Nephrology Dialysis Transplantation

Nephrol Dial Transplant (1998) 13 [Suppl 3]: 57 61 Nephrology Dialysis Transplantation The importance of hyperphosphataemia in the severity of hyperparathyroidism and its treatment in patients with chronic renal failure Francisco Llach and Michael Yudd1 Newark Beth Israel Medical Center Nephrology Division, Newark, and 1East Orange VA Center, Nephrology Division, East Orange, NJ, USA important are dietary P intake and the ingestion of phosphate-binding gels. Results from metabolic bal- ance studies indicates that aluminum (Al ) hydroxide gel, 72 200 ml/day, increases faecal excretion of P by 30 144% [5]; however, there is little relationship between the amount of Al hydroxide taken and either the net or relative increase in faecal P. When dietary P intake is <1.09/day and Al hydroxide is taken, faecal P often exceeds dietary intake [6]. However, when dietary P is increased to 2 g/day (64 mmol ), faecal P is usually less than the dietary intake despite ingestion of the gels. Thus, a high P intake can offset an effect of treatment with Al hydroxide or calcium carbonate, emphasizing the need for P restriction together with P binders. Key words: calcitriol; dietary restrictions; hyperphosphataemia; phosphorus binders; secondary hyperparathyroidism Introduction Over the last two decades, significant advances have been made in the pathogenesis of secondary hyperpara- thyroidism (2HPTH) in chronic renal failure (CRF). Thus, calcitriol deficiency and hyperphosphataemia are the most important factors [1,2]. Both calcitriol therapy and appropriate control of hyperphosphatae- mia if instituted early may prevent and/or ameliorate 2HPTH. This in turn results in marked improvement in the bone lesion, osteitis fibrosa, an important clinical expression of 2HPTH. Prevention of hyperphosphataemia is of paramount importance. This has become more relevant after the recent observations that phos- phorus, per se, directly stimulates parathyroid hormone (PTH ) synthesis [3]. Furthermore, hyperphosphatae- mia in dialysis patients has been shown to be a major factor in the worsening of HPTH [4]. We will discuss the clinical importance of hyperphosphataemia both prior to and during calcitriol therapy. Factors affecting serum phosphorus (P) in these patients are summarized in Table 1. Of these, the most Table 1. Factors affecting serum phosphorus in dialysis patients Dietary phosphorus intake Ingestion of phosphorus binders Treatment with vitamin D sterols Frequency, duration and efficiency of dialysis Balance between degradation and synthesis of protein Severity of bone resorption Parenteral alimentation Phosphorus-containing enemas Correspondence and offprint requests to: F. Llach, Newark Beth Israel Medical Center, Nephrology Division, D-4, 201 Lyons Avenue at Osborne Terrace, Newark, NJ 07112, USA. Methods of controlling hyperphosphataemia: Severe hyperphosphataemia usually develops in advanced CRF, most often in patients already on maintenance dialysis. The high serum P not only aggravates the 2HPTH, but it is also an important factor in the development of soft tissue calcifications. The goal of therapy is to reduce serum P to or near normal. In dialysis patients, pre-dialysis serum P should be maintained between 4.5 and 6.0 mg/dl (1.44 1.92 mmol/l). Dietary restriction The first important step to control serum P is to decrease the amount of P available for gut absorption. This is achieved by decreasing the intake of protein, especially avoiding protein food stuffs with a high content of P. With commencement of dialytic therapy, it is suggested by the National Cooperative Dialysis Study that patients should ingest a diet containing at least 1 g/kg/day of protein [7]. Metabolic balance studies suggest that a minimum protein intake of 1g/kg/day is necessary to maintain positive nitrogen balance [8]. Thus, Blumenkrantz et al. performed nitrogen balance studies in CAPD patients and noted 1998 European Renal Association European Dialysis and Transplant Association

58 F. Llach and M. Yudd near neutral balance when a protein diet of 1 g/kg/day hypercalcaemia most likely due to the use of a high was given, and positive balance was always achieved dialysate Ca concentration ( 3.5 meq/l ). Schaeffer et al. with a dietary protein of 1.2 g/kg/day [8]. have made similar observations [18]. They compared the efficacy of Ca acetate vs Ca carbonate in a 15 week Phosphorus binders cross-over study. Compared with baseline values, both binders significantly reduced serum P and increased Aluminum containing P binders was used for many serum Ca. However, the average amount of elemental years in the control of serum P in patients with CRF. Ca given with Ca acetate was 25.4 mmol as compared As discussed earlier, it was effective and apparently with 46.9 mmol with Ca carbonate (P<0.001). The safe. However, over the last decade, it has become incidence of hypercalcaemia was similar in both groups clear that significant amounts of Al are absorbed by of patients. Similar observations have been made by the gut, resulting in aluminum toxicity [9]. This is other investigators. Thus, it appears that Ca acetate is especially important in certain high risk group of a more efficient binder of P than Ca carbonate, and patients such as diabetic patients [5], prior to parathy- since a lesser amount of elemental Ca needs to be roidectomy [10], aplastic or adynamic bone disease administered, this may lead to lower incidence of [11] and concomitant ingestion of alkalizing agents hypercalcaemia. [12]. Thus, in general, chronic administration of Al Magnesium (Mg) salts are becoming an important binders should be avoided. alternative to the use of Ca-containing P binders. The Calcium salts has been shown to be effective P effect of Mg supplementation on gut phosphorus binders. As the search for a substitute for non-al- absorption has been evaluated by Fine et al. using the containing binders intensified, calcium (Ca) carbonate gastrointestinal waste-out technique [19]. Normal sub- has become the alternative binder. It is inexpensive jects ingested a meal supplemented by 0 38 mmol of and contains a high proportion of elemental Ca (40%). Mg acetate. The fractional gut absorption of P Numerous studies have shown that Ca carbonate is an decreased from 72 to 56% with 5 mmol of Mg acetate, effective P binder. Slatopolsky et al. evaluated the and 28% of the ingested P was absorbed. These experi- effect of this binder in 20 dialysis patients [13]; overall, mental studies were confirmed in clinical studies performed good control of P was achieved during 2 months of by O Donovan et al. [20]. They used Mg treatment. However, because of the ensuing hypercal- carbonate in 28 patients for 2 years, as a substitute for caemia, one-third of the patients still required some Al Al hydroxide. Mg carbonate was administered in doses hydroxide to control serum P. In subsequent studies, of 21 63 mmol/day for the pre-study period, and these investigators evaluated the long-term effect of Ca dialysate Mg concentration was changed from carbonate together with a lower dialysate Ca concen- 0.85 mmol/l to a free Mg dialysate. With the administration tration in 21 patients [14]. None of those patients of Mg carbonate, a significant reduction in pretration needed supplemental Al hydroxide because hypercalca- dialysis Al was observed, and serum P was under emia was largely avoided with the use of a dialysate control and remained unchanged from previous values. Ca of 2.5 meq/l. Magnesium did not change, remaining between 1.01 Calcium acetate is an effective alternative P binder. and 1.33 mmol/l. Seemingly, Mg carbonate was well Sheik et al., using the gastrointestinal wash-out tolerated by all the patients. Other investigators have method, have evaluated the effect of Ca acetate on Ca also observed the effectiveness of Mg salts as P binders. and P reabsorption as compared with Ca carbonate Thus, Mg carbonate binder together with a free Mg [15]. In normal subjects ingesting a meal containing dialysate is an important alternative to other binders. 11.1 mmol of P, Ca carbonate (25 mmol of elemental Its use not only controls the hyperphosphataemia, but Ca) decreased gut P absorption from 8.5 mmol to also, by decreasing Ca intake, it minimizes the episodes 4.9 mmol/l, whereas Ca acetate decreased it to an of hypercalcaemia. Its use is advisable in dialysis average of 2.9 mmol. The amount of Ca absorbed after patients with HPTH who respond to calcitriol therapy. Ca carbonate was 7.4 mmol as compared with Thus, in these patients, as PTH approaches normal as 5.6 mmol after Ca acetate. Thus the amount of P the result of calcitriol therapy, bone remineralization found per amount of Ca absorbed was practically is almost complete and the tendency to develop hypercalcaemia twice that of Ca acetate. These observations were and hyperphosphataemia is greater since confirmed in studies by Mai et al. in six haemodialysis bone cannot take more minerals. patients [16]; after treatment with Ca carbonate, P absorption decreased by 40% of the ingested load while Ca acetate decreased P absorption by 21.7%. Dialysis of phosphorus Studies by Emmett et al. have evaluated the long- Removal of P by dialysis conceptually should be the term effect of Ca acetate on divalent ion metabolism an appropriate way to control hyperphosphataemia. in 91 dialysis patients [17]. All P binders were discon- Unfortunately, the various dialytic techniques available tinued for 2 weeks before the 3 month study. Ca can not achieve this goal. Recently, Hou et al. have acetate resulted in an increase in serum Ca and a evaluated P removal in dialysis patients treated by decrease in serum P. The dose of elemental Ca necessary dialysis with a blood flow of 300 and a dialysate flow for P control was 10 15 mmol per meal of 500 ml/min [21]. The pre-dialysis P averaged (400 600 mg per meal ), and 17 patients developed 6.8 mg/dl (2.2 mmol/l ). They observed a high rate of

Importance of hyperphosphataemia in hyperparathyroidism 59 P removal in each stage of dialysis, which steadily increased concentrations during the inter-dialytic interval declined during the 4 h of dialysis. The decline was in these patients. Presumably this arises because due to an efflux of P from the intracellular space and bone resorption is markedly increased with efflux of P bone to the extracellular space as the result of the from bone to blood. In these patients, a marked early decrease in serum P. Overall, 1 g of P was reduction in serum P often follows parathyroidectomy removed with each dialysis. Removal of P by dialysis or when parathyroid hormone (PTH) is decreased by was not affected by the type of dialyser membrane, the i.v. calcitriol. Another problem with the hyperphosphataemia dialytic technique or the dialysate Ca concentration. of these patients may be the development, Thus, Shinaberger et al. observed a net P removal of at the parathyroid gland level, of non-responsiveness 500 600 mg during 4 h of conventional haemodialysis to the PTH-inhibitory action of calcitriol. Thus, which increased only to 600 700 mg during 3 h of high recently, we have observed worsening of 2HPTH in efficiency or high flux haemodialysis [22]; no significant two patients receiving an appropriate dose of intraven- changes were observed using acetate, polysulphone, ous calcitriol [25]. In these two patients, although and other highly permeable membranes. Interestingly, there was an initial response to i.v. calcitriol character- correction of the anaemia with erythropoietin decreases ized by a marked decrease in PTH, as severe hyperphosphataemia P removal by 18%. Recently, it has been suggested developed, a gradual and steady that bicarbonate rather than acetate may increase the increment of PTH was observed ( Figure 1). This intracellular pool of P and thus decrease the serum P occurred despite the presence of mild hypercalcaemia concentration. However, preliminary studies compar- and appropriate blood levels of calcitriol. ing dialysate containing the two buffers showed no Appropriate knowledge of the dietary habit of the significant differences in the transference of P [23]. In patient is of utmost importance. Thus, the number of CAPD patients, the clearance of P is ~4.7 ml/min meals per day and the amount of P ingested with each with each dialysate exchange; 65 mg (2.1 mmol ) is meal should be evaluated so that the dose of the P recovered, resulting in a daily removal of P of 307 mg binder prescribed is commensurate with the size of the (9.9 mmol ). Thus, CAPD in general is not better than meal. Schiller et al., using the gastrointestinal washout haemodialysis in removing P. technique in normal subjects, observed that the However, in the presence of appropriate dietary dose and time of administration of the P binder had a intake and adequate nutrition, the presence of hyperphosphataemia significant effect on the amount of P absorbed by the may be a reflection of inadequate dia- gut [26]. Thus, when 25 mmol of Ca acetate was given lysis. In these situations, it is important to ensure that during a standard meal, the percentage of P absorbed adequate dialysis is administered by checking and being decreased from a baseline of 78 to 31%. On the other certain that the Kt/V is >1.2. Over the last few years, hand, when Ca acetate was given in the fasting state the USRD data have shown that the presence of or 2 h post-prandially, the percentage of P absorbed hyperphosphataemia is associated with increased morbidity by the gut increased to 42%. Likewise, Ca absorption and mortality in the US dialysis population. after Ca acetate ingested during the meal was 21% and This is more clear once serum P increases >6.5 mg/dl. it increased to 40% when given in the fasting state. These observations clearly suggest that the larger dose Failure to control hyperphosphataemia of the P binder should be given during the largest meal of the day. The most common cause is poor compliance, both Likewise, intestinal absorption of P also increases with diet and P binders. Often this problem is related after calcitriol therapy [28]; thus, hyperphosphataemia to a lack of both educational dietary training and is not uncommon after oral calcitriol [1,5]. The magni- support from the dietician and nursing staff. A close tude of this increment seems to be less with i.v. than interaction with a social worker is also essential, since with oral calcitriol. food containing low biological value protein with a high content of P may be all the patient can afford. It is clear that this is a difficult problem with no easy Hyperphosphataemia during calcitriol therapy solution. However, a supporting nursing staff with frequent counselling by the dietician and appropriate As can be seen in Figure 2, hyperphosphataemia may follow-up by the social worker is usually most not only lead to soft tissue calcification, and worsening beneficial. of HPTH, but it may also alter the response to calcitriol The variability in dissolution rate among the different therapy. Thus, another emerging cause of failure to brands of Ca salts was noted by Kobrin et al. [24]. control 2HPTH despite appropriate calcitriol therapy He noted in two patients, using abdominal X-rays, the is the presence of significant hyperphosphataemia. Of presence of undisintegrated tablets in the bowel. particular interest is the observation in our previous Furthermore, intact tablets were found in the faeces study [25] of two patients, in whom we observed a of one patient. In general, generic brands seem to be decreased basal and maximal PTH after 10 weeks of the worst offenders. calcitriol treatment. These patients later developed Severe secondary hyperparathyroidism usually is reflected in a more severe hyperphosphataemia; there may also be a more rapid rebound of serum P to severe hyperphosphataemia and simultaneously the serum PTH increased, despite continued calcitriol therapy. These findings suggest that P per se may lead

60 F. Llach and M. Yudd Fig. 1. The effect of severe hyperphosphaetamia (left) on PTH (on the right) in a patient with significant hyperparathyroidism receiving calcitriol, 2 mg i.v., three times a week at the end of each dialysis. Note the initial decrease in PTH and phosphorus with initiation of calcitriol therapy. However, as the patient developed hyperphosphataemia because of a well-documented poor dietary compliance, there is a progressive increase in PTH to levels above baseline (reference 25). to worsening of 2HPTH and resistance to the inhibitory effect of calcitriol on PTH synthesis. Fernandez and Montoliu evaluated parathyroid function and hyperphosphataemia in dialysis patients. The presence of hyperphosphataemia displaced the PTH Ca curve References toward the right in only 3 days [27]. We have recently Fig. 2. Diagram describing the various ill effects of hyperphosphaeta- mia in patients with CRF. roidectomy was carried out in two of these patients. Thus, persistent hyperphosphataemia, not amenable to strict dietary counselling, may lead to resistance to calcitriol and surgical intervention. In summary, control of hyperphosphataemia is of the utmost importance in patients with advanced CRF. Hyperphosphataemia, if not controlled, leads to severe 2HPTH and soft tissue calcifications. Restriction of dietary P together with an appropriate protein intake is an essential first therapeutic step. Calcium salts are the P binders of choice at the present time; however, Mg carbonate is an excellent alternative. The dose of the P binder should be individualized and prescribed in a manner commensurate with the P content of each meal. Al-containing P binders should be avoided whenever possible. Finally, during calcitriol therapy, hyperphosphataemia may develop and, unless it is controlled, worsening of HPTH and resistance to calcitriol therapy may develop. Acknowledgements. The authors thank Leda Reeves for providing secretarial assistance in the preparation of this manuscript. evaluated the problem of hyperphosphataemia in 18 1. Llach F, Coburn JW. Renal osteodystrophy and maintenance dialysis. In: Maher JF, ed. Replacement of Renal Function by patients with severe HPTH (PTH>1200 pg/ml ) receiv- Dialysis, Dordrecht/Boston/Lancaster: Klewer Academic ing i.v. calcitriol therapy for 18 months [28]. Calcitriol Publishers, 1989: 911 952 therapy was started once serum P was <6.5 mg/dl; the 2. Slatopolsky E, Bricker NA. The role of phosphorus restriction mean initial dose was 4 mg i.v. after each dialysis. The in the prevention of secondary hyperparathyroidism in chronic mean PTH prior to therapy was 1650 pg/ml and, after renal disease. Kidney Int 1973; 4: 141 3. Hernandez A, Concepcion MT, Rodriguez M, Salido E, 18 months of therapy, it had decreased to 225 pg/ml. Torres A. High phosphorus diet increases prepro PTHm RNA However, in three of these patients, isolated episodes independent of calcium and calcitriol in normal rats. Kidney Int of hyperphosphataemia were noted and this was 1996; 50: 1872 1878 accompanied by a delta increase in PTH of 950 pg/ml. 4. Walling MW. Intestinal Ca and phosphate transport: differential This increase in PTH occurred despite appropriate i.v. responses of vitamin D metabolites. Am J Physiol 1977; 133: 3488 5. Llach F, Nikathar B. Current advances in the therapy of dosing of calcitriol. As the hyperphosphataemia was secondary hyperparathyroidism and osteitis fibrosa. Miner controlled with dietary counselling, the PTH decreased Electrolyte Metab 1991; 17: 250 255 and, by the end of the 18 months, PTH was 6. Clarkson EM, Luck VA, Hynson WV. The effect of aluminum <200 pg/ml. However, in three other patients, hydroxide on calcium, phosphorus and aluminum balances, the serum parathyroid hormone concentration and the aluminum repeated episodes of persistent hyperphosphataemia content of bone in patients with chronic renal failure. Clin Sci developed. This precluded the appropriate use of 1972; 43: 519 vitamin D. By the end of the follow-up period, parathy- 7. Gotch FA, Sargent JA. A mechanistic analysis of the National

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