Dipyridamole Decreases Renal Phosphate Leak and Augments Serum Phosphorus in Patients with Low Renal Phosphate Threshold

J Am Soc Nephrol 9: 1264-1269, 1998

DOMINIQUE PRIE,* FRANOISE BENQUE BLANCHET,* MARIE ESSIG,* JEAN-PIERRE JOURDAIN,t and GERARD FRIEDLANDER* *Sen,jce de Phvsiologie-Explorations Fonctionnelles, Hopital Bichat, Assistance Publique-H#{244}pitaux de Paris, Paris, France, and D#{233}partement de Physiologie Universit#{233} Paris 7, Facult#{233}de M#{233}decine Xavier Bichat, Paris, France; and Service de Rhumatologie, Hopital Henri Mondor, Creteil, France.

Abstract. It has been shown that an acute infusion of dipyrid- mo, with maximal values reached within 9 mo. This improve- amole increased renal phosphate reabsorption in rats and hu- ment persisted after 12 mo of treatment. In 28 patients, 1,25- mans. A prospective study was performed to determine dihydroxyvitamin D concentrations were above the normal whether chronic treatment by dipyridamole given orally could range (>42 pg/ml) and normalized in parallel with the increase decrease renal phosphate leak and increase serum phosphorus of serum phosphorus. The 24-h calcium excretion (which was in patients with idiopathic low renal phosphate threshold initially increased in patients with high vitamin D concentra-

(TmPO4/OFR < 0.77 mM). Sixty-four patients with low tions) and urolithiasis decreased under treatment. Ionized se- TmPO4/OFR were included and treated with dipyridamole (75 rum calcium and parathyroid hormone remained unchanged. mg, 4 times daily) for more than I 2 mo. Serum phosphorus, After 2 yr, treatment was discontinued in three patients; serum TmPO4/OFR, parathyroid hormone, serum calcium, and 1,25- phosphorus and TmPO4/OFR decreased within 1 mo after dihydroxyvitamin D were measured sequentially before treat- discontinuation. Dipyridamole at a dose of 75 mg 4 times daily ment, and after 3, 6 to 9, and I 2 mo of treatment. Under increases low TmPO4/OFR and improves hypophosphatemia chronic treatment with dipyridamole, TmPO4/OFR and serum in patients with renal phosphate losses and can be used to treat phosphorus significantly increased in 80% of patients within 3 these patients.

Phosphate plays a critical role in cell metabolism and bone been demonstrated that dipyridamole, a well known antiag- mineralization. Under physiologic conditions, serum phospho- gregant and vasodilatory drug, lowered urinary phosphate ex- rus is strictly maintained above 0.8 mM. The kidney is the cretion in rats (9) and in humans (10). The aim of this pro- principal organ that regulates phosphate balance by reabsorb- spective study was to determine whether treatment by ing, mainly in the proximal tubule, approximately 80% of the dipynidamole increases serum phosphorus in patients with hy- phosphate filtered by the glomerulus in adults, a process that is pophosphatemia due to idiopathic increased urinary losses of controlled by parathyroid hormone (PTH) (1 ,2). Increased un- phosphate. nary phosphate losses can be secondary to hormone hyperse- cretion (hyperparathyroidism, secretion of PTH-related pep- tide), can be due to inherited or acquired renal tubular Materials and Methods dysfunction (Fanconi’s syndrome, tubular acidosis), or can be This study was conducted in the department of clinical investiga- related to a circulating soluble factor (oncogenic osteomala- tion at Hopital Bichat and was approved by the center’s ethics committee and the scientific review committee of the D#{233}l#{233}gationa la cia), but urinary phosphate leak can also be idiopathic (3,4). Recherche Clinique Assistance Publique-H#{244}pitaux de Paris. Written This chronic renal phosphate loss can lead to hypophos- informed consent was obtained from each subject. All measurements phatemia, urolithiasis, or bone demineralization (4-8). The were made on site. treatment of renal phosphate leak usually consists of increasing phosphate intake by oral phosphate and/or vitamin D therapy. However, this treatment may induce nephrolithiasis. It has Inclusion Criteria The patients included in this study were referred to our department by their physicians for suspicion of renal phosphate leak. Serum

Received October 7, 1997. Accepted January 21, 1998. phosphorus and fractional excretion of phosphate (FEPO4) were mea- Correspondence to Dr. Dominique Pri#{233},D#{233}partement de Physiologic Univer- sured in our laboratory, and the ratio between the maximal tubular site Paris 7, Facult#{233}de M#{233}decine Xavier Bichat. Unite INSERM U426, 16 rue reabsorption rate for phosphate and GFR (TmPO4/GFR) was calcu- Henri Huchard, Paris 75018. France. lated according to the nomogram of Bijvo#{235}tand Walton ( I 1).

1046-6673/0907- 1264$03.00/0 Patients with low TmPO4/GFR (<0.77 mM) and hypophos- Journal of the American Society of Nephrology phatemia (<0.8 mM) were included. A total of 64 patients was Copyright (0 1998 by the American Society of Nephrology studied. J Am Soc Nephrol 9: 1264-1269, 1998 Dipyridamole Increases Serum Phosphorus 1265

Table 1. Main characteristics of patients with or without renal lithiasis

Characteristic With Renal Lithiasis Without Ren al Lithiasis Unp aired t Test

n 18 46 Age (yr) 46. 1 ± 2.0 50.7 ± 1 .6 NS GFR (mi/mm per 1 .73 m2) 85 ± 3 89 ± 2 NS Serum phosphorus (mM) 0.79 ± 0.02 0.77 ± 0.02 NS TmPO4/OFR (mM) 0.60 ± 0.02 0.58 ± 0.01 NS Ionized serum calcium (mM) 1.20 ± 0.01 1.21 ± 0.02 NS PTH(pg/ml) 33±2 38± 2 NS l,25(OH)2vitamin D (pg/ml) 49.3 ± 2.8 37.6 ± 1.9 P < 0.005 Calcium excretion (mmol/24 h) 6.0 ± 0.6 3.5 ± 0.4 P < 0.005

Exclusion Criteria TmPO4/ GFR The exclusion criteria were: mmol/ I . Age >70 yr: *** *** *** . Hypercalcemia (ionized Ca, > 1 .25 mM); 0.80 -i . Increased PTH in plasma >62 pg/mI;

. Chronic alcoholism, diabetes mellitus, intestinal malabsorption; 0.75 - . Neoplasia, mesenchymal tumor; . Familial hypophosphatemia; 0.7 - . Renal tubular acidosis, decrease of GFR (<70 ml/min per 1.73 m2); and 0.65 - . Previous history of cardiovascular disease (angina pectoris, myo- cardial infarction). 0.6 - Management of Patients, Protocols Initial Investigation. Patients were infused with inulin and p- 0.55- aminohippurate to determine GFR and renal plasma flow (RPF), respectively. Urine was obtained by spontaneous voiding. After an 0.5 - initial bladder emptying, the subjects provided urine samples over four consecutive 30-mm periods, and blood samples were collected at the same time. These periods were referred to as basal periods. Dipyridamole was then infused intravenously (1 mg/kg body wt, maximal dose of 60 mg) over a 30-mm period. Thirty minutes after the end of the dipyridamole infusion, urine and blood samples were Basal Post dipyridamole collected during three consecutive 30-mm periods. These three pen- Figure 1. Effect of dipyridamole infusion on TmPO4/GFR in patients ods were referred to as dipynidamole periods. with renal phosphate leak (middle bar). TmPO4/GFR was increased During each 30-mm period, we measured GFR, RPF, serum cal- by 24% after dipyridamole infusion. Bars marked with L or 0 repre- cium, serum phosphorus, calcium and phosphorus excretion, serum sent patients with or without urolithiasis. The effect of dipyridamole and urinary creatinine, urinary cAMP, and fractional excretion of was similar in both groups. ***P < 0.001. phosphate. PTH and 1 ,25-dihydroxyvitamin D (I ,25(OH),vitamin D) were measured on blood samples collected during the second 30-mm period of the basal and dipyridamole periods. Serum PTH concentrations investigations were performed during the first 3 mo of treatment and were determined by an immunoradiometric assay recognizing the after 6 to 9 and 12 mo of treatment. These investigations were intact 1,84 PTH (kit ELSA-PTH, CIS Biointernational, Gif-sur- conducted as the initial one except there was no dipyridamole infusion Yvette, France). Normal values ranged from I I to 62 pg/ml. and urinary samples were collected over five consecutive 30-mm Serum 1,25(OH)2vitamin D concentrations were measured by RIA periods. (INCSTAR, Stillwater, MN). Values from 15 to 42 pg/mI were considered normal. Electrolyte concentrations were determined using routine standard methods. Urinary cAMP concentrations were mea- Statistical Analyses sured by RIA (Amersham, Buckinghamshire, United Kingdom). The Data from basal periods were compared with dipyridamole periods ratio between the maximal tubular reabsorption rate for phosphate and using a paired t test. Differences were considered significant when the GFR (TmPO4/GFR) was calculated according to the nomogram of P < 0.05. Data collected during the successive investigations were Bijvo#{235}tand Walton (I I). compared with the data obtained during the initial basal period, using Follow-Up of Patients. Patients were treated by dipyridamole a 2-way ANOVA with repeated measures and a least significant given orally (75 mg, 4 times daily). Lower doses were tested in four difference test when P < 0.05 All results were expressed as mean ± patients (not included in this study) and shown to be ineffective. New SEM. 1266 Journal of the American Society of Nephrology J Am Soc Nephrol 9: 1264-1269, 1998

Table 2. Lack of effects of dipyridamole infusion on calcemia, serum parathyroid hormone (PTH) concentration, and cAMP/creatininunia

Variable Before Dipyri damole Infusion After Dipyrid amole Infusion

Serum phosphorus (mmol/L) 0.78 ± 0.01 0.77 ± 0.02 Serum ionized calcium (mmol/L) 1.20 ± 0.01 1.21 ± 0.02 PTH (pg/ml) . 36.9 ± 1.6 34.6 ± 1.8 cAMP/urinary creatinine (nmol/mmol) 348.9 ± 20.6 347.3 ± 20.7

TmPO4/ GFR serum phosphorus mM mmol/ I

0.85 0.68

0.83 -

0.64 I ** 0.81

0.79

0.6 { 0.77

0 I I I I 0 3 9 12 0.56 Months of treatment 1 0 Figure 3. Evolution of serum phosphorus during chronic treatment by

0 3 9 1 2 dipyridamole. **p < 0.01; *** < 0.001 compared with values before treatment. S. patients with urolithiasis; #{149},patients without Months of treatment urolithiasis: no symbol, both groups. Figure 2. Evolution of TmPO4/GFR during chronic treatment with dipyridamole. **P < 0.01; *** < 0.001 compared with values before treatment. #{149},patients with urolithiasis; #{149},patients without to dipyridamole infusion was similar in patients with and urolithiasis: no symbol, both groups. without renal stones (Figure 1). To determine whether a long-term treatment by dipyridamole increases serum phosphorus, the patients were treated with Results dipynidamole given orally (300 mg divided in four daily dos- Sixty-four patients with low TmPO4/GFR (27 women, 37 es). Serum phosphorus and TmPO4/OFR were sequentially men; mean age, 49.4 ± 1.3) were included in this study. These measured. Under these conditions, dipyridamole still signifi- patients exhibited two types of clinical features: 46 were re- cantly increased TmPO4/OFR with a maximal effect within 9 ferred to our department for investigation of arthralgia, myal- mo (Figure 2). The maximal values of TmPO4/OFR, however, gia, muscle weakness, and/or bone demineralization and 18 for were below those observed after the acute infusion of dipyrid- a history of renal lithiasis (calcium oxalate and/or calcium amole (compare Figures 1 and 2). Dipyridamole treatment was phosphate exclusively). These two subgroups differed only in similarly effective on TmPO4/GFR in both patient groups the serum concentration of I ,25(OH).,vitamin D and calcium (Figure 2). In parallel, the increase of renal phosphate reab- excretion, which were significantly higher in patients with sorption led to a significant improvement of serum phosphorus renal lithiasis (Table 1). within 3 mo (Figure 3). Serum phosphorus reached a plateau As a first step, we showed that an acute infusion of dipy- after 9 mo of treatment. The improvement (serum phosphorus nidamole did increase renal phosphate reabsorption in these after 3 mo of treatment > serum phosphorus during the first patients, as reported previously in an other group of subjects investigation) was observed in 5 1 of 64 patients, persisted (10). Patients were infused with dipynidamole during the first beyond 1 2 mo of treatment, and was similar in patients with or investigation, and we compared TmPO4/OFR before and after without urolithiasis (Figure 3). Patients who initially com- the infusion. As shown in Figure 1 , dipynidamole significantly plained of bone pain or muscle weakness reported an improve- improved TmPO4/GFR in all patients by 24%. Serum phos- ment of their physical condition under treatment. Serum phorus, serum PTH concentration, serum ionized calcium, and PTH concentration and serum calcium remained unchanged cAMP excretion remained unchanged (Table 2). The response (Table 3). J Am Soc Nephrol 9: 1264-1269, 1998 Dipyridamole Increases Serum Phosphorus 1267

Table 3. Evolution of serum calcium and serum PTH concentration during the treatment by dipyridamolea

Time of Tre atment (mo) Variable 0 3 9 12

Ionized serum calcium (mmolIL) 1 .20 ± 0.0 1 1 .2 1 ± 0.0 1 1.20 ± 0.0 1 1 .2 1 ± 0.01 PTH (pg/ml) 36.9 ± 1.6 37.9 ± 1.9 34.8 ± 2.3 36.8 ± 3.1

a PTH and serum calcium concentrations were unchanged.

1-25(OH)2vitamin D Under dipynidamole treatment, 24-h calcium excretion de- p9/ ml creased only in patients with initially high vitamin D levels

(baseline: 5.9 ± 0.6; 12 mo: 4.5 ± 0.5 mmol/24 h; P < 0.05) and in patients with renal stones (baseline: 6.0 ± 0.6; 12 mo: 50 4.0 ± 0.3 mmol/24 h; P < 0.05). After 2 yr, the treatment was discontinued in three consent- ing patients for 1 mo, and the serum phosphorus and the TmPO4/OFR were measured. As shown in Table 4, serum 40 phosphorus and TmPO4/OFR decreased in these three patients after discontinuation of the treatment.

30 Discussion This prospective study indicates that in patients with hypophosphatemia due to renal phosphate leak, treatment by

0 I I 1 dipynidamole improves serum phosphorus by increasing renal 0 3 9 1 2 phosphate reabsorption. We examined patients with hypophosphatemia and low Months of treatment TmPO4/GFR. These patients had no other proximal tubular Figure 4. Effect of dipyridamole on 1,25-dihydroxyvitamin D dysfunction, and the sensitivity of the kidney to PTH was ( I ,25(OH),vitamin D) synthesis in patients with initially normal (- - -) normal as assessed by urinary cAMP to urinary creatinine or high (-) l,2S(OH),vitamin D concentrations. *P < 0.05 com- ratios, which were not different from those of control subjects pared with values before treatment. #{149}.patients with urolithiasis; U, (data not shown). An increase of phosphate intake could not patients without urolithiasis. explain low TmPO4/GFR because serum phosphorus concentrations were below normal values. Because hypophosphatemia is known to increase renal I a- Chronic renal phosphate leak is known to induce hypophos- hydroxylase activity and I ,25(OH),vitamin D plasma concen- phatemia and osteopenia or urolithiasis (4-8,13), but the fre- tration in humans ( 1 2), we considered the effect of treatment quency of low TmPO4/GFR among these patients remains to with dipynidamole on I ,25(OH).,vitamin D synthesis. The Se- be studied. We reported previously that dipynidamole increased rum concentration of l,25(OH)2vitamin D was initially in- phosphate uptake in proximal tubular cells in culture and renal creased (>42 pg/ml) in 28 patients (among these, 15 had renal phosphate reabsorption in rats and in humans (9,10). Dipynid- lithiasis) and decreased toward normal values within 9 mo amole may increase phosphate reabsorption by at least two under treatment, whereas it remained unchanged in patients mechanisms. First, dipynidamole is known to inhibit adenosine with initially normal vitamin D levels (Figure 4). Similar uptake (14,15). In the proximal tubule, adenosine is generated results were observed if groups were made according to the from cAMP, which is metabolized in AMP and then adenosine history of urolithiasis (Figure 4). by phosphodiesterases and the ecto-S’-nucleotidase, respec-

Table 4. Modifications of serum phosphorus and renal phosphate threshold before and after discontinuation of treatment for 1 moa

After 1 mo After 2 yr of Dipyridamole Variable Before Treatment Discontinuation of Treatment Treatment

Serum phosphorus (mmolIL) 0.77 ± 0.01 0.93 ± 005b 0.81 ± 0.04 TmPO4/GFR (mmolIL) 0.56 ± 0.04 0.67 ± 0#{149}02b 0.54 ± 0.05

a Results are given as mean ± SEM. n = 3.

b p < 0.05 compared with basal values. 1268 Journal of the American Society of Nephrology J Am Soc Nephrol 9: 1264-1269, 1998

tively. cAMP and AMP do not enter the cells, unlike adenosine effect of dipynidamole on serum phosphorus led to a significant ( 16, 17). In the cell, adenosine is successively metabolized in decrease of l,25(OH)2vitamin D concentration in serum. AMP, ADP, and ATP and can generate cAMP (9). Blocking The normalization of calcium excretion and the decrease of adenosine uptake increases adenosine concentration in the tu- phosphaturia under dipyridamole treatment in patients with bular lumen, as we observed in the urine of patients reported urolithiasis and low TmPO4/GFR suggest that stone recurrence here (data not shown). Adenosine might stimulate type 1 might be reduced, but this point requires further study. Simi- adenosine receptors expressed on proximal tubular cells (18) larly, additional studies with a longer follow-up of patients are and hence inhibit cAMP synthesis and stimulate phosphate needed to assess the effect of dipyridamole on the bone mass. transport (19). Furthermore, dipyridamole, by decreasing aden- In conclusion, in this prospective study we reported that osine intracellular levels, might hamper cAMP formation. dipynidamole, given orally, increased renal phosphate reab- Second, dipynidamole is a potent inhibitor of the multidrug sorption and serum phosphorus and can be used to treat pa- resistance P-glycoprotein activity (20). It is a member of the tients with idiopathic renal phosphate leak. AlP binding cassette family (like cystic fibrosis transmem- brane conductance regulator) that is expressed in the renal proximal tubule (2 1) and regulates cell volume-activated chlo- Acknowledgment ride channels (22). We can hypothesize that the P-glycoprotein This work was supported by a grant from the D#{233}l#{233}gationa la Recherche Clinique Assistance Publique H#{244}pitaux de Paris (Contrat may downregulate NaPi cotransporter activity in the proximal de Recherche Clinique: P9408 12/A0B940 18). tubule. 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