymes and metabolites per-
formed on muscle and leukocytes of children with PEM, pyruvic kinase (PK) is of
special interest. This rate-limiting, adenosine triphosphate (ATP)-generating,
magnesium-dependent enzyme is activated by physiologic intracellular concentra-
tions of potassium and inhibited by high concentrations of sodium, as found in se-
vere PEM. Kinetic studies in muscle extracts have shown that apart from a reduced
activity in muscle (33) and leukocytes (34), the capacity of PK to form complexes
with substrate at the potassium and sodium concentrations found intracellularly in
severe PEM is strikingly affected. Evidence for impaired synthesis of PK and a pos-
sible alteration in its tertiary or quaternary structure has thus been obtained. Theo-
retically, this adaptive process might obviate the functional effects of the potassium
deficit (6).

RENAL ADJUSTMENTS

A long time ago, Marriott (35) described the coexistence of two features, "lack
of water and lack of nourishment," accompanying the clinical picture of severe
PEM, with death occurring because of intractable dehydration. Since then several
reports have described the presence of polyuria in malnourished adults (36-38) and
children (3,39). Other investigators have studied the structure and function of the
kidneys of children with PEM, but neither urinalysis nor serum concentrations of
blood urea nitrogen and creatinine have shown signs suggesting renal damage (36).
In 1955, Gordillo-Paniagua and Cortez (39) carried out a clinical study on 263
children with various degrees of malnutrition, presenting with acute dehydration
secondary to diarrhea. No differences in the clinical manifestations of dehydration
relating to the nutritional status were found except for the high incidence of oliguria.
This sign was present in about 70% of well-nourished children or with mild malnu-
trition, whereas only 14% of 99 children with severe malnutrition showed oliguria.
No satisfactory explanation of this phenomenon has been provided. Although Mc-
Cance (37) suggested that polyuria stemmed from excessive ingestion of water, this
was not the case in children of this study.

Glomerular Filtration Rate and Renal Plasma Flow

In 1956, Gordillo-Paniagua et al. (40), in the Hospital Infantil of Mexico, studied

10 children with PEM, aged 13 to 33 months. They showed all the clinical and bio-
chemical characteristics of PEM (3). Seven of these children were apparently satis-
factorily hydrated, while the other three showed severe dehydration. Simultaneous
314 RENAL FUNCTION IN PEM

clearance of inulin and para-aminohippurate were carried out in these children, as

well as in 25 well-nourished children, following standard procedures (41). A
marked reduction in glomerular nitration rate (GFR) was observed in all the mal-
nourished children, with the lowest figures being found in the dehydrated children.
Renal plasma flow (RPF) was also reduced in all but one child. However, the reduc-
tion in these two variables did not always occur in parallel; therefore, the filtration
fraction varied from 0.07 to 0.55 (Fig. 3).
These results were later confirmed by similar studies performed by Alleyne (42)
and Arroyave et al. (43). With recovery, there was steady improvement in renal
function (Table 2).
So far, the most complete study on severely dehydrated and malnourished infants
has come from Kerpel-Fronius et al. (44). These investigators found normal renal
clearances in atrophic (marasmic) infants, but in "athreptic" 1 infants and often in
infants with extrarenal azotemia, there were decreased clearances of inulin and para-
aminohippurate, and hypostenuria (permanent low density in the urine) was ob-
served (Table 2). The reductions in cardiac output and renal oxygen consumption in
this group were considered to show a disparity between circulation and cellular met-
abolic requirements, with a consequent reduction in clearances. The mechanism by
which reduced oxygen consumption causes reduction in glomerular filtration rate
was not clarified. However, normal GFR and RPF were found in PEM children who
were free of clinically obvious infections and acute electrolyte disturbances (45).
There is as yet no clear explanation for the reduction in GFR observed in PEM.
Presumably, this phenomenon is not the result of permanent structural glomerular
damage, since it is easily reversed after dietary repletion. Glomerular histopatho-
logic lesions have not been observed in the kidneys of children dying from advanced
malnutrition (46).
The process of glomerular filtration involves several features that are altered dur-

GFR F F
R.RF. RPF

3 0 0 _ ,-0.60
• GFR
<
2 5 0 . .0.50
• FF
FIG. 3. Glomerular filtration rate
2 0 0 . .0.4 0 (GFR), renal plasma flow (RPF), and
filtration fraction (FF) in chronic
1 5 0 . .0.3 0 severe malnutrition. Averaged renal
• function data. Filtration fraction was
1 0 0 . -0.2 0 too varied to average. (From Gordillo-
Paniagua et al., ref. 41.)
5 0 . .0.10 •

NORMAL: MALNOURISHED
25 CASES 10 CASES

'"Athrepsia" was a term used by Kerpel-Fronius to describe a severely marasmic infant with super-
imposed infection.
 RENAL FUNCTION IN PEM 315

TABLE 2. Glomerular filtration rate and renal plasma flow in malnourished children

No. of Repleted
Investigator (ref.) patients C,N' CpAH* FF or normal C,Na CPAH* FF

Alleyne (42)* 8 47.1 249.4 0.21

7° 42.9 184.0 0.27 14 92.4 321.2 0.29
Arroyave et al. (43) 9 13.7 — — 17 45
Kerpel-Fronius et al. (44) 17 24.0 108.4 0.29
Gordillo-Paniagua et al. (40) 10 23.0 107.5 0.22 25 64 294 0.23

•In ml/min.
b
Alleyne data are corrected by weight.
c
Edematous at the time of study.
C|N, Inulin clearance; CPAH, paraamino hippurate clearance; FF, filtration fraction.
From Klahr S, Alleyne GAO, ref. 27.

ing chronic malnutrition: renal mass and glomerular filtering surface; glomerular
capillary permeability; RPF; and hydrostatic, oncotic, and intratubular pressure.
Morrison and Alleyne (47) have shown that the weight of the kidneys of children
with advanced malnutrition is less than the weight of kidneys of well-nourished chil-
dren (Table 3). Using intravenous pyelograms, they showed an increase in size of
the kidneys after nutritional repletion (27).
Pullman et al. (48) described clinical experiments in adults that showed a reduc-
tion in GFR and RPF in subjects fed a low-protein diet. Both variables increased
when the same subjects received a high-protein diet. Sargent and Johnson (49) also
found a decrease in GFR in normal subjects when fed a diet deficient in energy.
Bosch et al. (50) studied two groups of normal adults, one of which, receiving an
animal-protein diet, had a significantly higher GFR than the other group, which was
fed a vegetarian diet.
Thus, it is conceivable that a low protein intake may produce a reduction in the
glomerular capillary filtering surface as a consequence of the reduction in renal

TABLE 3. Kidney weights (g) from American children (AN), Jamaican children who died of
non-nutritional causes (JN), and Jamaican children who died of malnutrition (JM)

Age (months) AN JN JM No. children studied

0-3 39 31 14 1
6 48 44 18 18
9 61 46 25 10
12 67 — 43 7
15 71 34 5
18 81 54 54 3

(From Morrison, ref. 47.)

316 RENAL FUNCTION IN PEM

mass. It is also possible that a reduction in hydraulic conductivity may ensue in the
glomerular capillaries, decreasing glomerular permeability (27).
Since cardiac output and mean systemic blood pressure decrease during PEM, hy-
drostatic pressure becomes lower, decreasing glomerular nitration; however, the
marked reduction in plasma protein concentration decreases oncotic pressure, favor-
ing filtration. It is also possible that as a consequence of the reduction in reabsorp-
tion of salt and water in the proximal tubule, an increase in intratubular volume and
pressure may develop, opposing glomerular filtration (27).
Observations made in three malnourished children who were given a sodium
chloride load showed that there was an increase in the ratio of excreted to filtered
water; the excreted/filtered (E/F) ratio reached values above 0.1 when GFR was be-
low 10 ml/min-m2 (40) (Fig. 4). It is remarkable that the excreted urine represents
such a large proportion of the glomerular filtrate, often despite apparent clinical de-
hydration. Since removal of solute-free urine serves to defend concentration of
solutes in the body fluids, it is possible that reduction in the volume of glomerular
filtrate represents an effective renal response to conserve the volume of body fluids
(51).
Reduction in GFR to conform to diminished reabsorptive capacity means that the
glomeruli have taken over the volume-conserving function normally carried out by
the tubules. The importance of this reduction in GFR may be clarified by consider-
ing what might happen if this function were to remain normal when the tubular reab-
sorption fell sufficiently to cause a change of E/F ratio from 0.01 (which would be
considered a normal value) up to the value of 0.1 that was found in these malnour-
ished children. The appropriate response to a signal reporting reabsorptive tubular
failure is a reduction in GFR through a feedback control monitored at the macula

FIG. 4. Tubular reabsorption of

water of children with protein-energy
malnutrition during loading with so-
dium chloride in relation to glomerular
filtration rate (GFR). The lower the
GFR, the higher the excreted/filtered
(E/F) water ratio. An approximation of
the normal range is shown by the
hatched area. (From Metcoff et al.,
ref. 19.)
 RENAL FUNCTION IN PEM 317

densa (51). Renin may be activated in situ to angiotensin I and II, producing vaso-
constriction of the afferent glomerular arteriole and contraction of the glomerular
tuft, resulting in reversible glomerular shutdown as an autoregulatory response (52).
Kritzinger et al. (53) and Van Der Westhuysen et al. (54) have found high values of
plasma renin activity in children with kwashiorkor, which reverted to normal after
repletion. Godard et al. (55) also found very high values of plasma renin activity in
children with PEM, but plasma renin substrate and aldosterone concentrations were
within the normal range. Other investigators (56) have reported variable aldosterone
excretion in children with PEM. Thus, it is possible that an autoregulatory mecha-
nism takes place in chronic malnutrition, similar to that proposed by Thurau and
Boylan (57) in acute renal failure, though many details on signal transmission and
on the pathway leading to angiotensin II formation remain to be investigated.

Renal Concentration and Dilution Capacity

The suspicion that a defect in the renal concentrating ability is present in children
with severe malnutrition arose from the failure to respond with oliguria that was ob-
served in a group of children with PEM and acute dehydration (39).
In order to explore the nature of this impairment, concentration and dilution tests
were performed in 12 preschool children with PEM (58). Maximal urine osmolality
after a 12-hr period of water deprivation reached an average value of 550 mOsm/kg
of water, while in six well-nourished children, the maximal urine osmolality had an
average value of 1,100 mOsm/kg. Both groups also received an oral water load, af-
ter which the minimal urine osmolality was reached within 2 hr, with an average
value of 25 mOsm/kg in the PEM children and 35 mOsm/kg in the controls; at this
time, the first group had excreted 30% of the ingested water, while the controls had
excreted 70%. There was thus a slight delay in the time to excrete the water load in
the malnourished children.
A renal concentrating defect, which improves following protein repletion, has
also been described in malnourished children by Alleyne (42) and by McCance et al.
(59). Klahr et al. (60), studying adults with PEM, found the same defect in renal
concentrating ability and normal diluting capacity. The renal response to vasopres-
sin has been found normal in adults (27,60) and children (27) with PEM. Stimula-
tion of the neurohypophysis by intravenous nicotine administration revealed that
malnourished subjects are capable of secreting antidiuretic hormone (ADH) (27).
Administration of hypertonic saline has produced a reduction in urine volume and
an increase in urine osmolality, demonstrating integrity of the osmoreceptor mecha-
nisms. Gordillo-Paniagua et al. (40) studied osmolar clearance, free-water clearance
and free-water reabsorption in preschool age, nondehydrated children with PEM, as
well as in a group of well-nourished control children. The mean urine osmolality
was greater than that of the plasma in the controls, but it was hypotonic to plasma in
both groups of malnourished children. The group with dehydration had the lowest
serum osmolality. The nondehydrated PEM children excreted from 1.5 to 2% of the
318 RENAL FUNCTION IN PEM

"1

: T«H|0
too.
FIG. 5. Water excretion in six mal-
nourished children. Free-water clear-
.75 . ance (CH-O), osmolar clearance
(Co*™), and reabsorption of solute-
C
H2O free water (T^o) during sodium
.50.
2 i loading. S, without; C, with dehydra-
3 Co sm ^ t CH?O
tion. (From Gordillo-Paniagua et al.,
.2 5 _ 2 s ref. 41.)
Cosm Ul Cosm
5

MALNOURISHED MALNOURISHED
S/DEHVDRATION C/OEHVDRATION

amount of water filtered as free water, while in the dehydrated children, 8 to 9.5%
of the filtrate was cleared as solute-free water (Fig. 5).
These studies show that during PEM, children preserve the renal capacity to di-
lute urine and to excrete water, but they show a defect in the renal concentrating
ability. Since this impairment improves with protein repletion, it may be considered
as a functional abnormality.
The development of a hypertonic milieu in the interstitial fluid of the renal me-
dulla is considered to be the main feature of the concentrating mechanism. Active
sodium transport to the renal interstitial phase, mainly from the ascending limb of
the loop of Henle, and the reabsorption and recirculation of urea from the collecting
tubule fluid are the main contributors to the creation of hypertonicity in the renal
medulla (61,62). Impairment of sodium transport seems unlikely to explain the de-
fect in renal concentrating ability, since it would also affect renal diluting ability,
and this mechanism is preserved in chronic malnutrition. Experimental studies have
shown enhancement of water reabsorption in the renal medulla after accumulation
of urea in the renal interstitial fluid (61). Klahr and Alleyne (27), in balance studies
performed in malnourished adults, have found a positive nitrogen balance during the
first few weeks of protein repletion, with progressive increase in urea excretion and
urine osmolality. There was a good correlation between the values for urine osmo-
lality after fluid deprivation and urine nitrogen excretion (27). The results of those
experiments suggest that the renal concentrating defect found during PEM is mainly
due to the decreased accumulation of urea in the renal medulla.

Renal Regulation of Sodium

In health, sodium renal excretion keeps an equilibrium with sodium intake, and
the volume and composition of extracellular fluids are maintained relatively con-
stant. The sodium control system is in fact the volume control system. In diseases
associated with edema, the kidney retains more salt and water, and as a result, uri-
 RENAL FUNCTION IN PEM 319

nary sodium excretion is lower than the sodium intake. Alleyne (63) has shown in
children that urinary sodium excretion was lower during severe malnutrition than af-
ter nutritional repletion. Since there was no evidence of change in tubular reabsorp-
tion of sodium, the delayed sodium excretion was attributed to decrease in GFR.
Klahr and Alleyne (27) performed sodium balance studies in nonedematous PEM
adults before and after protein repletion and showed that they were able to decrease
their urinary sodium excretion to cope with the ingestion of a low-sodium diet, but
when receiving a high-sodium diet, they went into positive sodium balance and had
significant weight gain. After protein repletion, the renal ability to handle sodium
improved significantly.
Gordillo-Paniagua et al. (40) studied the effect of sodium chloride loading in
three dehydrated children with PEM. One of them received intravenous isotonic so-
lution, and no change was observed in GFR, RPF, and free-water clearances. The
other two patients received hypertonic solutions, and in one of them, free-water
clearance changed to water reabsorption at the same time as the child showed sig-
nificant clinical improvement. No changes were observed in the last child in serum
osmolality; GFR and RPF improved, but water excretion was steady (Fig. 6). Dur-
ing the control periods, a slightly positive water balance was observed, which in-
creased during the sodium chloride infusion. All the infused sodium and a large
fraction of the infused water were retained; expansion of extracellular fluid volume,
calculated according to Darrow's technique (64), was greater than the amount of re-
tained fluid in all three cases, the difference presumably representing the amount of
water shifted from the cellular compartment (endogenous water). Extracellular con-
tents of sodium before and after administration of the sodium load were obtained

GFR AVERAGE
VALUE S/mJ
V . OF GLOMERULAR
• FM 1 3
FILTRATE ( C i n )
1 NJL 1 0
« MEP S
C 1 mOsm/L SERUM

CH2O
C2C2]

r
H20

FIG. 6. Variation in free-water clearance (CH2O) and in reabsorption of osmotically free water
(TVo) during sodium chloride loading in three malnourished children. (From Gordillo-Paniagua
et aL, ref. 41.)
320 RENAL FUNCTION IN PEM

from the initial and final values of sodium concentration and the calculated volumes
of extracellular fluid; the difference in content of sodium in extracellular fluid minus
the amount of sodium retained from the infusion was taken to represent a shift of
water between intra- and extracellular compartments.

Renal Regulation of Acid-Base Equilibrium

Children and adults with PEM who do not have severe gastroenteritis usually do
not show metabolic acidosis (14,23), and malnourished adults have normal blood
pH and bicarbonate and reduced acid excretion (65). Both observations suggest that
endogenous acid production is reduced in malnutrition. Klahr et al. (66) found a re-
duced basal net acid excretion in malnourished adults with normal blood pH and
bicarbonate. After administration of NH4CI, they developed a greater degree of
metabolic acidosis than when tested again after protein repletion. The malnourished
adult can cope with reduced acid production but is unable to handle an increased
load. No differences in NH4 production were found in either the malnourished or the
protein-repleted group, but the amount of titratable acidity was four times higher in
the protein-repleted patients. Children with PEM did not excrete as much acid as
well-nourished or nutritionally rehabilitated children when they received NH4C1
(67).
Edelman et al. (68) studied children with growth retardation who had a mild com-
pensated metabolic acidosis. When they were given NH4C1, the excretion of titrat-
able acid and NH4 was significantly lower than in control children with normal
stature.
A defect in urinary acidification after NH4C1 administration has not been demon-
strated either experimentally or clinically. However, Smith (67) fed NH4C1 to chil-
dren with PEM and found that urine pH did not fall as low as it did after they had
recovered. Malnourished adults, children, and rats show a marked increase in urine
ammonia when given NH4C1; this may indicate that the intrinsic capacity of the kid-
ney to produce ammonia is unimpaired. Since there is no evidence of a decrease in
plasma glutamine in malnutrition, which may even be increased in adults on low-
protein diets, there is no lack of substrate for ammoniogenesis (27). However, it is
possible that in cases of PEM with severe potassium deficiency, changes in the renal
tubular cells may develop and inhibit ammoniogenic capacity. It is possible that the
apparently normal urinary ammonia in the PEM children represents increased renal
production of ammonia, and the low basal urinary ammonia of malnourished adults
and rats not only reflects the decreased acid load but indicates that they were not se-
verely potassium-deficient. Since urine acidification is not impaired, the reduced ti-
tratable acid production after acid loading in malnourished subjects indicates
reduced buffer availability. Indeed, Waterlow and Wills (69) have shown that mal-
nourished children are phosphate-deficient and have a low urinary excretion of
phosphate as a common finding.
 RENAL FUNCTION IN PEM 321

KALIOPENIC NEPHROPATHY

While studying renal concentrating ability in malnourished children, two patients

with PEM and dehydration secondary to diarrhea presented with polyuria, muscular
hypotonia, and paralytic ileus accompanied by severe hypokalemia (potassium lev-
els of 2.4 and 0.9 mmol/liter, respectively), hyponatremia, and normal total CO2
levels. In both patients, the electrocardiogram showed prolonged QT intervals and
T-wave inversion. Inulin and para-aminohippurate clearances were performed, and
markedly reduced values were found. Maximal urine osmolality after water depriva-
tion was 264 and 268 mOsm/kg, respectively. No changes occurred after vaso-
pressin administration. Urine potassium concentrations were 22 and 18 mmol/liter,
respectively. One of the patients recovered, and 1 month later, all the clinical and
renal function abnormalities disappeared. The other patient died; postmortem exam-
ination of the kidneys showed normal glomeruli with vacuolated degeneration of the
epithelial cells of the convoluted proximal tubules (70).
Reports of similar morphologic renal lesions have appeared in the literature in re-
gard to patients who died from diverse gastrointestinal disorders (71-73); further-
more, these renal lesions have been found to be associated with severe hypokalemia
in clinical and experimental studies (74-77). Finally, several investigators have de-
scribed a correlation between chronic potassium deficiency, renal function abnor-
malities, and renal tubular degeneration known as kaliopenic nephropathy (78-80).
Proper treatment with potassium supplements may lead to recovery of the whole
picture, but refractoriness to treatment may lead to chronic renal insufficiency
(70,80).
Chronic malnutrition is a complex situation where the low protein intake associ-
ated with repeated episodes of vomiting and diarrhea may result in severe potassium
deficiency (70). In most children with chronic severe malnutrition presenting renal
function alterations, these are potentially reversible, suggesting an adaptive regula-
tory mechanism. However, in those cases where the deficiency of potassium has
been very important, kaliopenic nephropathy may ensue and worsen the prognosis.

PERSPECTIVES FOR FUTURE INVESTIGATIONS

There is no direct evidence for an increased prevalence of chronic renal disease in

children with PEM. Nevertheless, it seems noteworthy that about 25% of poor Mex-
ican patients attending our clinic because of end-stage kidney disease did not have a
previous history of renal disease. It may be that these children had developed inter-
stitial nephritis characterized by polyuria, without any abnormalities in the urine
sediment or blood chemistry.
Brenner et al. (81) have proposed that an increased solute load per nephron
(hyperfiltration) may result in progressive glomerular damage. Experimental and
clinical studies have suggested that a high protein intake in patients with a reduced
322 RENAL FUNCTION IN PEM

renal mass may cause an increased perfusion of the remnant glomeruli, leading to
their eventual deterioration. Therefore, one may propose that in patients with PEM
on a sustained high-protein diet, a low GFR could result in a long-term rise in glo-
merular pressures and flow, favoring hyperfiltration and impairing the selective per-
meability of the glomerulus. Additionally, an increased flux of plasma proteins
across the glomerular capillary may well serve as a stimulus to proliferation of mes-
angial cells and glomerular sclerosis (82).
The possibility of a variable GFR, as well as the concept of hyperfiltration, impli-
cates a renal functional reserve, i.e., the capacity of the kidney to increase its level
of operation under certain demands. When subjected to an acute protein load, pa-
tients exhibiting a loss of renal mass because of chronic kidney disease show a
smaller increase in GFR compared with controls, indicating a proportional decrease
in renal functional reserve (50).
In line with these findings, one may propose an investigation on the impact of nu-
tritional rehabilitation of children with PEM on their renal functional reserve in
terms of their risk of subsequently developing chronic renal failure.

ACKNOWLEDGMENT

We wish to thank Mrs. Magdalena Arenas for her secretarial assistance and to
Mr. Bruno Ignacio Ramos for his professional assistance.

REFERENCES

1. Smith HW. Lectures on the kidney. Lawrence, Kansas: University extension division, University of
Kansas, 1943;3.
2. Metcoff J. Observations on the renal defense of body composition in children. Am J Clin Nutr
1956;4:543-60.
3. Gomez F, Ramos-Galvan R, Cravioto J, Frenk S. Malnutrition in infancy and childhood, with spe-
cial reference to kwashiorkor. Adv Pediatr 1955;7:131-69.
4. Wellcome trust working party. Classification of infantile malnutrition. Lancet 1970;ii:302-3.
5. Frenk S. Protein-energy malnutrition. In: Anreil G, Metcoff J, eds. Pediatric nutrition. London:
Butterworth, 1985;153-93.
6. Metcoff J. Biochemical effects of protein-calorie malnutrition in man. AnnuRevMed 1967;18:377-
422.
7. Klose E. Zur Kenntniss der Korperzusammensetzung bei Ernahrungsstorunge. Jahrb Kinderh
1914;18:154-87.
8. Garrow JS, Fletcher K, Halliday D. Body composition in severe infantile malnutrition. J Clin Invest
1965;44:417-25.
9. Frenk S, Metcoff J, Gomez F, et al. Intracellular composition and homeostatic mechanisms in se-
vere chronic infantile malnutrition. II. Composition of tissues. Pediatrics 1957;20:105-12.
10. Waterlow JC, Mendez CB. Composition of muscle in malnourished human infants. Nature 1957;
180:1361-2.
11. Smith R. Total body water in malnourished infants. Clin Sci 1960;19:275-85.
12. Kerpel-Fronius E, Kovach S. Volume of extracellular body fluids in malnutrition. Pediatrics 1948;
2:21-4.
13. Hansen JDL, Brmkman GL, Bowie MD. Body composition in protein-calorie malnutrition. S Afr
MedJ 1965;39:491-5.
 RENAL FUNCTION IN PEM 323

14. Ganow JS, Smith R, Ward EE. Electrolyte metabolism in severe infantile malnutrition. Oxford:
Pergamon Press, 1968.
15. Viart P. Blood volume (5lCr) in severe protein-calorie malnutrition. Am J Clin Nutr 1976;29:25-37.
16. Metcoff J, Frenk S, Antonowicz J, et al. Relations of intracellular ions to metabolite sequences in
muscle in kwashiorkor: a new reference for assessing the significance of intracellular concentrations
of the ions. Pediatrics 1960;26:960-72.
17. Montgomery RD. Magnesium metabolism in infantile protein malnutrition. Lancet 1960;ii:74-5.
18. Cadell JL. Magnesium in the therapy of protein calorie malnutrition in childhood. J Pediatr 1965;
66:392-6.
19. Metcoff J, Frenk S, Gordillo G, et al. Intracellular composition and homeostatic mechanisms in se-
vere chronic infantile malnutrition. IV. Development and repair of the biochemical lesion. Pediat-
rics 1957;20:317-36.
20. Salge B. Ein Beitrag zur Pathologie des Mehlnahrschadens der Sauglinge. Jahrb Kinderh
1912;76:125-42.
21. Soto AR, Gordillo-Paniagua G, Uribe F, Menier G. Relation de la osmolaridad seiica con el estado
nutricional del nino. Bol Med Hosp Infant Mex 1958;15:3-12.
22. Soto AR, Garcia AL, Gordillo-Paniagua G, Tellez-Gir6n R. Osmolaridad serica y equilibrio elec-
trolitico durante la deshidratacion del nino desnutrido. Bol Med Hosp Infant Mex 1956;13:626-31.
23. Chirinos GP, Ramos-Galvan R. El patr6n electrolitico en ninos con desnutricion de tercer grado.
Bol Med Hosp Infant Mex 1964;2:89-92.
24. Lopez-Montano E. Retencidn de electrolitos intra y extracelulares en ninos diarreicos con desnutri-
cion de 3er grado. Tesis recepcional. Universidad Nacional Aut6noma de Mexico. Mexico, 1954.
25. Darrow DC. Retention of electrolytes during recovery from severe dehydration due to diarrhea. J
Pediatr 1946;28:515-9.
26. G6mez F, Ramos-Galvan R, Cravioto J, et al. Estudios sobre el nino desnutrido. XVIII. Niveles s€-
ricos de calcio, fosforo inorganico y fosfatasa alcalina en ninos preescolares con desnutricion croni-
ca severa y en el curso de su recuperation nutricional. Bol Med Hosp Infant Mex 1956;13:865-74.
27. Klahr S, Alleyne GAO. Effects of chronic protein-calorie malnutrition on the kidney. Kidney Int
1973;3:129-41.
28. Sandstead HH, Shukry AS, Prasad AS, et al. Kwashiorkor in Egypt. I. Clinical and biochemical
studies with special reference to plasma zinc and serum lactic dehydrogenase. Am J Clin Nutr
1965:17:15-26.
29. Bradfield RB, Yee T, Baertl JM. Hair zinc levels in Andean Indian children during protein-calorie
malnutrition. Am J Clin Nutr 1969;22:1349-53.
30. Erten J, Arcasoy A, Cavdar AO, Cin S. Hair zinc levels in healthy and malnourished children. Am
JClinNutr 1978;31:1172-4.
31. Golden BE, Golden MHN. Plasma zinc, rate of weight gain, and the energy cost of tissue deposi-
tion in children recovering from severe malnutrition on a cow's milk or soya protein based diet. Am
J Clin Nutr 1981;34:892-9.
32. Coello-Ramirez P, Diaz-Bensussen S. Zinc deficiency in malnutrition. In: Lifshitz F, ed. Pediatric
nutrition. New York: Marcel Dekker, 1982;197-207.
33. Metcoff J, Frenk S, Yoshida T, et al. Cell composition and metabolism in kwashiorkor (severe
protein-calorie malnutrition in children). Medicine 1966;45:365-90.
34. Yoshida T, Metcoff J, Frenk S. Reduced pyruvate kinase activity in leucocytes of infants with
protein-calorie malnutrition. Am J Clin Nutr 1968;21:162-6.
35. Marriott WM. Some phases of the pathology of nutrition in infancy. Am J Dis Child 1920;20:
461-5.
36. Keys A, Brozek J, Henschel A, et al. The biology of human starvation, vol. 1. Minneapolis: Univer-
sity of Minnesota Press, 1950;664-74.
37. McCance RA. Aspects of renal function and water metabolism. Studies of undernutrition, Wupper-
tal, 1946-1949. London: Medical Research Council Special Report Series 272-276, 1950-1951;
175-92.
38. Schittenhelm A, Schlecht H. Uber odem Krankheit mit hypotonischer bradykardie. Bert Klin Wo-
chenschr 1918;55:1138-43.
39. Gordillo-Paniagua G, y Cortez JR. El sindrome de deshidratacion en el nino desnutrido. Bol Med
Hosp Infant Mex 1956;13:803-12.
40. Gordillo-Paniagua G, Soto AR, Metcoff J, et al. Intracellular composition and homeostatic mecha-
nisms in severe chronic infantile malnutrition. III. Renal adjustments. Pediatrics 1957;20:303—16.
324 RENAL FUNCTION IN PEM

41. Soto AR, Gordillo-Paniagua G, Lopez ME, et al. Exploracion renal por las pniebas de depuraci6n
y saturacion de inulina y PAH en ninos normales. Bol Med Hosp Infant Mex 1956;13:793-802.
42. Alleyne GAO. The effect of severe protein caloric malnutrition on the renal function of Jamaican
children. Pediatrics 1967;39:400-ll.
43. Arroyave G, Wilson D, Behar M, Schrimshaw NS. Serum and urinary creatinine in children with
severe protein malnutrition. Am J Clin Nutr 1961;9:176—9.
44. Kerpel-Fronius E, Varga F, Vonoezky J, Kun K. Relation of O2 consumption to circulation in dif-
ferent stages of infantile malnutrition. Pediatrics 1951;7:623-6.
45. Paniagua R, Santos D, Munoz R, et al. Renal function in protein-energy malnutrition. Pediatr Res
1980;14:1260-2.
46. Bras G, Waterlow JC, DePass E. Further observations on the liver, pancreas and kidney in malnour-
ished infants and children. The relation of certain histopathological changes in the pancreas and
those in liver and kidney. West Indian MedJ 1957;6:33-42.
47. Morrison EY, Alleyne GAO. Malnutrition, kidney size and composition. Arch Latinoam Nutr 1976;
26:7-14.
48. Pullman TN, Alving AS, Dern RJ, Landowne M. The influence of dietary protein on specific renal
functions in normal man. J Lab Clin Med 1954;44:320-32.
49. Sargent F, Johnson RE. The effects of diet on renal function in healthy men. Am J Clin Nutr
1956;4:466-81.
50. Bosch JP. Saccaggi A, Lauer A, et al. Renal functional reserve in humans. Effect of protein intake
on glomerular filtration rate. Am J Med 1983;75:943-50.
51. Metcoff J, Frenk S, Gordillo-Paniagua G, et al. Intracellular composition and homeostatic mecha-
nisms in severe chronic infantile malnutrition. IV. Development and repair of the biochemical le-
sion. Pediatrics 1957;20:317-36.
52. Echnermann J, Briggs J. Function of the juxtaglomerular apparatus: Local control of glomerular he-
modynamics. In: Seldin DW, Giebisch G, eds. The kidney: physiology andpathophysiology. New
York: Raven Press, 1985;669-97.
53. Kritzinger EE, Kanengoni E, Jones JJ. Plasma renin activity in children with protein energy malnu-
trition (kwashiorkor). SAfrMedJ 1974;48:499-501.
54. Van Der Westhuysen JM, Kanengoni E, Jones JJ, et al. Plasma renin activity in edematous and ma-
rasmic children with protein energy malnutrition. S AfrMedJ 1975;49:1729-31.
55. Godard CM, Munoz M, Sanchez MA, et al. A study of the renin—angiotensin—aldosterone system
in severe infantile malnutrition, lnt J Pediatr Nephrol 1986;7:39-44.
56. Luric AO, Jackson WPU. Aldosteronuria and the edema of kwashiorkor. Am J Clin Nutr 1962;
11:115-26.
57. Thurau K, Boylan JW. Acute renal success. The unexpected logic of oliguria in acute renal failure.
Am J Med 1976;61:308-15.
58. Gordillo-Paniagua G. Trastornos renales en ninos con desnutricion avanzada. Bol Med Hosp Infant
Mex 1964;31:699-714.
59. McCance RA, Crowne RS, Hall TS. The effect of malnutrition and food habits on the concentrating
power of the kidney. Clin Sci 1969;37:471-90.
60. Klahr S, Tripathy K, Garcia FT, et al. On the nature of the renal concentrating defect in malnutri-
tion. Am J Med 1967;43:84-96.
61. Gottschalk CW. Osmotic concentration and dilution of the urine. Am J Med 1964;36:670-85.
62. Jaenike JR. Urea enhancement of water reabsorption in the renal medulla. Am J Physiol 1960;
199:1205-10.
63. Alleyne GAO. Renal and cardiac function in severely malnourished Jamaican children. M.D. The-
sis, University of London, 1965.
64. Darrow DC, Yannet H. The changes in the distribution of body water accompanying increase and
decrease in extracellular electrolyte. J Clin Invest 1935;14:266.
65. Hood VL. Fluid and electrolyte disturbances during starvation: protein-caloric malnutrition. In:
Kokko JP, Tannen RL, eds. Fluids and electrolytes. Philadelphia: W.B. Saunders Co, 1986;733-
41.
66. Klahr S, Tripathy K, Lotero H. Renal regulation of acid-base in malnourished man. Am J Med
1970;48:325-31.
67. Smith R. Urinary acidification defect in chronic infantile malnutrition. Lancet 1959;i:764.
68. Edelman CM, Houston IB, Soriano JB, et al. Renal excretion of hydrogen ion in children with idio-
pathic growth retardation. J Pediatr 1968;72:443-51.
 RENAL FUNCTION IN PEM 325

69. Waterlow JC, Wills VS. Balance studies in malnourished Jamaican infants. I. Absorption and reten-
tion of nitrogen and phosphorus. Br J Nutr 1960; 14:183-98.
70. Gordillo-Paniagua G. La nefrosis kaliopenica en la desnutricidn avanzada. Gac Med Mex 1959;89:
935-41.
71. Kulka JP, Pearson CM, Robbins SL. A distinctive vacuolar nephropathy associated with intestinal
disease. Am J Pathol 1950;26:349-77.
72. Odessky L, Burdison WR. Intestinal lipodystrophy (Whipple's disease) occurring with parathyroid
hyperplasia and nephrosis: report of a case with autopsy. Arch Pathol 1950;49:307-20.
73. Jensen E, Baggenstoss AH, Bargen JA. Renal lesions associated with chronic ulcerative colitis. Am
JMedSci 1950;219:281-90.
74. Keye JD. Death in potassium deficiency: report of a case including morphologic findings. Circula-
tion 1952;5:766-70.
75. Follis RH, Orent-Keiles E, McCollum EV. The productions of cardiac and renal lesion in rats by a
diet extremely deficient in potassium. Am J Pathol 1942;18:29-39.
76. Schrader GA, Prickett CO, Salmon WD. Symptomatology and pathology of potassium and magne-
sium deficiencies in the rat. J Nutr 1937;14:85-109.
77. Kerpel-Fronius E, Romhanyi G, Gati B, Dobak E. Influences of depletion of potassium, of sodium,
or of water on function and structure of the kidney. Pediatrics 1960;26:939—49.
78. Relman AS, Schwartzs WB. The nephropathy of potassium depletion: a clinic pathologic entity (ab-
str). J Clin Invest 1955;34:959.
79. Conn JW, Johnson RD. Kaliopenic nephropathy. Am J Clin Nutr 1956;4:523-8.
80. Hollander W, Blythe WB. Nephropathy of potassium depletion. In: Strauss MB, Welt LG, eds.
Diseases of the kidney, 2nd ed. Boston: Little, Brown, 1971;675—712.
81. Brenner BM, Meyer TW, HostetterTH. Dietary protein intake and the progressive nature of kidney
disease: the role of hemodynamically mediated glomerular injury in the pathogenesis of progressive
glomerular sclerosis in aging, renal ablation, and intrinsic renal disease. N Engl J Med 1982;
307:652-9.
82. Velosa JA, Glasser RJ, Nevins TE, Michael AF. Experimental model of focal sclerosis. II. Correla-
tion with immunopathologic changes, macromolecular kinetics, and polyanion loss. Lab Invest
1977;36:527-34.

DISCUSSION

Dr. Suskind: Can the changes in renal function in the marasmic child be differentiated from
those in a child with kwashiorkor?
Dr. Gordillo-Paniagua: I did not find differences between them, either in renal clearance,
in the concentrating defect, in diluting function, or in excretion of free water.
Dr. Monckeberg: What is your opinion regarding high concentrations of protein during
treatment of severely malnourished children?
Secondly, malnourished infants are often dehydrated because of acute diarrhea. UNICEF
has recommended a solution of approximately 90 mEq of sodium per liter. I think that this is
too high. In our experience, more than 60 or 70 mEq produces hypernatremia, which puts a
malnourished child at great risk. Could you comment on this?
Dr. Gordillo-Paniagua: Although I have the impression that children with severe protein-
energy malnutrition (PEM) do recover all renal function parameters once nutritional repletion
has occurred, we really should begin to study renal-functional reserve to be sure. I am con-
cerned about giving large quantities of protein initially to children with reductions of glo-
merular filtration rate (GFR) that is 50% below normal values. There are experimental and
clinical studies showing that a chronic protein load administered to subjects with diminished
renal mass might produce glomerular hyperfiltration, leading to development of glomerular
sclerosis with later deterioration of renal function (1,2). My own advice would be not to ex-
326 RENAL FUNCTION IN PEM

ceed 5 g/kg-day of protein to these children. This is, of course, a problem that needs further
investigation.
Regarding sodium, Alleyne (3) has demonstrated that urinary sodium excretion is less dur-
ing severe malnutrition than after repletion. It is conceivable, therefore, that severely mal-
nourished and dehydrated children may develop edema or hypervolemia if they receive
solutions containing 90 meq/liter of sodium.
In the past, when we tried to bring up serum osmolality from 270 mOsm/liter to 290
mOsm/liter, we had some circulatory complications such as acute pulmonary edema. We
were, however, using intravenous fluids with 75 mEq/liter of sodium. Oral loading might not
be as harmful, but it still may be risky.
Dr. M. Mehta: We were also concerned with the UNICEF recommendations. Our solution
was to alternate one feed of the high-sodium formula with either breast milk or plain boiled
water. My concern, however, is with having too many oral rehydration therapy (ORT) solu-
tions, which may, in fact, confuse the population.
Dr. Gordillo-Paniagua: Although high doses of sodium may be a solution for some chil-
dren, there is clearly a potential risk for the malnourished child. We know that if we suddenly
increase the serum osmolality, by giving large amounts of sodium, we may produce a hyper-
volemia and acute pulmonary edema.
Dr. Jackson: It is possible to promote the loss of edema in children taking 0.6 g protein/
kg-day without any change in the concentration of serum albumin (4). Presumably, this re-
lates to the treatment of infection, the repletion of potassium, and, perhaps, magnesium defi-
ciency.
Brooke and Kerr (5) showed that the prevalence of urinary tract infection in malnourished
males may be as high as 10%. The infection is generally cleared with standard therapy and
does not seem to be associated with any longer term sequelae, unlike what one would expect
in a normal child. In your experience, have you found that infection is associated with pyelo-
nephritis or gives rise to more chronic renal damage?
Dr. Gordillo-Paniagua: I have not seen an increase in urinary tract infection or nephritis
in malnourished children. They have one defense, which is polyuria, and one weakness,
which is hypokalemia.
Dr. Suskind: We also saw a significant increase in the prevalence of urinary tract infection
in the children we studied.
Dr. Keusch: Of male children with acute kwashiorkor, 25 to 30%, although not necessarily
symptomatic, may have urinary tract infections. The bacterial cultures cleared spontaneously
without any antimicrobial therapy in most of the children.
While we think bacteriuria may be a source of gram-negative bacteremia, its frequency in-
dicates that there are changes in the urinary tract surface mucosa in which suppression of host
defenses allows colonization to occur. Although this bacteriuria clears spontaneously, the
prevailing thought is to treat it specifically, although perhaps this is unnecessary.
Dr. Suskind: Decreased urinary secretory lgA has been reported. Our observations were
similar to those made in South Africa: that there is a decreased respiratory secretory IgA.
Dr. Soriano: With ultrasonography, we can now follow the size of the kidney in the mal-
nourished child during recovery to see if the kidney increases quickly or slowly, paralleling
the increase in lean body mass. Such a study could be complemented with functional studies
to better understand the relationship between the structure and function of the kidney in mal-
nutrition.
Dr. Warrier: Are you aware of any study implicating aminoglycosides in terms of long-
term effects on kidney function?
 RENAL FUNCTION IN PEM 327

Dr. Gordillo-Paniagua: Dr. Leopoldo Vega, who studied the renal excretion of aminogly-
cosides in malnourished children, found that these children had a reduction in the proximal
tubular excretion with a consequent lengthening of its half life. He (personal communication)
recommends administering this antibiotic to malnourished children with the same caution one
would use if they had renal insufficiency, in order to avoid nephrotoxic or ototoxic effects.
Dr. Keusch: An enormous number of studies have been done on the question of the sodium
content in oral rehydration solutions. The composition of the WHO formula is based on early
cholera work. The safety of that formula depends on two factors. Are the children regulating
their own fluid intake? What is the status of renal function?
It is important that the WHO ORS with 90 mEq of sodium be supplemented with free
water, preferably breast milk. Hypertonic dehydration is not a phenomenon in the breast-fed
child, but the result of formula feeding in the developing world. It is not an important issue
in the selection of ORS for developing countries. There may be a rationale for countries that
do not have cholera to consider a single formula with a lower sodium content. But, to my
knowledge, and there have been extensive studies by the WHO/CDC (Centers for Disease
Control) program, there is no evidence of any harm in using the 90-mEq/liter solution for di-
arrhea of any etiology, including rotavirus, with losses of only 25 mEq as opposed to 90
mEq/liter or greater, as in cholera.
Dr. Guesry: I am surprised to hear you say this, because there was a paper written by Kohn
and Blum (6) showing severe hypernatremia and hyperkalemia in infants receiving 90 meq of
sodium per liter.
Regarding potassium-losing nephropathy, in our work on Bartter syndrome, we found an
abnormally high excretion of prostaglandin (PG)E2a- There is also, of course, a deficiency of
long-chain polyunsaturated fatty acids, which induces secretion of prostaglandins. Has any-
one looked at the excretion of prostaglandins in PEM?
Dr. Gordillo-Paniagua: I am not aware of any studies, but I believe there should be. Re-
garding oral rehydration with Na (90 meq/liter), I completely agree that this is a solution for
the treatment of dehydration in rural areas, particularly where there is cholera, but not for
routine hospital treatment, where we can, and should, tailor the treatment according to the
specific patient needs.
Dr. Pudjiadi: I feel we should be cautious about the use of high sodium. We had an inci-
dent of a malnourished baby who when given the high-sodium solution became severely
edematous.
Dr. Monckeberg: An excess of sodium given to a malnourished child may cause brain
damage. In addition, we have observed that in undernourished, dehydrated children, renal
plasma flow can decrease to about one-third of normal. There is, simultaneously, a diminu-
tion of glomerular filtration, which almost stops renal function.
At the same time, dehydration due to diarrhea is always accompanied by metabolic acido-
sis and transpiration, increasing water loss via lung and skin.
All of this results in two important phenomena: a tendency to dehydration with hyperna-
tremia and loss of renal capacity to regulate sodium excretion.
Because 90 mEq of sodium will, therefore, lead to hypernatremia, it is preferable to give
less sodium rather than risk overdose, at least until the capacity of renal regulation has been
reestablished.
Dr. Keusch: In terms of a public health approach for the treatment of dehydration, I believe
ORT should be considered appropriate for both the well-nourished as well as the moderately
malnourished child. The oral rehydration fluid with the 90 mEq of Na plus the provision of
free water, preferentially in the form of breast-feeding, is well handled by the malnourished
328 RENAL FUNCTION IN PEM

child. There is an enormous body of data collected by WHO that clearly demonstrates that.
No doubt, medical triage should be added to this concept.
Dr. Okeahialam: The use of the UNICEF ORT solution in developing countries is both
safe and cost-effective. It is most appropriate for the well-nourished child with diarrhea. In
this capacity, ORT functions as early intervention to avoid deaths due to dehydration. It re-
duces the need for setting up intravenous fluid therapy and the involvement of doctors in the
management of most cases of acute diarrhea. We must be aware that most cases of PEM in
developing countries are precipitated by diarrhea and dehydration, making ORT effective in
preventing severe malnutrition.
Dr. Suskind: Has anyone studied renal function in previously malnourished children?
Dr. Gordillo-Paniagua: Although I am not aware of any studies, I suspect that mycotoxins
may be involved in the unexplained chronic uremia that I have seen in several chronically
malnourished children. Similar etiologic agents have been suggested to explain endemic geo-
graphic nephropathies like Balkan nephropathy (7).
Dr. Soriano: Perhaps an experimental model could be set up in protein-energy-deprived
animals that are re-fed with a high-protein diet to see if glomerular sclerosis can be repro-
duced with high protein intake after protein depletion, similar to what has been seen by Bren-
ner (2) following protein administration to rats with reduced renal function.
Dr. Gordillo-Paniagua: I agree that this would be experimentally difficult. It is important
to consider, however, that many adolescents who were malnourished children appear with
chronic renal failure without a previous history of renal disease. One can only speculate that
their early episode of malnutrition had something to do with their present renal failure. I
think, perhaps, that this end-stage renal disease may develop as a result of a chronic disease
such as interstitial nephritis, which, since it presents with an often overlooked polyuria, has
had a silent clinical course that evolved into chronic renal failure.
We would like to be able to study patients who had had severe early malnutrition, chal-
lenge them with an acute protein oral load in order to explore their renal-functional reserve,
and assess their potential risk for developing further renal insufficiency.

REFERENCES

1. Bosch JP, et al. Renal functional reserve in humans. Effect of protein intake on glomerular filtration
rate. AmJMed 1983;75:943-50.
2. Brenner BM, et al. Dietary protein intake and the progressive nature of kidney disease: the role of
hemodynamically mediated glomerular injury in the pathogenesis of progressive glomerular sclerosis
in aging, renal ablation and intrinsic renal disease. N EnglJ Med 1982;307:652-9.
3. Alleyne GAO. Renal and cardiac function in severely malnourished Jamaican children. M.D. Disser-
tation, University of London, 1965.
4. Golden MH, et al. Albumin and nutritional oedema. Lancet 1980;i: 114-6.
5. Brooke OG, Kerr DS. The importance of routine urine culture in malnourished children. J Trop Pedi-
atr Environ Child Health 1973;19:348-9.
6. Kohn A, Blum D. Hyperkalaemia and UNICEF type rehydration solutions (letter). Lancet 1980;
i:1082.
7. Hall PW, et al. Renal function studies in individuals with the tubular proteinuria of endemic Balkan
nephropathy. Q J Med 1972;41:385-93.