A. Fournier

1-Alpha-Hydroxyvitamin D3 Derivatives in the Treatment of Renal Bone Diseases: Justification and Optimal Modalities of Administration

The use of 1 alpha-hydroxyvitamin D3 [1 alpha(OH)D3] derivatives in a uremic patient is justified only in the treatment of hyperparathyroidism (i.e. when plasma intact parathyroid hormone - PTH - levels are above five or three times the upper limit of normal according to whether the patient is on continuous ambulatory peritoneal dialysis or on hemodialysis and between 0.5-1.5, 1-2 and 2-3 times the upper limit of normal for a creatinine clearance of, respectively, 30, between 30 and 10, or below 10 ml/min/1.73 m2). The following prerequisites have however to be satisfied: (1) a good vitamin D3 repletion should be secured by plasma 25(OH(D) levels of 20-30 ng/ml (if necessary by administration of native vitamin D or 25(OH)D3), and (2) phosphate retention (which is aggravated by the increased phosphate intestinal absorption induced by the 1 alpha (OH)D derivatives) and the consequent possible hyperphosphatemia should be prevented or corrected by the oral administration of alkaline salts of calcium given before the meals as phosphate binders without inducing hypercalcemia. These prerequisites explain the narrow therapeutical margin of 1 alpha (OH)D3 derivatives in uremic patients before dialysis (more so in the adult than in the child) and the possible broadening of this margin in the patients on dialysis by the use of low dialysate calcium concentrations (1.25-1.00 mmol/l) in order to prevent hypercalcemia by inducing a negative perdialytic calcium balance. Once hyperphosphatemia is prevented by oral calcium, 1 alpha (OH)D3 derivatives have the advantage to suppress the transcription of the prepro PTH gene by a mechanism independent of an increase in plasma calcium. Controlled randomized trials have not confirmed the claimed advantage in efficacy and safety of the parenteral versus the oral route nor of the intermittent versus the daily mode of their administration. The advantages of using the so called nonhypercalcemic hyperphosphatemic vitamin D3 derivatives in combination with oral calcium over 1 alpha(OH)D3 derivatives in the treatment of uremic hyperparathyroidism are still waiting for clinical demonstration. Vitamin D derivatives have no place in the treatment of aluminic bone diseases which necessitate long term deferoxamine treatment and prevention of aluminum exposure by the dialysate and the phosphate binders. They are not indicated in the treatment of idiopathic adynamic bone disease which is due to uremia per se combined with an excessive PTH suppression for the degree of renal failure. This low bone turnover pattern is associated with an increased risk of hypercalcemia and hyperphosphatemia and necessitates only a stimulation of PTH secretion by inducing a negative calcium balance with a lower dialysate calcium concentration or simply by discontinuing the oral calcium supplement in the uremic patient not yet dialyzed. In rare cases this pattern is due to a granulomatosis and is corrected by prednisone.

Long-Term (6 Months) Cross-Over Comparison of Calcium Acetate with Calcium Carbonate as Phosphate Binder

A previous short-term study of 10 weeks in 8 patients had shown us that with half the dose of elemental calcium, calcium acetate (CaAc) could control predialysis plasma phosphate (PPO4) as well as calcium carbonate (CaCO3) but that the incidence of hypercalcemia was not decreased. To better appreciate the value of CaAc in comparison to CaCO3, CaAc was given to 28 patients on chronic hemodialysis (6 men, 22 women, age 61 +/- 14 years; dialyzate Ca:1.5 mmol/l) for 6 months to replace CaCO3 at half the dose of elemental calcium (1,235 +/- 521 versus 2,375 +/- 1,470 mg/day). Because of gastrointestinal intolerance, CaAc had to be discontinued in 5 patients after 1-5 months. Magnesium hydroxide [Mg(OH)2] given in 18 of them in association with CaCO3 was discontinued and reintroduced in 6 patients in order to keep PPO4 < 2 mmol/l. Mean dosage of Mg(OH)2 was 2.09 +/- 1.4 g/day with CaCO3 and 0.9 +/- 0.5 with CaAc. Predialysis plasma concentrations of calcium and phosphate were monitored weekly during the 3 months of the control period under CaCO3 and during the 6-month administration of CaAc. Plasma calcium (PCa) was comparable with the 2 treatments (2.47 +/- 0.11 vs. 2.5 +/- 0.10 mmol/l), but PPO4 was significantly lower with CaAc (1.82 +/- 0.26 vs. 1.73 +/- 0.23 mmol/l). Plasma alkaline phosphatase remained constant (122 +/- 66 vs. 122 +/- 70; normal < 170 UI/l) as well as plasma intact PTH (121 +/- 153 vs. 121 +/- 146; normal < 54 pg/ml) and plasma aluminum (0.34 +/- 0.23 vs. 0.32 +/- 0.20 mumol/l).(ABSTRACT TRUNCATED AT 250 WORDS)

Renal and Hypertensive Complications of Extracorporeal Shock Wave Lithotripsy: Who Is at Risk?

Extracorporeal shock wave lithotripsy (ESWL) is now used in the treatment of about 90% of renal and ureteral stones. Because of the non-punctual delivery of energy to the stone, a small volume of renal parenchyma is injured giving place to a fibrous scar which can be shown by highly resolutive imaging techniques like magnetic nuclear resonance. Isotopic clearances point to a reduction of 15% in the renal plasma flow on the side of the lithotripsy, but this alteration appears to be transient in nature. In a few cases an abrupt onset of transient hypertension has been reported in clear relation to a compressive perirenal hematoma. The responsibility of ESWL in the late occurrence of permanent hypertension is, however, still uncertain, probably because of the difficulty in showing that this occurrence is not only related to the older age of the patient. The American Food and Drug Administration-sponsored multicentric study begun in 1992 should solve this issue in the future. Recent articles suggest that altered renal function prior to ESWL would predict the late occurrence of hypertension and worsening of renal failure. Furthermore, age and the resistance index of arcuate or interlobar renal arteries (measured by Doppler) could help to screen patients at risk of developing hypertension. In practice in patients over 60 years of age and/or with a plasma creatinine of >to 300 micromol/l, ESWL should be performed with caution, and renal function and blood pressure should be carefully monitored.

Evaluation de la phosphatase alcaline osseuse sérique au cours des affections métaboliques de l'os: Comparaison des méthodes immunologiques et électrophorétique

Resume Lelectrophorese sur gel dagarose (Isopal®, Beckman) et les techniques immunologiques (Irma: Ostase®, Hybritech et Elisa: Alkphase-B®, Metra) constituent les principales methodes utilisees pour la quantification de la fraction osseuse de la phosphatase alcaline (PAL). La phosphatase alcaline osseuse (PAL-O), marqueur de lactivite des osteoblastes, a ete mesuree chez des patients qui presentent differentes affections metaboliques osseuses secondaires a un Paget (n = 10), a un hyperparathyroidisme biologique (n = 20), a une cirrhose hepatique (n = 10) ou a une insuffisance renale chronique (n = 24) ainsi que chez des sujets temoins (n = 15). La correlation des methodes, electrophoretique dune part et immunologiques dautre part, est forte (Irma: r = 0,89; Elisa: r = 0,91), excepte lorsque les valeurs de PAL-O sont faibles: sujets controles (Irma: r = 0,71; Elisa: r = 0,65) et insuffisants renaux (Irma: r = 0,76; Elisa: r = 0,67) probablement en raison des reactions croisees avec les autres fractions de PAL. Les deux techniques immunologiques sont fortement correlees (r = 0,96). Comparativement a la population controle, les trois methodes montrent une augmentation significative de lactivite de la fraction osseuse de la PAL accompagnant les modifications du metabolisme osseux (Paget, hyperparathyroidisme, cirrhose hepatique). Au cours de linsuffisance renale chronique, la PAL-O (Isopal, Elisa) nest pas significativement augmentee, excepte avec Irma. Les methodes immunologiques sont acceptables en raison de leur fiabilite et de leur rapidite; cependant, lorsque les valeurs de PAL-O sont basses (insuffisance renale), le systeme electrophoretique semble preferable pour eviter les reactions croisees.

Pathologie osseuse et insuffisance rénale. Actualités sur les explorations biologiques

Resume Dans cette mise au point, ont ete abordees successivement l’interpretation des dosages d’hormone parathyroidienne chez l’insuffisant renal et l’utilisation des marqueurs du remodelage osseux chez l’insuffisant renal et le transplante renal.

Steady-state captopril renography: Continuous monitoring of the captopril-induced increase in99mTc-MAG3 mean parenchymal transit time in renovascular hypertension

Steady-state captopril renography (SSCR) is an original technique for assessing the captopril-induced increase in technetium-99m mercaptoacetyltriglycine99mTc-MAG3 mean parenchymal transit time (MPTT) in kidneys affected with functional renal artery stenosis (RAS). The steady-state parenchymal activity achieved by constant infusion of99mTc-MAG3 is directly linked to the MPTT of the radiopharmaceutical. This steady-state parenchymal activity was continuously monitored from 15 min before to 60 min after a single dose of captopril in order to detect possible disruption of the steady state. SSCR was performed in 11 hypertensive patients with unilateral RAS and in two with RAS of a solitary kidney before renal revascularization (RR). In four of these patients, an additional SSCR was performed after RR. Of the ten patients whose hypertension was cured or improved by RR, one presented an uninterpretable SSCR and six presented a positive SSCR on the affected side. Control SSCR performed in four of these six patients was bilaterally negative. SSCR was also bilaterally negative in the three patients who showed no blood pressure response to RR. These preliminary results tend to indicate that, in spite of the stability of pre- and post-captopril hydration and data acquisition conditions allowed by this steady-state technique, the sensitivity is lower than expected. However, the reason for the false-negative results does not seem to be inherent to SSCR.

Recent Advances in the Treatment of Renal Osteodystrophy

Renal osteodystrophy becomes clinically significant when the following features are present: clinical symptoms (pain, muscle weakness, pruritus), radiological signs (subperiosteal erosions, osteopenia, fractures or pseudofractures, slipped epiphysis with coxa vara or genu valgum in children, metastatic calcification) and marked plasma abnormalities, particularly uncontrollable hyperphosphatemia. Clinically significant bone disease is not usually seen in adults until they have been on dialysis for several years but may be seen earlier (even before dialysis has been started) in children. Such bone disease may be due either to hyperparathyroidism or to aluminum (Al) bone disease. In favor of hyperparathyroidism are the following features (1, 2): rarity of pain and fractures, greater elevation of alkaline phosphatase, greater elevation of parathyroid hormone (PTH) plasma concentration and lower basal plasma concentration of Al (<300 µg/l) with smaller increase of plasma Al after i.v. administration of desferoxamine (increase <175 µg/l). It is only by bone biopsy, however, that it is possible to differentiate with certainty osteitis fibrosa, the bone expression of hyperparathyroidism, from osteomalacia or adynamic bone disease, both of which have been linked to Al intoxication (1, 2).

Unexplained Hypercalcemia in a Hemodialysis Patient

A woman on long‐term chronic hemodialysis has developed persistent mild hypercalcemia. Her calcium supplement (phosphate binder) has been discontinued and aluminum binders started; calcitriol is not being given. Serum aluminum levels are very low as is intact PTH. Thyroid function is normal and phosphate levels slightly elevated. Dialysate calcium level was reduced several months ago to 1.25 mmollL. Physical exam, bone survey, bone scan, chest x‐ray and mammography are negative. Is there anything related to dialysis that might explain this picture?

Plasma Cardionatrin and Volume and the Renin Angiotensin Aldosterone System in Normotensiye and Hypertensive Pregnancy

Cardionatrin is the 28 aminoacid atrial natriuretic peptide which is released into the circulation from its storage granules when the atria are stretched, (1,2). This peptide has both remarkable natriuretic and vasodilating properties and suppresses the renin angiotensin aldosterone system. It may therefore be Implicated in the pathogenesis of hypertension. So far it has been investigated only In essential hypertension and shown to be increased (3). It has not yet been evaluated in pregnancy induced hypertension (PIH) or preeclampsia. Therefore we measured plasma concentrations of cardionatrin in pregnant women with normal blood pressure as well as in women with PIH and preeclampsia during pregnancy and after delivery, simultaneouly with their plasma volume, blood uric acid, plasma renin activity (PRA) and plasma concentrations of aldosterone(PA).