The interaction of PTH and dietary phosphorus and calcium on serum calcitriol levels in the rat with...

Nephrol Dial Transplant (1996) 11: 1553-1558

Original Article

NephrologyDialysis

Transplantation

The interaction of PTH and dietary phosphorus and calcium on serumcalcitriol levels in the rat with experimental renal failure

A. Martin-Malo1, M. Rodriguez1, M. E. Martinez2, A. Torres3 and A. J. Felsenfeld4

'Unit of Investigation and the Department of Nephrology, Hospital Universitario Reina Sofia Cordoba; 2Hospital La Paz,Madrid; 'Department of Nephrology, Hospital Universitario, Tenerife, Spain; and 4Department of Medicine, West LosAngeles VA Medical Center and UCLA, Los Angeles, CA, USA

AbstractBackground. Renal failure results in decreased calci-triol production, a key factor in the development ofsecondary hyperparathyroidism. Phosphorus accumu-lation and high parathyroid hormone (PTH) levels,both inherent to renal failure, have different effects oncalcitriol production; moreover, dietary calcium load-ing may have a separate inhibitory effect on calcitriolproduction. This study was designed to evaluate therelative effects of PTH and dietary phosphorus andcalcium on serum calcitriol levels.Methods. Renal failure was surgically induced and ratswere divided into normal, moderate renal failure, andadvanced renal failure based on the serum creatinine.Each group was subdivided and received either a high-phosphorus diet (HPD, 0.6% Ca, 1.2% P) or high-calcium diet (HCaD, 1.2% Ca, 0.6% P) for 14-16 daysto determine the relative effects of dietary calcium andphosphorus loading on serum calcitriol. In additionthe effect of PTH and phosphorus on calcitriol stimu-lation was determined with a 48-h PTH infusioncombined with either a low (0.16%) or high (1%)phosphorus diet; both diets had negligible calcium

Results. With decreasing renal function, PTHincreased and was greater in rats fed the HPD thanthe HCaD; serum calcitriol decreased as renal functiondecreased and was lower in normal rats and rats withmoderate renal failure fed a HCaD (/><0.01). Thecalcitriol response to a PTH infusion decreased asrenal function decreased (P<0.05) but was greater ona low- (0.16%) than a high- (1%) phosphorus diet

Conclusions. Dietary calcium loading either directlydecreases serum calcitriol or acts by modifying thestimulatory effect of PTH; the stimulatory effect ofPTH on serum calcitriol is modified by dietary phos-phorus; in moderate renal failure, serum calcitriollevels depend on a complex interaction between PTH

Correspondence and offprint requests to: Mariano Rodriguez MD,Unit of Investigation, Hospital Reina Sofia, Avda. Menendez PidalS/N, 14004 Cordoba, Spain.

and dietary calcium and phosphorus; and in advancedrenal failure, serum calcitriol levels are low and aredifficult to stimulate, presumably because of the lossof renal mass.

Key words: calcitriol; calcium; phosphorus; PTH; rat;renal failure

Introduction

A calcitriol deficiency is an important pathogenic factorin the development of secondary hyperparathyroidismin renal failure [1,2]. Although calcitriol synthesis isdecreased in renal failure because of a reduction inrenal mass [3,4], clinical studies of patients with moder-ate renal failure have reported both low and normalserum calcitriol levels [3-6]. This may be due to thebalance between the inhibition of calcitriol by anincreased phosphorus load with or without hyperphos-phataemia [7,8] and stimulation of calcitriol byincreased PTH levels [9,10]; moreover, although notusually considered as a factor, dietary calcium andchanges in serum calcium may also affect calcitriolproduction [5,11,12].

While reducing the magnitude of dietary phosphorusabsorption, a high-calcium diet may, as has been shownin azotaemic rats [11], independently reduce calcitriollevels. The daily amount of calcium consumed in anormal human diet is approximately 800 mg. Thus,the daily use of 2 g of a calcium-based phosphatebinder will result in a doubling of calcium ingestion.

In patients with moderate renal failure, it is unclearto what extent PTH and the dietary content of phos-phorus and calcium are capable of modifying calcitriolproduction. Clarification of the relative roles of thesefactors may help to explain the observed differences inserum calcitriol levels and may lead to a better under-standing of the prevention and treatment of secondaryhyperparathyroidism. The goal of this study was toevaluate in rats with different levels of renal function,the relative effects of secondary hyperparathyroidism

© 1996 European Dialysis and Transplant Association-European Renal Association

by guest on January 16, 2016http://ndt.oxfordjournals.org/

Dow

nloaded from

1554 A. Martin-Malo el al.

and changes in dietary phosphorus and calcium on(1) the serum calcitriol level and (2) the ability tostimulate calcitriol during a PTH infusion.

Subjects and methods

Male Wistar rats weighing 125-140 g underwent varyingdegrees of renal ablation to obtain different levels of renalfunction. The first group of rats underwent sham operations;the second group, ligation of one branch of the main renalartery in the hilum of the left kidney, followed 1 week laterby right nephrectomy (2/3 Nx); and the third group, ligationof two branches of the main renal artery in the hilum of theleft kidney, followed 1 week later by right nephrectomy (5/6Nx). Rats were pair fed and randomly placed on either ahigh-phosphorus diet (HPD) containing 1.2% phosphorusand 0.6% calcium or a high-calcium diet (HCaD) containing1.2% calcium and 0.6% phosphorus. Both diets contained100 IU/100 g of vitamin D and had a similar caloric content.The study protocol is summarized in Figure 1. In our previ-ous studies in azotaemic rats, the ingestion of a HPD resultedin phosphorus retention which exacerbated secondary hyper-parathyroidism [13,14]. The calcium content of the HCaDhas been shown to moderate but not prevent the developmentof secondary hyperparathyroidism [11]. Rats were startedon their respective diets on the day of the right nephrectomyor the corresponding sham operation. The two dietary groupswere designed to simulate situations of patients with poordietary control (HPD) and of compliant patients on calcium-based phosphorus binders (HCaD).

Fourteen to 16 days after the initiation of the study diets,rats were fasted overnight and blood was obtained formeasurement of creatinine, phosphorus, calcium, and PTH.Based on the serum creatinine concentration, rats wereassigned to one of three groups: normal renal function(HPD, « = 17 and HCaD, n = 22), serum creatinine less than0.5 mg/dl; moderate renal failure (HPD, «=13 and HCaD,n= 13), serum creatinine ranging from 0.5 to 0.7 mg/dl; andadvanced renal failure (HPD, «=16 and HCaD, «=10),serum creatinine greater than 0.7 mg/dl. Immediately afterblood was obtained, rat 1-34 PTH (Bachem, Torrance, CA)was infused at a constant rate of 0.11 ug/100 g body weight/hfor 48 h via a subcutaneously implanted miniosmotic pump(Model 2001, Alza, Palo Alto, CA). The pumps were filledwith PTH dissolved in isosmotic saline with 2% cysteine andHO was added to achieve a pH of 1.5. After the 48-h PTH

infusion, rats were sacrificed and blood was obtained formeasurement of calcium, phosphorus, creatinine, and calci-triol. Since the measurement of calcitriol required a largealiquot of serum, calcitriol levels were obtained prior to PTHinfusion in additional rats with normal renal function, moder-ate renal failure, and advanced renal failure.

The model 2001 miniosmotic pump used for the PTHinfusion maintains a constant delivery of 1 ul/h and its fillingvolume is 200 ul; its functional life-span is at least 7 days.Thus, after 48-h of infusion, each pump was removed andimplanted in a rat from a different group; as a result, thesame pump was randomly used in three different groups ofrats and thus acted as a control for the effectiveness ofPTH delivery.

To evaluate the combined effect of PTH and dietaryphosphorus on calcitriol production, the diet was changedduring the PTH infusion to either 0.16 or 1% phosphorus ineach dietary group (HPD or HCaD) of the normal and themoderate and advanced renal failure groups; thus, half therats received either the 0.16 or the 1% P diet during the PTHinfusion. The calcium content of these two diets was negli-gible (<0.05%); this served to minimize intestinal absorptionof calcium and to prevent an effect of dietary calcium onPTH-induced calcitriol stimulation.

Serum calcium and phosphorus were measured withspecific kits (Sigma, St Louis, MO); serum creatinine wasmeasured with a creatinine analyser (Beckman Instruments,Fullerton, CA) and serum PTH with a N-terminal radio-immunoassay (Nichols Institute, San Juan Capistrano, CA).This assay has been previously validated for the determina-tion of circulating PTH in the rat [13,14] and has beenshown to provide similar values as the intact PTH assayfor the rat [15]. Serum levels of calcitriol were measuredusing a radioreceptor assay (Nichols Institute, San JuanCapistrano, CA); the intra-assay and interassay coefficientsof variation were 6.8 and 8.5% respectively. This assay hasbeen previously validated in the rat [13,14].

Statistics

Comparisons of the means of more than two groups was'performed by ANOVA followed by the Duncan test. Theunpaired / test was used to compare two different groups.Results are shown as the mean + standard error (SE).

HPD (High Phosphorus Diet)P=1.2%, Ca=0.6%.

HCaD (High Calcium Diet)P=0.6%, Ca=1.2%.

DAY 0 14

Fig. 1. Schematic representation of the study protocol.

, Diet:Ca=0%, P = 1%

>» Diet:Ca=0%, P=0.16%

Diet:Ca=O%, P = 1%

Diet:Ca=O%, P=0.16%

PTH infusion(0.1 iyg/ioog

16

by guest on January 16, 2016http://ndt.oxfordjournals.org/

Dow

nloaded from

Calcitriol and renal failure 1555

Results

Serum levels of calcium, phosphorus, PTH and calcitriolafter the high phosphorus diet (HPD) and high calciumdiet (HCaD) (Table 1, Figure 2)

The HPD resulted in a decrease in serum calcium onlyin rats with advanced renal failure; by contrast, theserum calcium was normal in all rats on a HCaDincluding those with advanced renal failure. The HPDresulted in hyperphosphataemia in rats with moderateand advanced renal failure; with the HCaD, the serum

PTH (pg/ml)

Cr <0.5 Cr 0.5-0.7 Cr >0.7

BCALCITRIOL (pg/ml)

Cr <0.5 Cr 0.5-0.7 Cr >0.7

Fig. 2. The serum concentration of PTH and B. calcitriol is shownin rats with different levels of serum creatinine. These rats weremaintained on a high-phosphorus diet (HPD) (closed bars) or ahigh-calcium diet (HCaD) (open bars). */><0.05 as compared withthe HCaD group.

phosphorus did not increase despite renal failure(Table 1).

The ingestion of a HPD induced marked secondaryhyperparathyroidism in azotaemic rats (Figure 2A),while rats with the same degree of renal failure on aHCaD had only a moderate increase in the serum PTHlevel. As shown in Figure 2B, the serum calcitriol leveldecreased as renal function decreased. Except inadvanced renal failure rats, serum calcitriol was greaterin the HPD than the HCaD group. Thus, in rats withnormal renal function, the basal serum calcitriol levelwas 179 + 15 and 112±8 pg/ml, (P<0.01) in the HPDand HCaD groups respectively and this difference wasnot associated with differences in serum phosphorus,calcium (Table 1) or PTH (Figure 2A). In rats withmoderate renal failure, the serum calcitriol was greaterin the HPD than the HCaD group (140+10 vs77+ 6 pg/ml, /><0.01) and this was associated with ahigher basal PTH level in the HPD group, (177 + 26vs 70 + 6 pg/ml, P<0.01) (Figure 2A). Since basalserum phosphorus was also increased in the HPDgroup (Table 1), the higher serum calcitriol level in theHPD group should be due to the higher PTH level.Finally, in rats with advanced renal failure, serumcalcitriol was similarly decreased in the HCaD andHPD groups.

The effect of PTH infusion on serum calcium andphosphorus (Table 1)

The 48-h PTH infusion increased the serum calciumin both the HPD and HCaD groups. However thecalcaemic response to PTH was less in rats with renalfailure and was further decreased by the ingestion ofthe 1% phosphorus diet. In advanced renal failure, thePTH infusion did not increase the serum calcium inrats ingesting the 1% phosphorus diet.

The combination of the PTH infusion and theingestion of the 0.16% phosphorus diet resulted inserum levels of phosphorus that were similarlydecreased in all groups of rats, including those withmoderate and advanced renal failure. In contrast, thecombination of the PTH infusion and the 1% phos-

Table 1. The serum calcium and phosphorus concentration ininfusion combined with either a 0.16 or 1% phosphorus diet

Cr<0.5mg/dl

HPD HCaD

the HPD and HCaD

Cr 0.5-0.7 mg/dl

HPD

groups

HCaD

before the PTH infusion and

Cr> 0.7 mg/dl

HPD

after the PTH

HCaD

Serum calcium (mmol/l)BASAL 2.58 ±0.03 2.45 ±0.05PTH + 1%P 3.55 + 0.10 3.20±0.12PTH + 0.16%P 4.30±0.20 4.28 + 0.02

Serum phosphorus (mmol/l)BASAL 2.5±0.1 2.7 + 0.1PTH + 1%P 1.6 + 0.1 2.0±0.2*PTH + 0.16%P 1.8 + 0.1 2.0±0.1

2.43 ±0.052.58 + 0.053.33 ±0.03

2.9±0.24.6±0.31.7±0.2

2.48 ±0.022.73±0.073.15 ±0.02

2.5±0.1*3.4±0.2*1.6 + 0.1

1.85 ±0.072.10±0.172.60 ±0.05

4.8 ±0.35.1+0.42.0±0.2

2.40 ±0.05*2.48 ±0.022.93 ±0.07

2.5±0.1*3.7 ±0.4*1.8 ±0.2

Mean±SE. */><0.05 as compared with HPD.BASAL, values before the PTH infusion; PTH + 1% P, values after the PTH infusion combined with a 1% phosphorus diet; PTH + 0.16%P, values after the PTH infusion combined with a 0.16% phosphorus diet.

by guest on January 16, 2016http://ndt.oxfordjournals.org/

Dow

nloaded from

1556

phorus diet resulted in an increase in serum phosphorusin all azotaemic groups, but levels were higher in theHPD group. Finally, in rats with normal renal func-tion, the infusion of PTH plus the 1% phosphorus dietresulted in a higher serum phosphorus in the HCaDthan HPD group, although the serum phosphorus wasin the low normal range for both groups.

Calcitriol stimulation during the PTH infusion in ratswith normal renal function (Figure 3)

The PTH infusion together with the ingestion of 0.16%phosphorus diet increased the serum calcitriol(P<0.01) to a similar level in the HPD and HCaDgroups (401 +38 vs 417+ 46 respectively). The infusionof PTH combined with the 1% phosphorus diet alsoresulted in a similarly increased serum calcitriol level(/><0.05) in the HCaD and HPD groups. However,in both groups, the magnitude of the increase in serumcalcitriol was less during the ingestion of the 1% thanthe 0.16% phosphorus diet despite no difference inserum phosphorus levels (Table 1).

Calcitriol stimulation during a PTH infusion in ratswith moderate renal failure (Figure 4)

After the PTH infusion, the serum calcitriol was greater(P<0.05) in the HCaD than the HPD group and ineach group the 1% phosphorus diet resulted in a lowercalcitriol level than the 0.16% phosphorus diet(Figure 4). In rats with moderate renal failure, differ-ences in the dietary content of phosphorus (0.16 and1%) during the PTH infusion led to differences inserum phosphorus (Table 1). Since the amount of PTHinfused was the same, the difference in the calcitriol

A. Martin-Malo et al.

CALCITRIOL (pg/ml)

CALCITRIOL (pg/ml)

500

HPD

CREATININE <0.5 mg/dl

Fig. 3. Serum calcitrol level in normal rats. Rats were maintainedon either a high-phosphorus diet (HPD) or high-calcium diet(HCaD). The basal calcitriol level (closed bars), calcitriol after the48-h PTH infusion plus the 1% phosphorus diet (cross-hatchedbars), and calcitriol after the 48-h PTH infusion plus the 0.16%phosphorus diet (open bars) are shown. */><0.05 as compared withbasal; jfP <0.05 as compared with the 48-h PTH infusion plus the1% phosphorus diet.

500

HPD HCaDCREATININE 0.5-0.7 mg/dl

Fig. 4. Serum calcitriol level in rats with moderate renal failure.Rats were maintained on either a high-phosphorus diet (HPD) orhigh-calcium diet (HCaD). The basal calcitriol level (closed bars),calcitriol after the 48-h PTH infusion plus the 1% phosphorus diet(cross-hatched bars), and calcitriol after the 48-h PTH infusion plusthe 0.16% phosphorus diet (open bars) are shown. *P<0.05 ascompared with basal; §P<0.05 as compared with the 48-h PTHinfusion plus the 1% phosphorus diet.

response between the 0.16 and 1% phosphorus dietshould be attributable to serum phosphorus.

In the HPD group, the PTH infusion with a 1%phosphorus diet failed to increase calcitriol (Figure 4).Moreover, even the 0.16% P diet did not result in asignificant increase in serum calcitriol during the PTHinfusion. Despite the fact that as compared with base-line, neither the 0.16% nor the 1% P diet increasedserum calcitriol during the PTH infusion, serum calci-triol was greater with the 0.16% diet than the 1%phosphorus diet (163 + 28 vs 96 + 23 pg/ml, P<0.05).In the HCaD group, serum calcitriol levels after thePTH infusion with the 0.16% and 1% phosphorusdiets were 245 + 19 and 179+ 24 pg/ml respectively(P<0.05).

Calcitriol stimulation during a PTH infusion in ratswith advanced renal failure (Figure 5)

In the HPD group, the PTH infusion with either the0.16% P or 1% P diet did not increase serum calcitriol(Figure 5). During the PTH infusion in the HCaDgroup, serum calcitriol was unchanged during theingestion of the 1% P diet but increased on the 0.16%P diet (47 + 7 vs 106±31 pg/ml, P<0.05).

Discussion

We have studied the respective roles of PTH anddietary calcium and phosphorus loading on the produc-tion of calcitriol and how this effect is modified byrenal failure. Our results indicate that in addition tothe effect of the residual renal mass, calcitriol produc-tion was stimulated by high PTH and inhibited by

by guest on January 16, 2016http://ndt.oxfordjournals.org/

Dow

nloaded from

Calcitriol and renal failure

CALCITRIOL (pg/ml)

500 -''

400^

300-

HPD HCaD

CREATININE >0.7 mg/dl

Fig. 5. Serum calcitriol level in rats with advanced renal failure.Rats were maintained on either a high-phosphorus diet (HPD) orhigh-calcium diet (HCaD). The basal calcitriol level (closed bars),calcitriol after the 48-h PTH infusion plus the 1% phosphorus diet(cross-hatched bars), and calcitriol after the 48-h PTH infusion plusthe 0.16% phosphorus diet (open bars) are shown. *P<0.05 ascompared with basal.

high dietary phosphorus and calcium. On the HPD,the inhibitory effect of phosphorus loading was coun-terbalanced by the concurrent increase in PTH. TheHCaD resulted in an inhibition of calcitriol despitenormal PTH levels in normal rats and elevated PTHlevels in rats with moderate renal failure. Except inadvanced renal failure, calcitriol production was stimu-lated by PTH and inhibited by phosphorus loading.

Rats with normal renal function

In normal rats on a HCaD, PTH and serum calciumwere normal; nevertheless the serum calcitriol level wasapproximately 60% of that in the HPD group. In aprevious study [11], the serum calcitriol level in normalrats on a HPD was similar to rats on a 0.6% calciumand 0.6% phosphorus diet; thus the calcitriol level inthe normal rats on HPD would appear to representnormal serum values. Thus a high-calcium diet wouldseem to decrease calcitriol levels by a mechanism thatis independent of changes in the serum levels of PTH,calcium and phosphorus. The administration of thesame amount of PTH to the HPD and HCaD groupsled to a similarly increased serum calcitriol concentra-tion despite concomitant increases in serum calcium;thus the stimulatory effect of high PTH overcame anyinhibitory effect of hypercalcaemia. In both groups a1% phosphorus diet reduced the calcitriol response toPTH; this demonstrates that dietary phosphorus load-ing has an inhibitory effect on calcitriol productionwhich opposes the stimulatory effect of PTH. Theeffect of dietary phosphorus on calcitriol productionwas observed despite no difference in the serum phos-phorus level. Thus in rats with normal renal function,PTH and dietary calcium and phosphorus separatelyaffected calcitriol production and their effects were

1557

observed in the absence of detectable changes in theconcentration of serum calcium and phosphorus.

Rats with moderate renal failure

The basal serum calcitriol was lower in rats withmoderate renal failure than normal rats which indicatesthat a decreased renal mass limited calcitriol produc-tion. However, serum calcitriol was considerablygreater in the HPD than the HCaD group; thus thestimulatory effect of PTH predominated over the inhib-itory effect of phosphorus loading which even resultedin hyperphosphataemia. Furthermore, the inhibitoryeffect of the high-calcium diet was also evident sincedespite PTH levels that were approximately twicenormal, calcitriol levels were less than in the HPDgroup. An extrapolation of the results of our study tothe clinical setting would suggest that the use of acalcium-based phosphate binder, which in recom-mended doses may double the daily intake of calcium,has the potential to reduce serum calcitriol levels;whether this sequence of events does occur in patientswith moderate renal failure receiving a calcium-basedphosphate binder needs to be evaluated.

In both the HPD and HCaD groups, the serumcalcitriol levels were increased after the PTH infusionbut were greater when rats ingested a low-phosphorus(0.16%) than a high-phosphorus (1%) diet. These dataindicate that rats with moderate renal failure have thecapability to increase calcitriol production in responseto PTH; moreover, for a similarly high PTH level, thedietary load of phosphorus with corresponding changesin serum phosphorus, becomes an important regulatorof calcitriol production. However for the same amountof PTH infused and the same dietary phosphorus load(1%), the rats on HCaD had a higher serum calcitriolthan the HPD group in which serum calcitriol did notincrease despite the PTH infusion; this may beexplained by the higher serum phosphorus in the HPDgroup. This result would indicate that proportionalchanges in PTH and phosphorus may neutralize eachother resulting in no change in calcitriol.

The PTH infusion combined with 0.16% phosphorusdiet resulted in higher calcitriol levels in the HCaDthan the HPD group. This difference cannot be attrib-uted to serum levels of calcium or phosphorus; how-ever, it is possible that the HPD rats with highercalcitriol levels and higher PTH at baseline had adownregulation of the PTH receptor due to the highPTH levels [16-18]. In addition one must also considerthe possibility that the greater phosphorus burdenpresent in the HPD group at the end of the study dietmay have contributed to the lower calcitriol level inthe HPD group during the PTH infusion.

The results of the PTH stimulation of calcitriol inthe groups with moderate renal failure may help toexplain some of the conflicting results of recent clinicalstudies in patients with moderate renal failure [5,6].Prince et al. reported that patients with moderate renalfailure (mean GFR 44 + 20ml/min) had serum calci-triol levels that were approximately one-half normal;

by guest on January 16, 2016http://ndt.oxfordjournals.org/

Dow

nloaded from

1558 A. Martin-Malo et al.

these patients increased serum calcitriol levels by morethan 50% after receiving a calcium restricted diet [5].Thus these investigators were able to demonstrate thata reduction in dietary calcium either directly or inconjunction with PTH was able to stimulate calcitriol.Our rats on a HCaD also increased calcitriol inresponse to a combination of calcium restriction andan increase in PTH. Conversely Ritz et al. [6] havereported an attenuated calcitriol response to exogenousPTH infusion in patients with moderate renal failure(mean GFR 53 ml/min). Before the PTH infusion,these patients had a normal serum calcitriol and almosta threefold increase in intact PTH; after the PTHinfusion, serum calcitriol increased by less than 14%in the azotaemic patients as opposed to a 100% increasein the normal controls. In essence, these azotaemicpatients may be analogous to the rats in the HPDgroup in which baseline serum calcitriol approachednormal with a fourfold increase in PTH; moreoverthese rats failed to further increase calcitriol during aPTH infusion. Thus it is possible that calcitriol produc-tion may be maximally stimulated by a three- tofourfold increase in PTH and higher PTH levels donot further stimulate calcitriol production. This maynot be an unreasonable assumption since in normalhumans, the maximal PTH level is three to four timesgreater than the basal PTH [19].

Rats with advanced renal failure

In rats with advanced renal failure, serum calcitriollevels were decreased in both HPD and HCaD groups.Except for a modest increase to subnormal levels inthe HCaD groups, calcitriol could not be stimulateddespite the combination of PTH infusion with a phos-phorus restricted diet. These findings resemble resultsfrom clinical studies in patients with advanced renalfailure [3,4,7,20].

The results of this study are summarized as follows:(1) calcitriol production decreases with renal failure;(2) calcitriol production can be modulated in normalrats and in rats with moderate renal failure; by contrastin advanced renal failure, calcitriol production isinvariably low; (3) calcitriol production decreases withdietary calcium loading and this effect can be observedeven in the absence of hypercalcaemia and despite highPTH levels; and (4) PTH stimulates and dietary phos-phorus inhibits calcitriol production and both cancounteract the effect of the other.

In conclusion, the serum calcitriol concentration inmoderate renal failure may be low, normal, or evenhigh depending on a complex interaction between thedifferent effects of PTH, and dietary phosphorus andcalcium.

Acknowledgements. This work was supported by grants from theFIS #95/1143 and the Fundocion Hospital Reina Sofia-CajaSur.

References

hormone in isolated bovine parathyroid cells. Proc Natl AcadSci USA 1985; 82: 4270-4273

2. Fukagawa M, Kaname S, Igarashi T, Ogata E, Kurokawa K.Regulation of parathyroid hormone synthesis in chronic renalfailure in rats. Kidney Int 1991; 39: 874-881

3. Reichel H, Deibert B, Schmidt-Gayk H, Ritz E. Calcium meta-bolism in early chronic renal failure: implications for the patho-genesis of hyperparathyroidism. Nephrol Dial Transplant 1991;6: 162-169

4. Pitts TO, Piraino BH, Mitro R et al. Hyperparathyroidism and1,25-dihydroxyvitamin D deficiency in mild, moderate, andsevere renal failure. J Clin Endocrinol Metab 1988; 67: 876-881

5. Prince RL, Hutchison BG, Kent JC, Kent GN, Retallack RW.Calcitriol deficiency with retained synthetic reserve in chronicrenal failure. Kidney Int 1988; 33: 722-728

6. Ritz E, Seidel A, Ramisch H, Szabo A, Bouillon R. Attenuatedrise of 1,25 (OH )2 vitamin D3 in response to parathyroid hor-mone in patients with incipient renal failure. Nephron 1991;57: 314-318

7. Portale AA, Booth BE, Halloran B, Morris RC Jr. Effect ofdietary phosphorus on circulating concentrations of 1,25-dihydroxyvitamin D and immunoreactive parathyroid hormonein children with moderate renal insufficiency. J Clin Invest 1984;73: 1580-1589

8. Portale AA, Halloran BP, Morris RC Jr. Physiologic regulationof the serum concentration of 1,25-dihydroxyvitamin D byphosphorus in man. J Clin Invest 1989; 83: 1494-1499

9. Garabedian M, Holick M, DeLuca HF, Boyle IT. Control of25-hydroxycholecalciferol metabolism by parathyroid glands.Proc Natl Acad Sci USA 1972; 69: 1673-1676

10. Booth BE, Tsai HC, Morris RC Jr. Parathyroidectomy reduces25-hydroxyvitamin D3-l-alpha-hydroxylase activity in the hypo-calcemic vitamin D-deficient chick. J Clin Invest 1977; 60:1314-1320

11. Bover J, Rodriguez M, Trinidad P et al. Factors in the develop-ment of secondary hyperparathyroidism during graded renalfailure in the rat. Kidney Int 1994; 45: 953-961

12. Bushinsky DA, Riera GS, Favus MJ, Coe FL. Evidence thatblood ionized calcium can regulate serum 1,25(OH)2D3 inde-pendently of parathyroid hormone and phosphorus in the rat.J Clin Invest 1985; 76: 1599-1604

13. Rodriguez M, Martin-Malo A, Martinez ME, Torres A,Felsenfeld AJ, Llach F. Calcemic response to parathyroid hor-mone in renal failure: role of phosphorus and its effect oncalcitriol. Kidney Int 1991; 40: 1055-1062

14. Rodriguez M, Felsenfeld AJ, Llach F. Calcemic response toparathyroid hormone in renal failure: role of calcitriol and theeffect of parathyroidectomy. Kidney Int 1991; 40: 1063-1068

15. Jara A, Bover J, Lavigne J, Felsenfeld AJ. A comparison of twoparathyroid hormone assays for the rat: the new immunoradi-ometric with the competitive-binding assay. J Bone Miner Res1994; 9: 1629-1633

16. Mahoney CA, Nissenson RA. Canine renal receptors for para-thyroid hormone. Down regulation in vivo by exogenous para-thyroid hormone. J Clin Invest 1983; 72: 411-420

17. Tamayo J, Bellorin-Font E, Sicard G, Anderson C, Martin K.Desensitization to parathyroid hormone in the isolated perfusedcanine kidney: reversal of altered receptor-adenylate cyclasesystem by guanosine triphosphate in vitro. Endocrinology 1982;111: 1311-1317

18. Ureiia P, Kubrusly M, Mannstadt M et al. The renalPTH/PTHrP receptor is down-regulated in rats with chronicrenal failure. Kidney Int 1994; 45: 605-611

19. Brent GA, LeBoff MS, Seely EW, Conlin PR, Brown EM.Relationship between the concentration and rate of change ofcalcium and serum intact parathyroid hormone levels in normalhumans. J Clin Endocrinol Metab 1988; 67: 944-950

20. Lucas PA, Brown RC, Woodhead JS, Coles GA.1,25-dihydroxycholecalciferol and parathyroid hormone inadvanced chronic renal failure: effects of simultaneous proteinand phosphorus restriction. Clin Nephrol 1986; 25: 7-10

1. Silver J, Russell J, Sherwood LM. Regulation by vitamin Dmetabolites of messenger ribonucleic acid for preproparathyroid

Received for publication: 21.11.95Accepted in revised form: 2.4.96

by guest on January 16, 2016http://ndt.oxfordjournals.org/

Dow

nloaded from