Early dietary phosphorus restriction and calcium supplementation in the prevention of renal

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1 Early dietary phosphorus restriction and calcium supplementation in the prevention of renal Giuseppe Maschio, M. D., Nicola Tessitore, M. D., A ngela D Angelo, M.D., Ermanno Bonucci, M. D., A ntonio Lupo, M. D., Enrico Valvo, M. D., Carmelo Loschiavo, M. D., Antonia Fabris, M. D., Paolo Morachiello, M.D., Guido Previato, M. D., and Ernico Fiaschi, M.D. ABSTRACT The clinical applicability ofthe experimental proportional reduction of dietary phosphorus intake has been evaluated in two groups of patients with chronic renal failure. Fortyfive patients with plasma creatinine values of.9 to 3.5 mg/dl (glomerular filtration rate 35 to 15 mi/mm) were kept for I to 4 years on a diet containing 40 kcal/kg, about 0. g/kg of protein. 00 to 750 mg of phosphorus, and 1500 to 000 mg ofcalcium (with oral supplementation). Vitamin D or its analogs were prescribed in 7 1% of the patients. This treatment was effective in preventing the biochemical and morphological (bone biopsy) features of secondary hyperparathyroidism. No metabolic or morphological complications, such as protein depletion or osteopenia, were observed. Since elevation of serum parathyroid hormone, impaired homeostasis of plasma phosphate after a phosphate load, and abnormal bone histology are present even in early renal failure, 4 patients with plasma creatinine values of 1. to.8 mg/dl (glomerular filtration rate 0 to 30 ml/min) were kept for to 18 months on a diet containing 40 kcal/kg, about 0.8 g/kg of protein, 800 to 900 mg of phosphorus, and 1500 to 000 mg of calcium (with oral supplementation). An additional treatment with vitamin D or its analogs was performed in 41% of the patients. After 18 months of follow-up, this regimen resulted in a fall of serum parathyroid hormone values with no progression or amelioration of bone lesions (defective mineralization and increased bone resorption) in the affected patients. A rational approach for preventing bone disease in patients with chronic renal failure seems ready to be developed. Am. J. Clin. Nuir. 33: , Between 1970 and 1974, most of our patients with chronic renal failure had been kept on a diet in which the content of protein and phosphorus was reduced approximately in proportion to the observed decrement of creati.nine clearance and ranging from about 40 to 0 g/day of protein and from about 50 to 300 mg/day of phosphorus (I, ). The calcium content ranged from 500 to 900 mg/ day, with oral supplementation in many patients. An additional treatment with vitamin D or its analogs was not given regularly. This unintentional clinical application of the well-known proportional reduction of dietary phosphorus intake, as suggested on experimental basis by Sbatopolsky et al. (3), was followed by a surprising rarity of clinical and radiological signs of renal osteodystrophy. Bone biopsy results were available in 55 patients. Both light and electron microscopic studies showed osteomabacia as the main pathological feature in 5 1% of the patients. An associated hyperparathyroidism was observed in an additional 1% of the patients, and in 33% of them the bone tissue was normal. The comparison with a group of3o patients who came to our Units in chronic renal failure and with no previous dietary protein and phosphorus restriction showed a completely different pattern, with a considerable decrease in the percentage of normal bone and increase in osteoclastic bone disease (Fig. I). The survey of this 4-year experience adds support to the view that the restriction of I From the Divisione di Nefrologia, Istituti Ospitalieri, Verona; I Clinica Medica, Universit#{4}, Padova; and I lstituto di Anatomia Patologica, Universit#{4}, Roma, Italy. Address reprint requests to: Giuseppe Maschio, M.D., Divisione Nefrologia, Istituti Ospitalieri, Verona, Italy. 154 The American JournalofClinicalNutrition 33:JULYI98O, pp Printed in U.S.A.

2 PREVENTION OF RENAL OSTEODYSTROPHY I 547 CR 4-1 mq/di LOW-PROTEIN (55) DIET CR3513 FREE (30) mg/di DIET 0/s LII NORMAL I:: OSTEOMALACIA!!hi:.!l OSTEOMALACIA nfj + HYPERPARATHYRO FIG. I. The frequency and the severity of bone lesions in two groups of patients with different protein and phosphorus intakes. The methods for bone tissue examination have been described elsewhere (see References and ). dietary phosphate is effective in reducing the frequency ofosteocbastic bone disease in renal failure. Our diets, however, contained reduced amounts of calcium as rebated to the needs of uremic patients, and the protein content was extremely low (bess than 30 g/ day) in many patients with advanced renal failure. In fact, calcium and protein depletion were frequently observed in the patients kept on the lowest protein and calcium intakes (Fig. ), and it is known that both these metabolic disorders are important factors in the pathogenesis of osteomalacic and osteoporotic components of renal osteodystrophy (5). However, we could not exclude the possibibity that the very bow-phosphorus diets might have contributed to the observed preyabence of osteomalacia in our patients. Since 1974, our approach to the dietary treatment of renal osteodystrophy has been somewhat different, and we have attempted to prevent phosphate retention by prescribing a protein-restricted diet at plasma creatinine values of about 3 mg/db (). Statistically, this value represents in most cases a gbomerular filtration rate (GFR), evaluated by means of I DISM the renal clearance of iothabamate, equal to or less than 30 mb/mm; that is the critical value at which phosphate retention usually occurs if the patients maintain their dietary phosphorus intake (7). During the last 5 years, 45 patients in chronic renal failure, with plasma creatinine values of.9 to 3.5 mg/dl and GFR, evabuated by means of iothabamate clearance (), of 35 to 15 mb/mm, have started a dietary regimen containing about 40 kcab/kg, 0. g/ kg of protein, 00 to 750 mg of phosphorus, and 1500 to 000 mg of calcium (with oral supplementation in all cases). About 75% of the ingested protein was of high biologic value. An additional, usually intermittent, treatment with vitamin D (300,000 to 00,000 IU twice a week) or its analogs (dihydrotachisterol, 0.50 to mg/day) was prescribed in 3 patients in order to keep plasma calcium within the normal range as long as possible. A reliable follow-up was available in 3 patients, and showed this regimen to be effective in maintaining normal mean values of plasma calcium and phosphate and in preventing the progression of secondary hyperparathyroidism (Fig. 3).

3 1548 MASCHIO ET AL. CR 411 mg/di 0 40g PROTEIN A = 3Oq PROTEIN 14 CREATININE mq/dl MUSCLE 1 PROTEIN NITROGEN q/100q El NORMAL RANGE [Ca] mq/di FF _%, : 4 years DURATION OF LOW-PROTEIN DIETS 0 I 0.4 p= n.s. A r a p < y x FIG.. A significant negative correlation between the duration of low-protein diets and muscle protein nitrogen content is shown only in patients kept on the lowest protein intakes. Muscle protein nitrogen was determined according to Bergstrom (4). (n = 3) t 0.0 t 0.90 t 1.00 ±.05 t i-pth pg/i i H-+ 0 mg/di [o4] 4. #{149} f f- NORMAL ---- RANGE MONTHS FIG. 3. No significant increase in plasma parathyroid hormone (PTH) values is observed during 4 years of protein-restricted diet and calcium supplementation. Plasma i-pth was determined according to Fischer et al. (8).

4 PREVENTION OF RENAL OSTEODYSTROPHY 1549 This was also evident on a morphologic basis: after years of protein-restricted diet, an isolated osteomabacia was observed in 4% of the examined patients, and an associated hyperparathyroidism in an additional 1% of them. The comparison with a group of patients who started the same dietary regimen at higher bevels of plasma creatinine (4 to mg/ dl) showed a significantly higher percentage of osteoclastic bone disease in this batter group. No evidence of protein depletion or diffuse osteopenia was observed in our patients. In fact, metabolic studies of diets with a similar composition have shown that patients usually achieve neutral or positive calcium and nitrogen balances (9). Our results add confirmation to the view that preventing phosphate retention by reducing its dietary intake is an important step in the prevention and treatment of renal bone disease, and that phosphate restriction should [P04] m q/d I I MEAN I NORMAL SUBJECTS (1) 4 -*PATIENTS WITH C.R.F. (0) CR.9-.0 mg/di AM PM INGESTION OF lg Pi begin at plasma creatinine values of about 3.0 to 3.5 mg/db (GFR about 30 mb/mm). This is in agreement with Sbatopobsky s recommendations (10). During the last few years, however, cvidence has been presented showing that disordered calcium metabolism and bone lesions may be observed even in incipient renal failure. Mabluche et al. (1 1) found a significant reduction of intestinal calcium absorption in 3% of their patients with a GFR between 75 and 50 mb/mm, and in 50% of those with a GFR between 40 and 30 mb/mm. At these values of renal function, elevation of serum parathyroid hormone (1), skeletal resistance to the calcemic action of parathyroid hormone (13), and abnormal bone histology (, 14) may also be observed. All these abnormalities could be explained if l,5(oh)-vitamin D3 synthesis is depressed in early renal failure ( 15). Llach et al. (1) have postulated that if patients with early renal failure maintain their dietary phospho- c HOURS AFTER P04 LOAD * * * e AM PM 3 DAYS * p<o.o01 FIG. 4. The increase in plasma phosphate is significantly greater in patients with moderate chronic renal failure (C.R.F.) than in controls and 8 hr after the phosphate load, and significant hyperphosphatemia is still evident on the day after the phosphate ingestion.

5 I 550 MASCHIO ET AL. rus intake, postprandiab hyperphosphatemia may occur, which in turn may suppress the renal synthesis of 1,5(OH)D3. If this were true, an impaired plasma phosphate homeostasis after a standard oral phosphorus load should be observed in patients with early renal failure. A phosphate tolerance study was performed in two groups of patients with chronic renal failure. The first group ( early renal failure ) had 13 patients with plasma creatinine of 1.55 to.80 mg/dl and GFR (iothalamate clearance) of 55 to ml/min. The diet contained 800 to 900 mg of phosphorus and about 1500 mg of calcium (with oral supplementation). The second group ( modcrate renal failure ) had 0 patients with plasma creatinine of.90 to.00 mg/dl and GFR (iothalamate clearance) of 5 to 1 1 ml/ miii. The diet contained about 700 mg of phosphorus and 1500 to 000 mg of calcium (with oral supplementation). Sixteen normal subjects were taken as controls. They were kept for 10 days prior to the study on the same diet that was prescribed for the first group of patients. [P04] 5. mg/di 4. MEAN t SD NORMAL SUBJECTS (1) #{13} -A PATIENTS WITH C.R.F(13) P1.55-.SOmg/dI 8 1 AM INGESTION OF lq Pi PM During the control day in normal subjects and in patients with moderate renal failure, the mean values of plasma phosphate were not significantly different. The increase in plasma phosphate concentration and 8 hr after the phosphate load in the second day was significantly greater in uremic patients than in controls, and significant hyperphosphatemia was still evident in the day following the phosphate ingestion (Fig. 4). Similar results were obtained in patients with early renal failure (Fig. 5). The mean values for plasma cabcium were not statistically different in normal subjects and in patients with moderate renal failure throughout the 1st and the nd day. During the 3rd day, however, plasma calcium values were significantly lower in uremic patients than in controls. Similar results were obtained in patients with early renal failure. During the 48 hr after the phosphate ingestion, the normal subjects excreted 8% of the 1000-mg load (i.e., the amount of phosphate excreted above the base-line bevel of excretion recorded during the control day). In contrast, both groups of patients excreted significantly a HOURS AFTER P04 LOAD * * AM PM I- ] DAYS * p.co.o1 FIG. 5. Plasma phosphate homeostasis is impaired also in patients with early chronic renal failure (C.R.F.) after a phosphate load.

6 PREVENTION OF RENAL OSTEODYSTROPHY 1551 less phosphorus (4 and %, respectively) than did the controls despite greater hyperphosphatemia (Fig. ). These results suggest that 1 ) a reduced tolerance to a standard phosphorus load may be found even in patients with early renal failure, and ) the prolonged hyperphosphatemia is explained by the limitations of phosphate excretion imposed by renal failure. According to these indications, during the last years 4 patients in chronic renal failure, with plasma creatinine values of 1. to.8 mg/dl and GFR (iothabamate clearance) of 0 to 30 mb/mm, have started a dietary regimen containing about 40 kcal/kg, 0.8 g/ kg of protein, 800 to 900 mg of phosphorus, and 1500 to 000 mg of calcium (with oral supplementation). An additional, usually intermittent treatment with vitamin D (300,000 to 00,000 IU once or twice a week) or dihydrotachisterob (0.50 to mg/day) was prescribed in 10 patients. At bone biopsy, both bight and electron microscopic studies showed osteomalacia in 30% of the patients and an associated hyperparathyroidism in an additionab 1%. A reliable follow-up was available in 0 patients and showed this regimen to be very effective in maintaining normal values of plasma caicium and phosphate and in pre- % venting the progression of secondary hyperparathyroidism (Fig. 7). A comparison was made between the two groups ofpatients who started early the protein-restricted diets. After an 18-month follow-up, plasma parathyroid hormone values and fractional excretion of phosphate were significantly greater in patients who started the diet at plasma creatinine levels of.8 to 3.5 mg/dl than in those who started an earlier treatment (Table 1). The morphological results in 14 patients who completed the 18-month treatment showed no progression ofosteodystrophy and some improvement of bone lesions (decrease of both osteomalacia and bone resorption) (Fig. 8). These results are in agreement with those obtained by Llach et ab. (1) in a few patients with early renal failure. No evidence of protein and phosphorus depletion was observed on the basis of repeated measurements of serum protein (transferrin and complement factors), of serum phosphate, and, in some patients, of muscle cell content of protein and phosphate. The patients adherence to the protein-restricted diet was very good: this was easily obtained in a country where the average protein intake is not more than 70 g/day. In conclusion, early phosphorus restriction, calcium supplementation and vitamin D ad- DAYS P04 LOAD 0 NORMAL SUBJECTS El PATIENTS WITH C.R.F I PATIENTS WITH C.R.F CR1558#{17} mq/di CR mq/di FIG.. During the 48 hr after the phosphate load, the normal subjects excreted 8% of the 1000-mg load, while patients with early or moderate renal failure (C.R.F.) excreted significantly less phosphorus (4 and %, respectively).

7 155 MASCH1O ET AL. ( n a 0) CREATININE mq/di to.40 *0.31 to.4 t0.4 3 n Jig! I i-pth 0 1 [Ca) 10 mg/di 8 [PoJ 4. mg/di NORMAL RANGE 0 1 F f I -+ F f i H 1 18 MONTHS FIG. 7. No significant change in plasma parathyroid hormone (i-pth) values is observed during the follow-up period. TABLE I Patients with renal failure after 18-mo treatment with protein-restricted diet Plasma P04 (mg/dl) Plasma Ca (mg/dl) Plasma i-parathyroid (ig/hiter) ± x 100 hormone -0. g/kg -0.8 glkg (PCR mg/di) In-8) 4.0 ± ± ± ±.0 (PCR.-.8 mg/di) In-0) 4.08 ± ± ± ± 1.88 #{17} a After the 1 8-month treatment, plasma i-parathyroid hormone values and fractional excretion of phosphate (Cpo4/C#{31}r X 100) were significantly lower in patients who started the phosphate restriction earlier. I) Not significant. ministration are effective means to prevent the development of both hyperparathyroidism and osteomalacia in patients with chronic renal failure. The degree of chronicity is probably critical for modulating the effects of phosphate restriction: in fact, the best results were obtained in those patients who started the protein-restricted diets very early in the course of their renal failure. In man, it might be difficult to reduce NSb NS <0.01 <0.01 dietary phosphorus in exact proportion to the fall in GFR. Moreover, the clinical applicability ofthe experimental studies is still under evaluation and might face some geographical difficulties (17). However, a rational approach for preventing bone disease-and, perhaps, for sbowering the progression of functional deterioration (18)-in patients with chronic renal failure seems ready to be developed. C]

8 PREVENTION OF RENAL OSTEODYSTROPHY 1553 (cr mg/di) S/ /0 70 BASAL (n :4) STUDY AFTER 18-MONTH TREATMENT (n :14) 0 calcium NORMAL : OSTEOMALACIA BONE mmmi OSTEOMALACIA UiibM HYPERPARATHYROIDISM FIG. 8. Improvement of bone histology in a group of patients after 18 months of protein-restricted diet and References supplementation. I. MASCHIO, G., E. BONUCCI, G. MIONI, A. D ANGELO, E. 0551, E. VALVO AND A. LUPO. Biochemical and morphological aspects of bone tissue in chronic renal failure. Nephron 1: 437, BONUCCI, E., G. MASCHIO, A. D ANGELO, E. 0551, A. LUPO AND E. VALVO. Morphological aspects of bone tissue in chronic renal disease. A histological and electron microscopic study. In: Vitamin D and Problems Related to Uremic Bone Disease, edited by A. W. Norman, K. Schafer, H. G. Grigoleit, D. Von Herrath, and E. Ritz. Berlin: Walter de Gruyter, 1975, p SLATOPOLSKY, E., S. CAGLAR, L. GRADOWSKA, J. CANTERBURY, J. REISS AND N. S. BRICKER. On the prevention of secondary hyperparathyroidism in cxperimental chronic renal disease using proportional reduction of dietary phosphorus intake. Kidney Internat. : 147, BERGSTROM, J. Muscle electrolytes in man, determined by neutron activation analysis on needle biopsy specimens: a study on normal subjects, kidney patients and patients with chronic diarrhoea. Scand. J. Clin. Lab. Invest. 14 (Suppl.): 8, RITZ, E., 0. MEHLS, H. MALLUCHE, B. KREMPIEN, H. SCMIDT-GAYK AND H. HEIMBERG. Unanswered problems in uremic bone disease. In: Vitamin D and Problems Related to Uremic Bone Disease, edited by A. W. Norman, K. Schaefer, H. G. Grigoleit, D. Von Herrath, and E. Ritz. Berlin: Walter de Gruyter, 1975, p FIASCHI, E., G. MASCHIO, A. D ANGELO, E. B0N- UCCI, N. TESSITORE AND P. MESSA. Low-protein diets and bone disease in chronic renal failure. Kidney Internat. 13 (Suppl. 8): S-79, BRICKER, N. S., J. BOURGOIGNIE AND H. WEBER. The renal response to progressive nephron loss. In: The Kidney, edited by B. M. Brenner, and F. C. Rector, Jr. Philadelphia: Saunders, 197, p FISCHER, J. A., U. BINSWANGER AND F. M. DIE- TRICH. Human parathyroid hormone: Immunological characterization ofantibodies against a glandular extract and the synthetic amino-terminal fragments 1-1 and 1-34 and their use in the determination of immunoreactive hormone in human sera. J. Chin. Invest. 54: 138, KOPPLE, J. D., AND J. W. COBURN. Metabolic studies of low-protein diets in uremia: I. Nitrogen and potassium; II. Calcium, phosphorus and magnesium. Medicine 5: 583, SLATOPOLSKY, E. Recommendations for the treatment of renal osteodystrophy in dialysis patients. Kidney Internat. 7 (Suppl. ): S-53, MALLUCHE, H. H., E. WERNER AND E. RITZ. Intestinal absorption of calcium and whole-body calcium retention in incipient and advanced renal failure. Mineral Electrol. Metabol. 1: 3, REISS, E., J. M. CANTERBURY AND A. KANTNER. Circulating parathyroid hormone concentration in chronic renal insufficiency. Arch. Internal. Med. 14: 417, LLACH, F., S. G. MASSRY, F. R. SINGER, K. KUR0- KAWA, J. H. KAYE AND J. W. COBURN. Skeletal resistance to endogenous parathyroid hormone in

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