Toxicology Letters, 46 (1989) 227-235 221

TXL 02134

Renal functional reserve

G. Friedlander, F. Blanchet and C. Amiel

U 251, Institut National de la SantP et de la Recherche MPdicale, Laboratoire de Physiologie r&ale,
FacultP de Midecine Xavier Bichat, UniversitP Paris VII, 16, rue Henri Huchard, 75018 Paris (France)

SUMMARY

Renal functional reserve represents the capacity of the kidney to increase its level of operation in
response to certain demands. The reserve of glomerular filtrationrate and of renal blood flow is discuss-
ed from the following points of view: evaluation, measurement;-tnechanisms involved and significance.
Data from the literature are discussed which show (i) that the mechanism of the hyperfiltration seen in
the early stage of diabetic nephropathy may be different from the hyperfiltration induced by infusion
of amino acids, (ii) that the remaining kidney in healthy kidney donors maintains its functional reserve,
and (iii) that the functional reserve is fairly well maintained as long as the glomerular filtration rate is
decreased only moderately. The reserve of tubular functional capacity is discussed from the point of view
of concentration and dilution and of acidification and alkalinization.

INTRODUCTION

The concept of renal functional reserve, which emerged recently, has been defined
as the ability of the kidney to ‘increase its level of operation under certain demands’
[ 11. Renal functional reserve is usually considered to be an increase in renal blood
flow and in glomerular filtration rate which can be elicited in a number of ways.
The concept might be extended, however, to other situations in which tubular func-
tion is challenged: maximal urinary concentration and dilution, and maximal
urinary acidification and alkalinization. This paper, therefore, addresses both the
reserve of renal blood flow and glomerular filtration rate and the reserve of tubular
functional capacity.

RESERVE OF RENAL BLOOD FLOW (RBF) AND GLOMERULAR FILTRATION RATE (GFR)

RBF and GFR have been shown to increase after an oral load of protein [2-51,
after infusion of amino acids 16-121 and after administration of several vasodilatory
drugs [ 13- 151. Functional reserve can be defined as the increment of GFR induced
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by an adequate stimulus, and the maximal GFR obtained during the manoeuvre
represents the filtration capacity [16,17].

Evaluation
One major problem in the evaluation of RBF and GFR functional reserve in man
is in defining a standardized stimulus. The most widely used stimulus has been an
acute oral protein load, consisting of cooked red meat representing 70-150 g protein
(l-2 g/kg body weight), usually ingested over a 30-min period [3,5,14,16,18-201.
Peak values of RBF and GFR are reached l-2 h after the load [3]. Amino acid infu-
sions have been shown to induce changes in GFR and RBF similar to those induced
by an oral protein load; but the infusion rates and duration of infusion used have
been highly variable, ranging from l-8 mg/min per kg body weight, and 45 min to
18 h, respectively [9-12,151. The time course of the renal response depends on the
infusion rate: peak values are reached 30-180 min after the beginning of infusion.
Infusions of individual amino acids, such as glycine and alanine, have proved to be
efficient in increasing RBF and GFR in dogs [2,7,8], but such infusions have not
been used extensively to evaluate renal functional reserve in man [21]. Increases in
GFR and RBF have also been observed during glucagon infusion, in both animals
and man [4,7,8,22-261. In man, significant increases in GFR were obtained with
glucagon infusion rates as low as 4 ng/min per kg body weight, which induced a
three-fold increase in basal plasma glucagon concentration [26]. The vasodilatory
drug dopamine is well known to increase RBF and GFR without affecting cardiac
output or systemic resistance when infused at a low rate (1.5-2 pg/min per kg body
weight) [13,15].

Measurement
GFR is usually measured as inulin clearance and RBF as p-aminohippurate
clearance. Iodinated substances such as ‘251-iothalamate and ‘311-iodohippurates
have also been used [10,13,15,24].
Alterations in GFR and RBF vary according to whether amino acids, dopamine
or a combination of the two is administered. During amino acid infusion, RBF and
GFR increase in the same proportion, resulting in a constant filtration [lo-12,151.
However, dopamine infusion induced a decrease in filtration fraction, due to a
marked increase in RBF and a modest increase in GFR [ 13,151. Combined infusion
of amino acids and dopamine increased the GFR to a greater degree than separate
infusions, and the filtration fraction was moderately decreased [15].

Mechanism
The mechanism(s) by which an amino acid (or protein) load increases RBF and
GFR is still unclear. Administration of amino acids is known to stimulate glucagon
synthesis in, and release from, endocrine pancreas [27-291. In turn, exogenous
glucagon mimics the renal effects of amino acids [7,8,12,22]. Moreover, amino
 229

acids failed to induce any change in renal haemodynamics when endogenous

glucagon release was blocked with somatostatin [4,8,11,12]. These findings indicate
that glucagon may mediate the renal effect of amino acids. Amino acid infusion
does not increase RBF or GFR in patients who have no endogenous glucagon
because of total pancreatectomy, while administration of exogenous glucagon in-
creased GFR in these patients [30]. Experiments in dogs have shown that glucagon
infusion in the renal artery cannot modify RBF or GFR, but portal infusion of
glucagon induced renal vasodilation [22]. This suggests that glucagon exerts its ef-
fects via the release by the liver of a humoral factor (‘glomerulopressin’), which re-
mains to be characterized [31-331. This hypothesis is further supported by the fact
that amino acids were ineffective in altering GFR in patients with severely impaired
hepatic function [33,34].
Other intrarenal and extrarenal mediators and hormones are believed to play a
role in amino acid-induced hyperfiltration. Inhibition of renal prostaglandin syn-
thesis with indomethacin has been shown to abolish the renal haemodynamic effects
of infused amino acids [14,18-211 and glucagon [23]. Similarly, a low sodium diet
prevents the vasodilatory effect of amino acids [35]. The finding that the converting
enzyme inhibitor captopril restores the effect of amino acids indicates a role for
angiotensin II in suppressing the response to amino acid infusion [35]. A further fin-
ding is that high protein diets alter the tubuloglomerular feedback signal [36, 371.
It has been reported that amino acids do not increase RBF and GFR in patients
deprived of growth hormone [38]. Although plasma concentrations of growth hor-
mone did not correlate with GFR values during moderate amino acid infusion [ 111,
it is conceivable that the presence of growth hormone is necessary for the activity
of amino acids at either the hepatic or the post-hepatic stage.
The renal vasodilatory effect of dopamine has been well documented. Receptors
of the DA1 subgroup, involved in activation of adenylate cyclase, have been located
in the renal vascular bed and in glomerular mesangial cells [39-411. Furthermore,
the dopamine-induced increase in RBF can be abolished in dogs by concomitant in-
fusion of the specific DA1 antagonist SCH 23390 [42].
Finally, it has been suggested recently that atria1 natriuretic peptide might play
a role in the hyperfiltration of early diabetes mellitus. Hyperglycaemia has been
shown to increase RBF in hyperfiltrating diabetic patients [43,44], whereas it had
no effect in normofiltrating diabetics or in controls [44]. This effect might be the
consequence of increased proximal reabsorption of sodium and glucose which
results in a decreased delivery of sodium to the macula densa and therefore in in-
creased GFR because of the intervention of tubuloglomerular feedback [45]. An
alternative explanation might be provided by the demonstration that there are
higher plasma concentrations of atria1 natriuretic peptide in hyperglycaemic diabetic
rats than in normoglycaemic ones [46]. This would suggest that increased, glucose-
dependent proximal reabsorption of sodium might induce extracellular volume ex-
pansion, leading to increased release of atria1 peptide.
230

Significance
Evaluation of functional reserve and filtration capacity in normal subjects has
made it possible to identify situations in which functional reserve is diminished or
abolished. This effect may be concomitant with either an increased basal GFR (thus,
hyperfiltration state) or a normal or decreased basal GFR.
Decreased functional reserve with maintained filtration capacity (hyperfiltration)
has been demonstrated in the early stages of diabetic nephropathy. The pathogenesis
of the hyperfiltration that occurs in this disease is not known, but several factors
have been incriminated, including hyperglycaemia [43,44,47], increased plasma con-
centrations of glucagon and growth hormone [48-501 and increased renal synthesis
of vasodilatory prostaglandins [5 1,521. The response of hyperfiltrating diabetic pa-
tients to a protein load was found to be quite different from that of patients with
other renal diseases, since GFR decreased following the protein load, while RBF re-
mained unchanged [5]. This fall in GFR could be the consequence of decreased per-
fusion pressure, related to a selective vasodilation of efferent arterioles, afferent
arterioles being already dilated. Early hyperfiltration has been shown to be
associated with late diabetic nephropathy [53], supporting the hypothesis that
hyperfiltration plays a role in the pathogenesis of diabetic nephropathy [50,54]. This
concept suggests that a diagnosis of hyperfiltration might be of predictive impor-
tance in the follow-up of diabetes.
In healthy kidney donors, the remaining kidney exhibits both an increased basal
GFR and an increased filtration capacity, while maintaining functional reserve;
thus, the percentage increase in GFR after a protein load is similar to that of normal
subjects [55,56].
The data summarized in Table I indicate that: (i) functional reserve in normal sub-
jects varies widely depending on the stimulus; and (ii) when expressed as stimulated
GFR minus baseline GFR, functional reserve decreases as GFR decreases; however,
when the increase is expressed as a percentage of basal GFR, the functional reserve
appears to be fairly well maintained as long as GFR is decreased only moderately
(to no less than 50% of the normal range).
Further investigation is needed to evaluate the clinical significance of altered renal
reserve. A possibly important issue is the usefulness of renal reserve for early detec-
tion of renal failure and as an indication for early conservative treatment with a low-
protein diet.

RESERVE OF TUBULAR FUNCTIONAL CAPACITY

Maximal concentrating and diluting capacity

Maximal urinary concentrating capacity The concentrating capacity of the
kidney depends on its ability (i) to generate and to maintain a corticopapillary
osmotic gradient and (ii) to make the collecting duct permeable to water, thus allow-
ing reabsorption of free water. Creation of the corticopapillary gradient depends
 231

TABLE I

RENAL RESERVE IN DIFFERENT CLINICAL SITUATIONS

Clinical situation Baseline Stimulated Difference in Reference

GFR GFR GFR no.
(ml/min) (ml/min)
ml/min %
_
Healthy subjects
Two kidneys 123 157 34 28 16
115 127 12 10 15
122 151 29 24 5
108 161 53 49 55
114 125 11 10 10

Kidney donors IO 83 13 19 16
61 14 I 10 15
115 137 22 19 55
19 98 19 24 56

Renal diseases
GFR > 90 ml/min 109 124 15 14 16
115 125 10 9 15

GFR = 30-90 mI/min 82 90 8 10 55

15 86 11 15 16
61 64 3 5 15
63 76 13 21 5

GFR < 30 ml/min 22 24 2 9 16

13 14 1 8 3

GFR = glomerular filtration rate.

primarily on sodium reabsorption by the thick ascending limb of Henle’s loop and
on the countercurrent multiplication system, whereas the permeability of the collec-
ting duct to water depends on the presence and efficiency of antidiuretic hormone
(ADH).
Concentrating capacity can be evaluated by overnight water restriction, which
results, in normal subjects, in a rise in urine osmolality above 800 mOsm/kg and
reduced urinary output (< 0.5 ml/min). Weight loss is usually less than 2% of body
weight.
The causes of decreased urinary concentrating capacity are summarized in Ref.
57. In nephrotoxicity, decreased urinary concentrating capacity is related to ac-
quired nephrogenic diabetes insipidus [58,59]. The diagnosis of this condition is bas-
ed on the demonstration of decreased urinary concentrating capacity which is not
improved by exogenous vasopression or by its antidiuretic analogue dDAVP
(desmopressin acetate).
Maximal urinary diluting capacity Maximal urinary dilution results from
an association of (i) adequate delivery of fluid to the dilution segment, (ii) efficient
232

reabsorption of sodium chloride by the thick ascending limb of Henle’s loop, and
(iii) impermeability of the collecting tubule to water in the absence of ADH.
Counterindications to investigation of maximal urinary diluting capacity are
situations in which the urinary output is obviously limited: advanced renal insuffi-
ciency, antidiuresis (congestive heart failure, hepatic cirrhosis), and, possibly, syn-
dromes of inappropriate secretion of ADH.
Maximal urinary dilution is achieved by giving an oral water load (20 ml/kg body
weight), which induces a fall in urine osmolality to below 100 mOsm/kg and an in-
crease in urinary flow rate to more than 10 ml/min. Usually, more than 80% of the
water load is excreted within 4 h. A drug-induced dilution defect might be the result
of either a syndrome of inappropriate ADH secretion or a potentiation of the renal
effect of ADH [59].

Maximal urinary acidification and alkalinization

Maximal solicitation of tubular acidification processes is evaluated on the basis
of urinary pH, ammonium and titratable acidity after an acid load (ammonium
chloride or calcium chloride). Urinary pH falls to less than 5, ammonium excretion
increases three- to five-fold, and titratable acidity increases as a function of the
decrease in urinary pH.
Maximal alkalinization is obtained after administration of a load of hypertonic
sodium bicarbonate, such that urinary pH increases to over 8 and the urinary bicar-
bonate concentration exceeds 90 mmol/l. Under these conditions, urinary PCOZ
reaches values above 80 mmHg (or urine minus blood PCOZ gradient over 40
mmHg). Fractional excretion of bicarbonate remains below 15%.
Such dynamic investigations are useful for identifying and localizing the defects
involved in tubular acidosis (summarized in Ref. 60), which is characterized by (i)
normal GFR, (ii) hyperchloraemic metabolic acidosis, and (iii) often, but not con-
sistently, insufficiently low urinary pH.
In this biological context, a normal response to an acid load excludes distal
tubular acidosis and suggests that it occurs in the proximal tubule. This can be con-
firmed by the presence of a low bicarbonate T, and more than 15% fractional bicar-
bonate excretion after an alkaline load.
An abnormal response to an acid load suggests distal tubular acidosis, which can
be confirmed by the presence of decreased Pco2, or decreased urine minus blood
Pco2 gradient, with maximal urinary alkalinization. Further information about the
mechanisms of distal tubular acidosis can be obtained from (i) neutral phosphate
infusion, which can prevent the back diffusion of H+ and therefore allow restora-
tion of normal urinary PCOZwhen the primary cause of the deficit in H+ gradient
is a back leak of H + ; and (ii) infusion of sodium sulphate, which increases luminal
electronegativity and therefore suppresses the effect of the chloride shunt, when this
mechanism is involved.
 233

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