Department of Medicine, University of British Columbia, Vancouver Hospital and Health Sciences Centre, Koerner Pavilion, Vancouver, British Columbia, Canada V6T 1Z3
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ABSTRACT |
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Insulin has been shown to be a
magnesium-conserving hormone acting, in part, through stimulation of
magnesium absorption within the thick ascending limb. Although the
distal convoluted tubule possesses the most insulin receptors, it is
unclear what, if any, actions insulin has in the distal tubule. The
effects of insulin were studied on immortalized mouse distal convoluted
tubule (MDCT) cells by measuring cellular cAMP formation with
radioimmunoassays and Mg2+ uptake with fluorescence
techniques using mag-fura 2. To assess Mg2+ uptake, MDCT
cells were first Mg2+ depleted to 0.22 ± 0.01 mM by
culturing in Mg2+-free media for 16 h and then placed in
1.5 mM MgCl2, and the changes in intracellular
Mg2+ concentration
([Mg2+]i) were measured with
microfluorescence. [Mg2+]i returned
to basal levels, 0.53 ± 0.02 mM, with a mean refill rate,
d([Mg2+]i)/dt, of 164 ± 5 nM/s. Insulin stimulated Mg2+ entry in a
concentration-dependent manner with maximal response of 214 ± 12 nM/s, which represented a 30 ± 5% increase in the mean uptake rate
above control values. This was associated with a 2.5-fold increase in
insulin-mediated cAMP generation (52 ± 3 pmol · mg
protein1 · 5 min
1). Genistein, a tyrosine kinase inhibitor,
diminished insulin-stimulated Mg2+ uptake (169 ± 11 nM/s), but did not change insulin-mediated cAMP formation (47 ± 5 pmol · mg
protein
1 · 5 min
1). PTH stimulates Mg2+ entry, in
part, through increases in cAMP formation. Insulin and PTH increase
Mg2+ uptake in an additive fashion. In conclusion, insulin
mediates Mg2+ entry, in part, by a genistein-sensitive
mechanism and by modifying hormone-responsive transport. These studies
demonstrate that insulin stimulates Mg2+ uptake in MDCT
cells and suggest that insulin acts in concert with other peptide and
steroid hormones to control magnesium conservation in the distal
convoluted tubule.
intracellular magnesium; fluorescence; insulin; genistein; tyrosine kinase; intracellular adenosine 3',5'-cyclic monophosphate; parathyroid hormone; aldosterone; extracellular calcium sensing; neomycin
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INTRODUCTION |
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INSULIN HAS PROFOUND EFFECTS on renal electrolyte transport, including magnesium conservation (3, 10, 11, 17, 22, 23, 27, 29). Insulin receptors are present in all tubule segments, so these actions may occur along the length of the nephron (4, 33). De Fonzo et al. (10, 11) first showed that insulin increases sodium reabsorption beyond the proximal tubule, and Kirchner (26) reported that insulin increased chloride transport in the loop of Henle. These micropuncture studies were supported by Ito et al. (25) using in vitro microperfusion of medullary thick ascending limb segments. Finally, Mandon et al. (29) have shown that insulin stimulates active NaCl transport and passive calcium and magnesium transport in the mouse cortical thick ascending limb. The effects of insulin on magnesium transport in other tubular segments have not been investigated. Among the tubular segments studied, insulin receptor binding is highest along the medullary thick ascending limb and distal convoluted tubule; so by inference insulin may affect electrolyte transport within these segments (4, 16, 33). The medullary thick ascending limb does not absorb much magnesium (29, 43). The distal tubule normally reabsorbs ~10% of the filtered magnesium, which is 70-80% of that delivered to it from the loop of Henle (39). As there is little magnesium reabsorption beyond the distal tubule, this segment determines the final amount excreted in the urine. Hormonal control of magnesium transport in the distal tubule likely plays an important role in determining renal magnesium homeostasis.
In the present studies, we use an immortalized mouse distal convoluted tubule (MDCT) cell line to determine the cellular mechanisms of insulin stimulation on Mg2+ uptake. The MDCT cell line possesses many of the properties of the intact distal convoluted tubule (19, 39). The MDCT cells exhibit amiloride-inhibitable sodium transport and chlorothiazide-sensitive NaCl cotransport. Amiloride and chlorothiazide also stimulate Ca2+ and Mg2+ entry in these cells (8, 19). Furthermore, parathyroid hormone (PTH) and calcitonin stimulate calcium (18, 19) and magnesium (unpublished observations) uptake, and arginine vasopressin (AVP) and glucagon enhance Mg2+ entry into MDCT cells (6). We have also reported that these hormones stimulate Mg2+ uptake by signaling pathways involving intracellular cAMP formation (6).
Furthermore, aldosterone potentiates glucagon- and AVP-stimulated Mg2+ uptake by increasing hormone-mediated cAMP production (9). Finally, activation of the extracellular polyvalent cation receptor with elevated Ca2+, Mg2+, or neomycin inhibited hormone-stimulated cAMP formation and Mg2+ uptake (1, 2). Accordingly, MDCT cells are useful in vitro models with which to investigate the cellular mechanisms of individual hormones and hormonal interactions that are difficult to study in situ with intact distal tubules. In these studies, we determined Mg2+ entry into MDCT cells by first Mg2+ depleting the cells by culturing in magnesium-free media for 16 h. The Mg2+-depleted MDCT cells were then placed in medium containing 1.5 mM magnesium, and the refill rate, d([Mg2+]i)/dt (where [Mg2+]i is the intracellular Mg2+ concentration), was measured with microfluorescent studies using mag-fura 2. Evidence supports the notion that Mg2+ uptake reflects transepithelial transport (39). Mg2+ uptake rate is rapid, concentration dependent, and selective for magnesium (8). In the present study, we show that insulin stimulates Mg2+ uptake into MDCT cells, and we characterize some of the interactions with PTH and aldosterone and the effects of the Ca2+/Mg2+-sensing receptor.
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METHODS |
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Materials. Basal Dulbecco's minimal essential medium and Ham's F-12 medium (DMEM-F12) were purchased from GIBCO (Life Technologies, Gaithersburg, MD). Fetal calf serum (FCS) was from Flow Laboratories (McLean, VA). Mag-fura 2-AM was obtained from Molecular Probes (Eugene, OR). The protein kinase A inhibitor, RpcAMPS (the Rp diastereoisomer of adenosine 3',5'-cyclic monophosphothionate) was purchased from Calbiochem (San Diego, CA). Insulin, genistein, and other materials were from Sigma (St. Louis, MO).
Cell culture. Immortalized MDCT cells were kindly provided to us by Dr. P. A. Friedman. They have been extensively characterized by Drs. P. A. Friedman and F. A. Gesek (19). The MDCT cell line was cultured in DMEM-F12, 1:1, media supplemented with 10% FCS, 1 mM glucose, 5 mM L-glutamine, 50 U/ml penicillin, and 50 µg/ml streptomycin in a humidified environment of 5% CO2-95% air at 37°C. For the cAMP determinations, the MDCT cells were cultured to confluence in 24-well plastic dishes. Sixteen hours prior to the cAMP measurements, the culture medium was changed to one containing 0.2% bovine serum albumin (BSA) in lieu of the FCS. For the fluorescence studies, confluent cells were washed three times with PBS containing 5 mM EGTA, trypsinized, and seeded on glass coverslips. Aliquots of harvested cells were allowed to settle onto sterile glass coverslips in 100-mm Corning tissue culture dishes, and the cells were grown to confluence over 4-6 days in supplemented media as described above. The normal media contained 0.6 mM magnesium and 1.0 mM calcium. In the experiments indicated, the cells were cultured in nominally magnesium-free media (<0.01 mM) for 16 h prior to study; 0.2% BSA replaced FCS during this period. Other constituents of the magnesium-free media were identical to those of the complete media.
cAMP measurements. cAMP was determined in confluent MDCT cell monolayers cultured in 24-well plates in DMEM-F12 media without serum as previously reported (6). After addition of the agonists, MDCT cells were incubated at 37°C for 5 min in the presence of 0.1 mM IBMX. The cAMP was extracted with 5% trichloroacetic acid, which was removed with ether acidified with 0.1 N HC1. The aqueous phase was dried, then dissolved in Tris-EDTA buffer, and cAMP was measured with a radioimmunoassay kit (Diagnostic Products, Los Angeles, CA).
Cytoplasmic Mg2+ measurements. Coverslips were mounted into a perfusion chamber, and the attached subconfluent cells were incubated with 5 µM mag-fura 2-AM dissolved in Pluronic acid F-127 (0.125%; Molecular Probes) for determination of intracellular Mg2+ concentration ([Mg2+]i) in media for 20 min at 37°C. Cells were subsequently washed three times with buffered salt solution containing (in mM) 145 NaCl, 4.0 KCl, 0.8 K2HPO4, 0.2 KH2PO4, 1.0 CaCl2, and 20 HEPES-Tris, at pH 7.4. The MDCT cells were incubated for a further 20 min to allow for complete deesterification and washed once before measurement of fluorescence.
Epifluorescence microscopy was used to monitor changes in the mag-fura 2 fluorescence of the MDCT cell monolayer. The chamber was mounted on an inverted Nikon Diaphot-TMD microscope, with a Fluor ×100 objective, and fluorescence was monitored under oil immersion within a single cell over the course of study. Fluorescence was recorded at 1-s intervals using a dual-excitation wavelength spectrofluorometer (Delta-scan; Photon Technologies, Princeton, NJ) with excitation for mag-fura 2 at 335 and 385 nm (chopper speed set at 100 Hz) and emission at 505 nm. Media changes were made without an interruption in recording.
The free [Mg2+]i was calculated from the ratio of the fluorescence at the two excitation wavelengths as previously described (8) using a dissociation constant (Kd) of 1.4 mM for the mag-fura 2 · Mg2+ complex. The minimum (Rmin) and maximum (Rmax) ratios were determined for the cells at the end of each experiment using 20 µM digitonin. Rmax for mag-fura 2 was found by the addition of 50 mM MgCl2 in the absence of Ca2+, and Rmin was obtained by removal of Mg2+ and addition of 100 mM EDTA, pH 7.2. The excitation spectrum of the cellular mag-fura 2 under these conditions was similar to that of free mag-fura 2 in the same solutions.
Statistical analysis. Representative tracings of fluorescent intensities are given, and significance was determined by Students' t-test or Tukey's analysis of variance as appropriate. A probability of P < 0.05 was taken to be statistically significant. All results are means ± SE where indicated.
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RESULTS |
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Insulin stimulates Mg2+ uptake in MDCT
cells. To determine Mg2+ uptake, subconfluent MDCT
monolayers were cultured in magnesium-free medium for 16 h. These cells
possessed a significantly lower
[Mg2+]i, 0.22 ± 0.01 mM, than cells cultured in normal media, 0.53 ± 0.02 mM. When the
Mg2+-depleted MDCT cells were placed in a bathing solution
containing 1.5 mM MgCl2,
[Mg2+]i
increased with time and leveled at a
[Mg2+]i of 0.49 ± 0.08 mM
(n = 9), which was similar to basal levels observed in normal
cells (Fig. 1). The average rate of refill, d([Mg2+]i)/dt, measured as
the change in [Mg2+]i with time,
was 164 ± 5 nM/s (n = 9 cells), as determined over the first
500 s following addition of 1.5 mM MgCl2 (6).
Mg2+ uptake is inhibited by a number of inorganic cations
such as La3+ and Mn2+ and by organic channel
blocks such as nifedipine but not Ca2+ (8). We used this
approach to determine the effects of insulin on Mg2+ uptake
into MDCT cells.
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Insulin added to the refill solution increased the rate of
Mg2+ entry into Mg2+-depleted MDCT cells.
Insulin, 107 M, increased the mean Mg2+
entry rate from 164 ± 5 to 214 ± 13 nM/s (n = 5) which
represented a stimulation of 30 ± 5% above control values measured
after 500 s (Fig. 2). Insulin increases
Mg2+ uptake so that
d([Mg2+]i)/dt is not linear
over the 500-s time frame, and therefore this value is an
underestimation. In all cases where measured, [Mg2+]i returned to basal levels,
0.47 ± 0.05 mM, in insulin-treated cells, similar to control
observations. The effect of insulin on Mg2+
uptake was concentration dependent, with maximal rate of stimulation at
10
7 M of 214 ± 13 nM/s (n = 5) and with
half-maximal stimulation at a concentration about
10
8 M. We have previously reported
that dihydropyridines inhibit Mg2+ uptake into
Mg2+-depleted MDCT cells (8). To determine whether
insulin-induced Mg2+ entry is mediated through a
dihydropyridine-sensitive pathway, we examined the effect of the
channel blocker, nifedipine, on the changes in
[Mg2+]i following placement in the
refill buffer solution containing 1.5 mM MgCl2. The
presence of 10
5 M nifedipine inhibited
insulin-stimulated Mg2+ uptake to 24 ± 2 nM/s, which was similar to that observed in control cells
(8). These findings support the notion that insulin-stimulated uptake
is the same as the entry pathway observed in control cells.
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Next, we determined the effect of genistein, a specific inhibitor of
tyrosine protein kinases, on insulin-stimulated Mg2+ uptake
(Fig. 3). Genistein inhibits by competing
with ATP for the binding site in the catalytic domain of tyrosine
kinases (46). Cells were pretreated with genistein, 50 µM, for 1 h
prior to the addition of insulin. Genistein inhibited
insulin-stimulated uptake to 170 ± 14 nM/s, suggesting
that the effect of insulin depends on receptor -subunit tyrosine
autophosphorylation or tyrosine kinase substrate phosphorylation.
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Insulin stimulates cAMP formation in MDCT cells. As cAMP
increases Mg2+ entry into MDCT cells, we determined the
effect of insulin on cAMP release in these cells (6). Insulin increased
cAMP syntheses in a concentration-dependent manner with a maximal
stimulation at about 106 M (Fig.
4). These studies show that MDCT cells have
insulin receptor signaling pathways that stimulate adenylate cyclase
activity, resulting in an increase in intracellular cAMP levels (36,
44, 47, 49). Accordingly, insulin may affect Mg2+ uptake
into MDCT cells by stimulating cellular cAMP formation (6). To test
this notion, we determined the effect of protein kinase A inhibition on
insulin-stimulated Mg2+ uptake. RpcAMPS, a competitive
inhibitor of protein kinase A, was applied 5 min prior to performing
Mg2+ uptake measurements (8). RpcAMPS did not inhibit
insulin-stimulated uptake, suggesting that activation of protein kinase
A is not involved with insulin actions (Fig. 3).
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Insulin and PTH stimulate Mg2+ uptake
by additive mechanisms. We have shown that PTH increases
Mg2+ entry into MDCT cells by intracellular pathways
involving, in part, cAMP-mediated pathways (unpublished observations).
As insulin associates with many different hormone signaling pathways,
including cAMP-dependent mediation, we measured cAMP formation and
Mg2+ uptake in cells treated with both hormones. PTH + insulin increased cAMP levels and Mg2+ entry rates to a
greater extent than each of the hormones alone (Fig.
5). These data give credence to the notion
that insulin potentiates PTH-stimulated Mg2+ uptake.
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Aldosterone does not potentiate insulin-stimulated Mg2+
uptake in MDCT cells. We have previously shown that aldosterone,
applied 16 h prior to experimentation, potentiates PTH-, calcitonin-, glucagon-, and AVP-mediated cAMP generation, which in turn increases Mg2+ uptake (4, 9). Although the cellular mechanisms are
not known, it has been speculated that aldosterone-induced proteins increase the receptor-adenylate cyclase coupling in epithelial cells
(12, 13). In the present study, we determined whether pretreatment of
MDCT cells with aldosterone for 16 h potentiates the acute
actions of insulin. Treatment of cells with aldosterone for 16 h prior
to study did not significantly increase insulin-mediated cAMP
generation nor insulin-stimulated Mg2+ uptake, even though
it increased PTH responses (Fig. 6).
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Activation of the extracellular
Mg2+/Ca2+-sensing mechanism does not inhibit
insulin-stimulated cAMP generation but diminishes Mg2+
uptake. MDCT cells possess extracellular
Mg2+/Ca2+-sensing mechanisms that, upon
activation with polyvalent cations such as Mg2+,
Ca2+, or neomycin, inhibit PTH-, calcitonin-, glucagon-,
and AVP-mediated cAMP generation and glucagon- and AVP-stimulated
Mg2+ uptake (1, 2). To determine whether activation of
Mg2+/Ca2+ sensing alters insulin actions, we
pretreated cells for 5 min with neomycin prior to the addition of
insulin and MgCl2. Neomycin did not affect insulin-mediated
cAMP formation but modestly diminished insulin-stimulated
Mg2+ uptake (Fig. 7). The mechanisms by
which the Mg2+/Ca2+-sensing receptor inhibit
insulin actions remain undefined. The Mg2+/Ca2+-sensing receptor is coupled to
Gi and Gs proteins that may interact with
insulin-mediated signaling pathways (1, 2).
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DISCUSSION |
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The distal tubule reabsorbs significant amounts of magnesium and plays an important role in determining the final urinary excretion rate (43). In contrast to more proximal segments of the nephron, distal magnesium transport processes are postulated to be active and transcellular in nature (39). Hormonal control of magnesium transport in this segment provides the fine-tuning of renal conservation, contributing to whole body magnesium balance. Micropuncture studies showed that magnesium reabsorption within the distal tubule is controlled by peptide hormones including PTH, glucagon, and calcitonin (43). More recently, we have shown that PTH, calcitonin, glucagon, and AVP stimulate Mg2+ entry into MDCT cells (unpublished observations and Ref. 6). The actions of these hormones are, in part, through cAMP-mediated pathways, as RpcAMPS inhibits hormonal responses. Aldosterone potentiates hormone-stimulated cAMP generation, thereby potentiating peptide hormone-responsive Mg2+ uptake (9). In the present study, we show that insulin stimulates Mg2+ uptake in MDCT cells through tyrosine protein kinase-mediated pathways. We infer from these results that insulin may modulate distal tubule magnesium transport and, together with peptide and steroid hormones, orchestrate renal magnesium conservation.
The evidence given here is that insulin stimulates Mg2+ entry into MDCT cells through genistein-sensitive tyrosine phosphorylation. Additionally, insulin stimulates cAMP formation in MDCT cells and presumably activates protein kinase A. We have shown that the peptide hormones PTH, calcitonin, glucagon, and AVP stimulate Mg entry by protein kinase A-, phospholipase C-, and protein kinase C-mediated pathways. The present studies suggest that insulin may potentiate or have additive effects on these peptide hormones. It is clear that insulin may modulate each of these pathways (5, 15, 21, 35, 38, 42). In relation to the kidney, Mandon et al. (29) have reported that insulin stimulates NaCl and magnesium transport in the perfused mouse cortical thick ascending limb. They further showed that insulin may potentiate AVP-responsive cAMP formation and magnesium transport in this segment. The potentiation of insulin and AVP may be explained by the two hormones having effects at different sites of the adenylate cyclase system (29). The interaction of insulin-mediated effects on peptide hormone responses is complicated, as aldosterone had no effect on insulin actions but potentiated PTH-stimulated cAMP (2) and Mg2+ uptake (unpublished observations). Finally, activation of Ca2+/Mg2+-sensing receptor inhibited insulin-stimulated Mg2+ uptake with no effect on intracellular cAMP formation. As in the cortical thick ascending limb, these actions may be explained by insulin inhibiting Gi and PTH activating Gs proteins of the adenylate cyclase system.
Insulin actions on cellular electrolyte transport. Insulin has clearly been shown to have antinatriuretic effects by its actions on tubular absorption within the loop of Henle (10, 11, 17, 26, 34). Using microperfusion studies, Ito et al. (24, 25) reported that insulin stimulates NaCl transport in isolated rabbit medullary thick ascending limb segments and showed that the actions were dependent on tyrosine kinase, phosphatidylinositol 3-kinase, and protein kinase C but independent of intracellular cAMP. As mentioned above, Mandon et al. (29) reported that insulin stimulates active NaCl and passive calcium and magnesium transport in perfused mouse cortical thick ascending limbs in vitro. They suggested that insulin acts on different levels on the adenylate cyclase-mediated pathways. The notion is that insulin may increase NaCl transport in the loop, thereby stimulating passive magnesium absorption. Insulin also stimulates sodium transport in A6 cells, which are a distal cell line from Xenopus laevis that has properties similar to the mammalian distal nephron (23, 31, 40). Insulin-stimulated sodium transport was partly inhibited by genistein, indicating tyrosine kinase was important (40). Insulin did not increase cAMP formation in A6 cells, nor did adenylate cyclase inhibition diminish transport (31, 41, 50). As genistein did not completely inhibit insulin actions, Rodriguez-Commes et al. (41) suggested that parallel non-tyrosine-kinase-dependent pathways were also involved. They showed that insulin actions in A6 cells required intracellular Ca2+ signaling, suggesting to these investigators that protein kinase C is needed for some of the responses. Clearly, the insulin receptor signaling pathways are different in the various epithelial cell types studied. In the present studies, we show that insulin stimulates Mg2+ uptake in MDCT cells through tyrosine kinase pathways not involving cAMP formation.
The role of insulin in renal magnesium handling. Micropuncture and microperfusion studies and experiments with isolated cells have shown that many hormones including insulin regulate magnesium absorption in the distal tubule. Interestingly, all of these hormones and factors also increase magnesium transport in the thick ascending limb of the loop of Henle (43). Accordingly, these hormone-mediated responses are serially organized to similarly regulate magnesium absorption in both the loop and distal tubule. This organization may be of benefit in that influences acting in either the loop or distal tubule may be modified by changes in the other segment.
The interactions of the various peptide and steroid hormones are complex (39, 43). It can be inferred that overall distal magnesium absorption is controlled by all of these influences initiated individually but coming together through shared intracellular signaling pathways. Few studies have been directed at describing these interactions. Clearly, control of renal magnesium handling is sufficiently important to warrant multiple hormonal control.
Finally, hypomagnesemia has been reported in ~25% of diabetic patients, and renal magnesium wasting has been associated with both type I and type II diabetes mellitus (20, 30, 37, 45, 48). As insulin stimulates magnesium conservation in the loop (29) and distal tubule (present report), insulin deficiency could explain the increase in urinary magnesium excretion. A number of indirect influences commonly present in diabetes mellitus may also explain an increase in magnesium excretion. First, uncontrolled hyperglycemia and hyperglycuria may increase excretion through osmotic diuresis (14, 28, 32). Second, metabolic acidosis commonly observed in diabetes may increase magnesium excretion by its actions within the distal tubule (7). Finally, hypophosphatemia and hypokalemia are often associated with diabetes, and both may decrease distal magnesium reabsorption (37, 39). Insulin deficiency with any one of these indirect entities may underlie the diminished magnesium reabsorption and hypomagnesemia commonly observed in diabetes mellitus.
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ACKNOWLEDGEMENTS |
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We thank Dr. Peter Friedman for providing the MDCT cell line.
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FOOTNOTES |
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This work was supported by Medical Research Council of Canada Research Grant MT-5793 (to G. A. Quamme) and by the Kidney Foundation of Canada.
The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. §1734 solely to indicate this fact.
Address for reprint requests and other correspondence: G. A. Quamme, Department of Medicine, Vancouver Hospital and Health Sciences Centre, Koerner Pavilion, 2211 Wesbrook Mall, Vancouver, BC, Canada V6T 1Z3 (E-mail:quamme{at}interchange.ubc.ca).
Received 25 February 1999; accepted in final form 6 August 1999.
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