1930 Volume 3 ‘ Number 12 . 1993

Renal and Intestinal P Transport Adaptation to LowPhosphorus Diet in Uremic Rats1

Mahmoud Loghman-Adham2

M. Loghman-Adham. Department of Pediatrics. Divi-

sion of Nephrology and Hypertension. University ofUtah School of Medicine, Salt Lake City, UT

(J. Am. Soc. Nephrol. 1993; 3:1930-1937)

ABSTRACTThe normal response of the kidney and intestine to alow-phosphorus diet (LPD) is an increased rate ofNat-dependent P transport by their brush bordermembranes (BBM). Dietary phosphorus restriction isused to reduce P accumulation in chronic renalfailure. It is not known, however, if the uremic statealters the adaptive responses to an LPD. The adap-

five response of the renal and intestinal BBM vesicles(BBMV) to LPD in acutely uremic (NX) and sham-

operated (SH) control rats placed on a normal dietor an LPD was studied. In renal BBMV, the initial Na�gradient-dependent P transport was lower in NXthan in SH rats. Na�-independent uptake was un-changed. Thyroparathyroidectomy did not reversethe reduced P transport in NX rats. Kinetic studiesshowed a reduction of the apparent Vrnax for P inBBMV from NX compared with SH rats (738 ± 69 and

1,078 ± 90 pmol/5 s.mg for NX and SH rats, respec-tively; P< 0.05; N= 5) with no change in the apparentKm. In intestinal BBMV, the initial Na’ gradient-de-pendent P1 transport was not different between SHand NX rats. There was also no difference in P trans-port kinetics between SH and NX rats. The adaptiveresponse to an LPD persisted in renal and intestinalBBMV from NX rats and was comparable to that ob-served in SH rats: +54% for SH versus +48% for NX ratsin kidney BBMV and +70.2% for SH versus +71.8% forNX rats in intestinal BBMV. It was concluded thaturemia does not affect the adaptive response of therenal or intestinal BBM to dietary phosphorus restric-tion.

I Realved March 6. 1992. Accepted January 26, 1993.

2 Correspondence to Dr. M. Loghman-Adham. Department of Pediatrics. Div�

slon of Nephrology and Hypertension, 50 North Medical Drive, University of UtahMdicoI Center. Salt Lake City, UT 84132.

1046-6673/0312-1930503.00/0Journal of the American society of NephrologyCopyright C 1993 by the American society of Nephrology

Key Words: Uremia, phosphate transport. brush border mem-

brane. adaptation

I norganic phosphate (P1) is transported across thebrush border membrane (BBM) of the renal proxi-

mal tubule and the intestinal epithelium via an ac-tive, Na� gradient-dependent transport process ( 1 -

3). This active transport is the site of various P�regulatory factors (1-4). Renal and intestinal P1transport can adapt to changes in the dietary phos-phorus intake. P transport can thus increase in re-

sponse to dietary phorphorus restriction and de-crease with excessive phosphorus intake (5-7). Atthe level of the BBM. these adaptive responses arereflected in changes in the Vm� for Na�-dependent P1transport without a change in Km (8.9).

Dietary phosphorus restriction is recommended toreduce P, accumulation in states of P, retention such

as chronic renal failure (CRF). Because the normaladaptive response to a low-phosphorus diet (LPD) isan increase in the rate of Na�-dependent P1 uptakeby the renal and intestinal BBM, the effectiveness of

the dietary Pi restriction may be reduced. Moreover,It is not known if the uremic kidney and intestineare capable of a normal adaptive response to dietary

Pt restriction. Studies in rabbit proximal tubules haveshown abnormal adaptive responses of this tubularsegment to hormones and other factors (10). We per-formed these studies to determine if the adaptiveresponse of renal and intestinal BBM persists inuremic (NX) rats. The results show that there is nodifference in the adaptive response of the renal andIntestinal BBM between NX and control animals.

METHODS

Production of Uremia

Uremia (CRF) was produced in Sprague-Dawleyrats weighing approximately 275 to 300 g by use of

the �/6, nephrectomy model (1 1 , 1 2). Rats were anes-

thetized with sodium pentobarbital (50 mg/kg/ip).and through a midline incision, the left kidney wasexposed and the upper and lower poles were ligatedwith 0 silk sutures. The kidney poles were then ex-cised, and bleeding was controlled by electrocautery.After a recovery period of 1 0 days, the contralateral

(right) kidney was removed through a flank Incision.Sham-operated (SH) animals underwent the same

procedures, except that the kidneys were manipu-

Loghman-Adham

Journal of the American Society of Nephrology 1931

lated without nephrectomy. Some animals under-

went thyroparathyroidectomy (TPTX) during the 5cc-ond surgery. The thyroparathyroids were exposedthrough a midline neck incision and excised by dcc-trocautery. The success of TPTX was confirmed byat least a 50% drop in plasma calcium levels 3 to 5 h

postsurgery. After blood collection, the TPTX an!-mals were placed on 3% glucose water containing 6.7mM calcium gluconate. After the second surgery. the

animals were left in cages for 1 wk with free accessto food and water. They were then divided into fourgroups receiving either a normal phosphorus diet

(0.95% P1. 1 .3% Ca2�: NPD) or an LPD (0.07% P1. 1.3%Ca2�) for an additional 5 days. After the completionof this period. the animals were anesthetized withpentobarbital and the remnant kidney and intestinewere removed for preparation of BBM vesicles

(BBMV).

Because of the short duration of diets, the animalswere not pair fed. There was no difference in finalweights between SH rats on LPD and those on NPD

(297 ± 28 versus 337 ± 9 g, respectively) and ne-phrectomized (NX) rats on LPD and those on NPD

(303 ± 8 versus 299 ± 1 1 g, respectively) (N = 12).Similarly. there was no difference in weights betweenSH and NX rats (same data).

Preparation of renal BBMV

BBMV were prepared by a Mg2� precipitation

method as previously described ( 1 3. 1 4). Kidneys fromtwo to three rats in each group were pooled. In SHanimals, only the portion of the left kidney corre-

sponding to the remnant kidney in NX rats was usedfor BBMV preparation.

Preparation of Intestinal BBMV

Intestinal BBMV were prepared by a double Mg2�precipitation method as described by Danisi et al.(15) and as reported in a previous publication (16).Intestines from three rats were pooled for each con-

dition. Because Na�-dependent P1 uptake is highestin thejejunum, only this segment was used. Jejunumwas defined as the first half of the small intestinedistal to the ligament of Treitz.

Transport Studies

The transport measurements were carried out at20#{176}Con freshly prepared BBMV by the use of a rapidfiltration method as previously described (13,14,16).The transport medium consisted of 100 mM manni-tol, 1 00 mM NaCl, 5 mM Tris/N-hydroxymethylpiper-azine-N’-2-ethanesulfonic acid (HEPES) (pH 7.5). andeither 0. 1 mM [32P]K2HPO4, 0.05 mM D-[3H]glucose,or 0.025 mM L-[3H]proline. For the measurement ofNat-independent uptake. NaC1 was replaced by 100

mM KC1. All transport measurements were carried

out in quadruplicate, and the results are expressedrelative to BBMV protein content, determined by themethod of Lowry et a!. ( 1 7). In renal BBMV, the initial

Na�-dependent Pt uptake was measured after 5 s of

incubation, which corresponds to the linear portionof uptake as determined previously (1 3). In intestinalBB. we conducted preliminary experiments to deter-mine the linearity of the Na�-dependent P, uptake.

Uptake remained linear after up to 20 s of incubationin BBMV from SH controls or NX animals. The initial

Na�-dependent uptake was, therefore, measured

after 1 5 5 of incubation In Intestinal BBMV. Theinitial Na�-independent uptake represented 2 to 7%and 35 to 57% of the uptake in the presence of Na�

in renal and intestinal BBMV, respectively. This com-ponent was not routinely measured.

Enzyme and Analytical Assays

The purity of the BBMV was assessed by the en-richment of the specific activity of the BBM-associ-

ated enzymes and the reduction of the activity of thebasolateral and mitochondrial enzymes. All enzy-matic assays were performed on BBMV and cortical

homogenates stored at -80#{176}C. BBM enzymes weredetermined by colorimetric methods previously de-scribed (1 3, 1 6, 1 8). Renal alkaline phosphatase activ-ity was enriched 1 1 .8 ± 1 .6 and 1 2.5 ± 2.4 times inSH and NX rats, respectively. Intestinal alkalinephosphatase was enriched 6.5 ± 0.9 and 4.9 ± 0.3times in SH and NX rats, respectively. Renal leucineaminopeptidase activity was enriched 7.5 ± 0.8 and7.3 ± 1 .5 times in SH and NX rats, respectively.

Intestinal leucine aminopeptidase was enriched 12.9± 1 .2 and 1 2.2 ± 2. 1 times in SH and NX rats,

respectively. Basolateral membrane contaminationwas assessed by the activity of Na�-K�-ATPase asmeasured by the method of Kinsolving et at. (19),

and mitochondrial contamination was assessed bythe measurement of succinate dehydrogenase by the

method of Pennington (20). The activity and enrich-ment of these enzymes were similar to those reportedin our previous studies ( 1 3, 1 6). Plasma and urine P,

were determined by the method of Chen et at. (21).Urea nitrogen and creatinine were determined bystandard methods.

The results were evaluated by t test for either groupor paired comparisons as specified in the Resultssection. Where appropriate, one-way analysis of var-iance was used for multiple comparisons. P values of�0.05 were considered nonsignificant.

RESULTS

Laboratory Values in Study Animals

Table 1 shows the values for plasma P1. creatinine,and BUN in the four groups of animals studied. After

P1 Transport Adaptation in Uremia

1932 Volume 3 ‘ Number 12 ‘ 1993

TABLE I . Laboratory values in study animals#{176}

Period I Period 2 Period 3

Plasma Phosphate (mmol/L)

SH/NPD 2.11±0.10 2.27±0.08 1.77±0.10SH/LPD 2.25 ± 0.08 2.23 ± 0.09 1.09 ± 0.07NX/NPD 2.09± 0.08 1.95± 0.14 1.57 ± 0.10

NX/LPD 2.36±0.10 1.90±0.06 0.93±0.10Plasma Creatinine (mg/dL)

SH/NPD 0.55 ± 0.05 0.50 ± 0.02 0.44 ± 0.03SH/LPD 0.44 ± 0.03 0.51 ± 0.02 0.48 ± 0.03NX/NPD 0.63 ± 0.06 1.34 ± 0.12 1.09 ± 0.09NX/LPD 0.58 ± 0.03 1.34 ± 0.11 1.12 ± 0.08

BUN (mg/dL)SH/NPD 19.9 ± 1.98 14.0 ± 0.98 15.8 ± 1.53

SH/LPD 17.1±1.40 16.6±1.34 13.0± 1.52NX/NPD 16.5± 1.45 52.2±6.04 47.4± 2.10NX/LPD 17.9±1.93 51.6±4.43 43.0±3.17

0 Rats underwent �/onephrectomy (NX) or sham nephrectomy (SH). One week after the second surgery. rats were placed on an NPD or an LPD for

5 days. Period 1. before initial nephrectomy; Period 2. at initiation of diets; Period 3, at the time of euthanasia and BBMV preparation. N = 17 to24 anImals per group.

the second nephrectomy. BUN and creatinine in-creased significantly in NX rats compared to SH an-imals, confirming the success of surgery in creatinga moderate degree of renal failure. Plasma P levelswere not different between groups before surgery(Period 1 ) or at the start of the diets (Period 2). Plasma

Pt levels decreased significantly in both groups of

animals on an LPD. Final plasma P1 levels (Period 3)on a given diet were not significantly different be-tween SH controls and NX rats.

Solute Transport in Renal BBMV From NX Rats

During the second stage of nephrectomy, some ratsunderwent acute TPTX. The animals were dividedinto three groups and placed on a normal rat chowdiet (0.95% P1) for 1 2 days before preparation ofBBMV. The results are summarized in Table 2. Theinitial Na� gradient-dependent P, transport was

lower in BBMV prepared from the remnant kidneysof NX-intact or NX-TPTX rats compared with that inrenal BBMV from SH rats (P < 0.01 ; n = 4; groups ttest). Furthermore, there was no difference in Na4-dependent P, uptake between NX-intact and NX-TPTX rats. Equilibrium uptake of P,. measured at1 20 mm, was not different between groups, suggest-Ing similar vesicle volumes.

The decreased BBMV uptake observed in NX ratswas specific for P1. because the initial (5 5) and the

equilibrium (90 mm) Na4-dependent uptakes of L-

proline and D-glucose were not different betweenBBMV from SH and NX-intact or NX-TPTX rats

(Table 2). This suggests that the decreased P1 uptakein acute uremia is not the result of a nonspecific

TABLE 2. Role of PTH in reduced P transport inacutely uremic rats#{176}

SH lntact/NX TPTX/NX

Na4-Dependent P Transport5 5 uptake 298 ± 17 158 ± 13b 197 ± 46

120 mm uptake 137 ± 16 146 ± I I 148 ± 21

Na4-Dependent D-GlucoseTransport

5 5 uptake 69 ± 6 75 ± 10 62 ± 7

90 mm uptake 39 ± 2 44 ± 3 42 ± I

Na4-Dependent i-ProlineTransport

5 5 uptake 95 ± 7 98 ± 18 105 ± 15

90 mm uptake 33 ± 5 39 ± 7 38 ± 6

0 Values are picomoles per milligram of protein. Rats underwent % NX

(lntact/NX). �/8 NX plus TPTX (TPTX/NX). or sham nephrectomy (SH).After surgery. the animals remained on normal P diets for 12 daysbefore transport measurements. Solute uptakes were measured in thepresence of 100 mM Na� gradient with 0.1 mM (P). 0.05 mM (D-

glucose). or 0.025 mM (L-proline) solute concentrations in the uptakemedia. Results are mean ± SE of four experiments.

b p < o.oi between SH and lntact/NX. Difference between lntact/NX

and TPTX/NX was not significant.

change in membrane permeability or the result ofmore rapid dissipation of the Na� gradient by theBBM.

Adaptive Response of P Transport to LPD

Figure 1 shows the adaptive response to an LPD by

the renal BBMV (Figure 1 A) and the Intestinal BBMV(Figure 1B) prepared from SH and NX rats. There was

1200

900

A*

+

600

300

B

0 Rats underwent % NX or sham nephrectomy (SH). One week afterthe second surgery. rats were placed on an NPD or an LPD for 5 daysbefore preparation of BBMV from their remnant kidney and jejunum.Na�-dependent P1transport was measured in the presence of increas-ing concentrations of K,H32P04 (25 to 1.000 MM). Results are means ±SE of three to five experiments. Data were analyzed by one-wayanalysis of variance for multiple comparisons.b p< 0.05 (1 versus 3; 2 versus 4 and I versus 2; 3 versus 4) (N= 5).

C p < 0.05 (5 versus 6; 7 versus 8). p = not significant (5 versus 7; 6

versus 8)(N= 3 to 4).

0wU)

jr-f--i

JO__ _NPD LPD NPD LPD

SHAM 5/6 NX

-�16O *

� I *

�120 I� 80

�.�40

10 _NPD LPD NPD LPD

SHAM 5/6 NX

Figure 1 . Adaptation of uremic kidney and intestine to anLPD. Animals were placed on either an NPD or an LPD for 5days before study. Initial Na4 gradient-dependent 32Ptransport was measured at 5 5 (renal BBMV, panel A) or 155 (intestinal BBMV, panel B) in vesicles prepared simulta-neously from animals in each group. Results are mean ± SEof three experiments. P< 0.005 from NPD.

a significant increase in the Na4 gradient-dependent

Pt uptake by BBMV prepared from SH or NX rats onan LPD, compared with BBMV from rats on an NPD.The extent of the adaptive response to an LPD (cx-

pressed as percent increase from control) was similarin BBMV from remnant kidney of NX rats comparedwith that of SH animals (+54% for SH versus +48%

for NX). Similarly. the extent of the adaptive responseto an LPD in intestinal BBMV was comparable in NXand SH rats (+70.2% for SH versus +71.8% for NX).

Kinetics of P Transport in Renal BBMV

Table 3 shows the kinetics of the adaptive responseof the renal BBMV from NX and SH animals. Therewas an Increase in the apparent Vm� for Na4-de-pendent P, transport in BBMV from both SH and NXanimals on LPD with no significant difference in the

apparent Km (Figure 2A). Furthermore, there was adecrease in the apparent Vm� for Na-dependent P1

transport in renal BBMV from NX rats compared with

Loghman-Adham

Journal of the American Society of Nephrology 1933

TABLE 3. Summary of kinetics of P transportadaptation#{176}

V max

(pmol/mg of protein . 5 5)

Km

(MM)

Kidney BBMVI.SH/NPDb 1,078±90 96±42. SH/LPD 1,747 ± 145 70 ± 6

3.NX/NPD 738±69 81±64. NX/LPD 1,451 ± 122 67 ± 9

Intestinal BBMV5. SH/NPDC 60 ± 6 60 ± 2

6. SH/LPD 180 ± 35 39 ± 107. NX/NPD 59 ± 7 83 ± 26

8. NX/LPD 171 ± 23 37 ± 6

that from SH animals on either dietary regimen(Table 3: Figure 3A). There was no significant differ-ence in the apparent Km for P, between BBMV fromSH and NX animals.

Kinetics of P� Transport in Intestinal BBMV

Similar to the findings in renal BBMV, there wasan increase in the apparent Vm� for P, transport inintestinal BBMV from LPD animals compared withBBMV from NPD animals. There was a small but

statistically nonsignificant reduction in the apparentKm values for animals on an LPD compared withthose on an NPD (Table 3: Figure 2B). Contrary to the

findings in renal BBMV, there was no difference inthe apparent Vm� between intestinal BBMV from SHand NX rats on either LPD or NPD (Figure 3B; Table3). Similarly, there was no significant difference In

the apparent Km for P in intestinal BBMV from SH

and NX animals.

DISCUSSION

In these studies, which were conducted in acutelyuremic rats, we confirmed our previous findings ofa reduced Ni4-dependent P1 transport in renal BBMVfrom chronically uremic rats (22). The differencewas specific for P1 transport with no change in theNa�-dependent transport of L-proline or D-glucose,indicating a lack of effect of uremia on BBM Na�

conductance. We have now provided kinetic data mdi-

8

0a,U)

‘A.)

0

0.

ECl)

4,0

EC

40

04)

U)

It)

0

a,EU)4)0

EC

7 80

U4)Cl)

� 60

0

a0’ 40EU)4,

0 20EC

NPD

i/[Pi] (mM)�

10 20 30

B B

*

T 8004)U)

�2 60

0

aa,EU)4,0

EC

-20

A 5/6NX

t� SHAM

30 40-20 -10 0 10 20

1 /[Pi] (mM) 1

30 40

P� Transport Adaptation in Uremia

1934 Volume 3 . Number 12 . 1993

-�o 0 1’O jO

1/[Pi] (mM)1

Figure 2. Kinetics of the adaptation of uremic kidney andintestine to an LPD. Animals were placed on either an NPDor an LPD for 5 days before study. Na4 gradient-dependent32P1 transport was measured at 5 s (renal BBMV, panel A) or15 s (intestinal BBMV. panel B) in the presence of 25 to1,000 MM P in uptake media. Kidneys or intestines fromthree animals were pooled from each group. Results arepresented as double reciprocal plots of 32P uptake in BBMVfrom SH and NX rats. Each datum point is the mean ± SE offour experiments. r = 0.94 to 0.99. 1/v, reciprocal of Puptake.

cating that the reduction of Na4-dependent P1 trans-

port by the uremic renal BBM is due to a lowerapparent Vmax for P,. suggesting either a reduction inthe number of Na�-P1 cotransporters or reduced mem-

brane fluidity in uremia.Our results differ somewhat from those described

by Hruska et at. (23) In uremic dogs. The latter studyshowed lower Na4 gradient-dependent uptakes forPt, L-proline. and D-glucose in BBMV from remnantkidney of dogs with CRF, compared with SH controls.The differences were abolished when uptake wasmeasured under Na� equilibrium conditions, suggest-ing an effect of uremia on Na� conductance. This was

further corroborated by demonstrating an increased22Na uptake in uremlc BBMV.

Recently, London et at. (24) showed that, in renalBBMV from uremic rats, there was an increase in Clpermeability without changes in 22Na uptake. Fur-

Figure 3. Effect of uremia on the kinetics of P transport byrenal and intestinal BBMV. Results shown are from animalson NPD. The initial Na� gradient-dependent P transport wasmeasured at 5 or 15 s in BBMV prepared from the kidney(panel A) or intestine (panel B) of SH or NX rats, respectively.Transport media contained 25 to 1,000 MM P1. Kidneys orintestines from three animals were pooled from each group.Results are presented as double reciprocal plots of 32Puptake. Each datum point is the mean ± SE of four experi-ments. Regression lines have been omitted in the lowerpanel for clarity. t= 0.94 to 0.99. V. P uptake.

thermore, there was a 19.6% increase in Na�-depend-ent glutamine uptake with no change in glutammnekinetics when the membrane potential was dissi-

pated with an ionophore. They concluded that in-creased C� permeability results in an inside-negative

membrane potential, explaining the increase in dcc-trogenic transport processes. Contrary to these ob-servations, we did not find an increase in the initialD-glucose or L-proline uptakes in renal BBMV fromNX rats, even though both solutes are transported by

an electrogenic transport process. The reasons forthese differences may be related to the use of differ-ent species. to the degree or the chronicity of CRF, or

to different methodologies.It Is generally believed that the major mediator of

increased P, excretion in uremia is a rising level ofPTH (25). In the study presented here, which was

Loghman-Adham

Journal of the American Society of Nephrology 1935

conducted in an acutely uremic rat model, the re-

duced P, uptake by the renal BBMV was not corrected

after parathyroidectomy. suggesting that PTH wasnot responsible for the reduced renal P1 reabsorptionin our animal model. A role for PTH-independent

factors in P, adaptation in uremia has also beendemonstrated by others (26-28).

We also confirmed our previous findings that, in

uremic rats, the intestinal Na�-P, cotransport is notreduced (22). In contrast to our findings In rats, there

Is evidence that humans with CRF have decreasedintestinal P, absorption compared with healthy sub-

jects (29). The reasons for differences betweenour results and those reported in humans may be re-lated to species differences or to the examinationof a specific Intestinal segment. Alternatively.1 .25(OH)2D3 levels might have been normal or nearnormal In our animals because of the relatively milddegree and the short duration of renal failure. Kineticstudies In intestinal BBMV showed that there was nodifference In the Vrn� or Km for Na�-dependent P,transport between NX and SH rats. This suggeststhat the intestinal and renal Na�-P, cotransportersare affected differently by the uremic state.

CRF results in a reduction of the ability of thekidneys to excrete P. leading to P, retention. TheImportance of P, retention in the pathogenesis ofsecondary hyperparathyroidism In CRF has beendemonstrated by Slatopolsky et at. (30). Studies in

uremic dogs have shown that a reduction in dietaryphosphorus intake in proportion to the decrease in

GFR may prevent the development of secondary hy-perparathyroidism (31 .32). Current treatment of hy-perphosphatemia in patients with CRF consists ofdietary phosphorus restriction and the administra-

tion of Pi binders. The administration of an LPDresults in an adaptive response. namely an increasein the maximal rate of Na4-dependent P, uptake bythe renal and intestinal BBM (5-7). The adaptiveresponse occurs rapidly in the kidney and somewhatslower in the intestine. It is not known, however, if

the renal and intestinal BBM of uremic animals arecapable of an appropriate adaptive response tochanges in dietary phosphorus intake. Such adaptiveresponses may reduce the effectiveness of dietaryphosphorus restriction in the treatment of hyper-phosphatemia of CRF, increasing the need for phos-phate binders. The latter have been associated withmany undesirable side effects (33-36).

In this study. we found that the uremic kidney and

intestine were able to adapt to a reduction of dietaryphosphorus intake. The magnitude of the adaptiveresponses were identical to those seen in control,nonuremic animals. The Increase In Na�-P, cotrans-

port was secondary to a higher apparent Vm� withno change in the apparent Km. Our results confirmthe findings of previous studies of dietary P1 adapta-

tion in renal and intestinal BBMV from nonuremic

animals (5-9) and extend these findings to a uremic

animal model.Despite the dual adaptation of the renal and intes-

tinal BBM to dietary phosphorus restriction, plasmaPt levels decreased significantly in animals placed onLPD compared with P, levels in animals remainingon NPD. This suggests that the adaptive response ofcontrol or uremic animals is not sufficient to negatethe reduction of plasma P, after the ingestion of an

LPD. Several factors may have resulted in the inabil-ity of the adaptive response to prevent the reductionof serum P1 levels. ( 1 ) the adaptive response involves

changes that are specific for the Na4 gradient-dc-pendent component of P1 transport. The Na4-inde-pendent transport is not affected. In renal BBM, the

Na�lndependent P1 uptake represents between 2 and7% of the total uptake. However, in the intestinalBBM. the Na4-independent component of P1 uptake

represents over 30% of the total uptake (16). (2) Inhumans as well as in rats, most of the P, reabsorptiontakes place in thejejunum. and this segment has the

highest Na-dependent uptake of all other intestinalsegments ( 1 6). P, uptake in the ileum is low and isalmost entirely Na” independent. It can be surmised

that the adaptive response of the jejunum will have

a relatively minor overall effect in increasing theplasma P, concentrations. Therefore, the magnitude

of the adaptive response may be significantlyblunted. The combined effects of the kidney andIntestine, however, may minimize the reduction ofplasma P, levels, which have occurred if these re-sponses were not operative. (3) In theory. the phos-phaturla induced by hyperparathyroidism in NX an-Imals may override the adaptive increase In P, ab-

sorption after an LPD. However, this Is unlikelybecause of the short duration of uremia and becauseserum P, levels decreased even in SH animals In

whom hyperparathyroldism is unlikely.It should be mentioned that the dietary phosphorus

restriction used in our animals was rather severe

(0.07% P1). This may also explain the inability of theadaptive response to counteract the reduction in theplasma P,. Dietary phosphorus restriction of thismagnitude is generally not feasible or practical in theclinical situation, where the patients continue to con-sume some phosphorus, despite dietary restriction.It Is possible that, in the presence of a less severedietary phosphorus restriction, the adaptive responseof the renal and intestinal BBM may have been suf-ficient to partially prevent the reduction of plasma P,

levels.

ACKNOWLEDGMENTS

Supported by a Baxter Extramural Grant from Baxter Heaithcare

Inc. and In part by DVA research funds. I am indebted to Dr. Christof

P1 Transport Adaptation in Uremia

1936 Volume 3 . Number 12 � 1993

Westenfelder for shared laboratory space at the Veterans Adminis-

tration Medical Center. The technical assistance of Susan A.

Scherer. Michael T. Totzke. George T. Motock. and Neal A. Custer is

greatly appreciated.

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