Renal osteodystrophy and aluminum bone disease in CAPD patients

James A. Delmez, Barbara N. Gearing

Our current understanding of renal osteodystrophy in CAPD patients is reviewed. The role of aluminum bone disease is examined.

Key words

Peritoneal, dialysis, osteodystrophy, aluminum, parathyroid hormone

From the Renal Division, Department of Medicine, Washington University School of Medicine and Chromalloy American Kidney Center, St. Louis, Missouri 63110.

Introduction

Renal osteodystrophy is virtually a universal complication of renal failure. Fortunately, great strides have been made over the past several decades in elucidating its pathophysiology and in initiating rational treatment. The term, renal osteodystrophy, is not specific. It encompasses the histological lesions of osteitis fibrosa, osteomalacia, mixed lesions, and aplasia.

Osteitis fibrosa (OF) is the result of high levels of parathyroid hormone (PTH) causing heightened bone resorption. Increased numbers of osteoclasts, increased amounts of woven osteoid, and rapid bone turnover are seen on bone biopsy specimens (1). The causes for excessive parathyroid secretion are multiple (Figure 1). Hypocalcemia due to hyperphosphatemia, decreased gastrointestinal calcium absorption, and skeletal resistance to PTH stimulates the secretion of this hormone. In addition, there is decreased clearance of PTH by the kidney and liver in renal failure (2) .More recently, evidence has been growing that the parathyroid gland in uremia is relatively insensitive to the suppressant effects of calcium (3). This, in part, may be due to the low levels of 1,25(OH)2D3 usually observed with renal failure.

The other end of the histological spectrum of renal osteodystrophy is that of osteomalacia. The hallmarks of this bone disease are unmineralized osteoid and slow bone turnover (1). Patients with osteomalacia tend to have low levels of PTH and normal to high serum concentrations of calcium (4) . It is likely that the majority of cases are due to aluminum (Al) accumulation either from dialysate contaminated with aluminum (epidemic form) or from ingestion of aluminum containing phosphate binders (sporadic form) (5, 6). Impaired mineralization may result directly from the deposition of aluminum along the bone mineralization front and/ or impaired secretion of PTH due to aluminum accumulation within the gland (7, 8).

The purpose of this paper is to review some of the effects of CAPD on mineral, vitamin D, PTH, and AI metabolism. Finally, an analysis of the results of several studies examining the short term changes in bone histomorphology during CAPD will be presented. Based on some of these data, hopefully a rational approach is possible for the prevention and treatment of renal osteodystrophy during CAPD therapy.

Calcium, phosphorus, and magnesium metabolism in CAPD

There is a wide disparity in the literature concerning mineral mass transfer during treatment with dialysis solution containing 3.5 mEq/L of calcium. For example, Parker et al (9) reported a net calcium influx of 300 mg/per day. A net gain of calcium from dialysate of 84 :!: 18 mg/day was noted by Blumenkrantz et al (10). Unfortunately, neither study measured ionized calcium (ICa) levels. We ( II) have shown a daily net calcium removal of 77 :!: 23 mg during periods of hypercalcemia (ICa > 5.0mg/L) and a net uptake of 48 :!: 13mg when patients were hypocalcemic (ICa < 4.4 mg/dl). In addition, ultrafiltration volume plays a role in determining calcium mass transfer. For example, when ICa levels were maintained at the upper limits of normal (4. 9 :!: 0.1 mg/ dl) with calcium supplements, there was a net uptake of 9.8 mg with each 1.5% solution but removal of 21 mg with 4.25% exchanges. This resulted in a positive calcium daily mass transfer of9.9mg. Kurtz et al (12) reported similar findings. Also, it is not surprising that dialysis solution calcium affects calcium mass transfer. Calderaro et al (13) found a negative balance of 50 :!: 9 mg per day using a dialysis solution calcium of 3 mEq/L. In another study (14), we found that patients not taking oral calcium supplements with an ICa level of 4.72 :!: .09 mg/ dl had a net uptake of 37:!: 17 mg/dl with standard 3.5 mEq-L Cadialysis solution which more than doubled to 84 :!: 6 mg/ d with the use of a dialysis solution containing 4.0 mEq/L of calcium (Table I). Although all of these data are predictable, they may be of some significance in the discussion of calcium carbonate in the prevention of aluminum toxicity.

To the best of our knowledge, Blumenkrantz et al (10) is the only group that has evaluated total-body calcium balance during CAPD. In this short term study the net calcium absorption by the bowel varied directly with dietary calcium intake. The balance was a positive 122 :!: 51 and 198 :!: 194 mg/ day on a 1.0 and 1.4 g/kg protein diet respectively. The significance of this is unknown.

A 1.2-1.5 g/kg protein diet has been recommended in order to maintain a slightly positive nitrogen balance ( 15) .This recommendation leads to an obligate ingestion of 500-1000 mg of phosphorus (P) per day. Assuming 50% P absorption, dialysate removal of P alone is not sufficient to maintain normal P levels. For example, we (11) were only able to remove 308 :!: 22 mg/day of P when the mean P level in the patients was 5.2 :!: 0.4 mg/dl. As one might expect, the total amount removed correlated with the serum P level. In balance studies Blumenkrantz (10) found a positive P balance despite the ingestion of 7.89 g/ day of aluminum hydroxide gels. The amount of P absorbed per day directly correlated with dietary P intake.

The original composition of magnesium in the dialysate was 1.5 mEq/L. This led to a positive magnesium balance. Blumenkrantz et al (10) determined a net intestinal magnesium absorption of 74 to 100 mg/ day. The quantity of magnesium removed in the dialysate was 46 :!: 7.5 mg/day, a figure which is close to our findings ( II) of 31 :!: 15 mg/day .Serum magnesium levels are usually high using a dialysate containing 1.5 mEq/L of magnesium ( II) but the long term consequences of this are unknown. A lower concentration of magnesium (0.5 mEq/L) is now available and its use should be considered in patients with hypermagnesemia.

Vitamin D metabolism

Patients with nephrotic syndrome have low levels of 25-0H D (16). Because patients on CAPD lose 5-8 g of protein into the dialysate per day, one would expect a priori that levels of this metabolite would be comparatively low. Unfortunately, the data is conflicting. We (II) have found normal levels after 6 months in patients not receiving vitamin D supplements. Moreover, the levels of D binding protein (molecular weight 570,000 daltons) was higher in patients on CAPD than those treated with hemodialysis despite a daily removal of 6.2 :t 2 mg of this protein into the peritoneal dialysate. Kurtz et al (12) demonstrated no tendency for 25-OH D levels to increase or decrease over 6-12 months of CAPD. Several others reported low levels of 25-OH D during CAPD. Dr. Gokal et al ( 17) reported a decline in 25-OH D to subnormal levels after 12 or more months of CAPD .At least 4 other investigators ( 18 21) also reported low levels of 25-OH D during treatment with CAPD. A possible explanation for these discrepancies may be variability in the amount of sunlight exposure in the study populations. Cassidy et al (22), for example, found a seasonal variation in the levels of 25-OH D . In fact, only I of 21 patients had a low level during the summer months. Although it is clear that 25-OH D and D binding protein are lost in the dialysate, our bias is that patients can often maintain normal 25-OH D levels if there is adequate substrate availability. In support of this concept were the high levels of 25-OH D reported by Calderaro et al (13) in CAPD patients receiving 50,000 U of vitamin D3 once a week.

Parathyroid hormone

The majority of serum PTH (molecular weight 9500 daltons) circulates in the form of inactive carboxyterminal fragments (molecular weight 5000 daltons) in patients with renal failure (23). We (II) have found that CAPD, unlike hemodialysis, removed substantial quantities of this hormone. Polyacrilamide gel electrophoresis of dialysate showed a pattern similar to that seen in plasma. Most of the immunoreactive PTH (iPTH) removed during CAPD was comprised of carboxy-terminal fragments. The mean iPTH clearance was 1.56 :t .73 ml/min and correlated with the clearance of inulin, a molecule of similar molecular weight. Therefore, CAPD unlike hemodialysis, affords an avenue for removal of iPTH and the levels may fall if secretion is controlled. Unfortunately, interpreting studies reporting the effects of CAPD on iPTH levels is extremely difficult. Calcium and phosphorus control as well as use of vitamin D preparations vary from center to center. In addition , different PTH radioimmunoassays recognize different portions of the molecule and have their own unique binding specificities. It is predictable that the reports are conflicting. Gokal (17), for example, found that PTH levels fell to the normal range in 30 of 40 patients after approximately one year of CAPD. Eleven were treated with I-hydroxycholecalciferol. Zucchelli (21) compared 17 patients treated by CAPD for 7-30 months with 19 patients treated with hemodialysis for a comparable period. He found a significant decline in iPTH levels in patients on CAPD compared with hemodialysis. No patients were treated with vitamin D. Unfortunately, there were no measurements of ionized calcium concentrations and it is unclear if the two groups had comparable calcium and phosphorus control. Kurtz (12), on the other hand, reports a subset of 5 patients on CAPD who developed severe secondary hyperparathyroidism during CAPD. These patients demonstrated high initial values of iPTH which continued to rise irrespective of serum calcium concentrations. This has also been our experience. In summary , if calcium and phosphorus balance can be optimally controlled, parathyroid hormone levels tend to fall or remain within acceptable limits. However, in the remaining 10 20% or so patients , more aggressive medical or surgical therapy may be needed. Obviously, the simplest way to suppress PTH secretion is to increase ICa levels via increased oral calcium and/or vitamin D supplements. Alternatively, one could attempt to increase dialysate mass transfer by increasing dialysis solution calcium. Another possibility would be to administer intraperitoneal 1,25(OH)P3. We become interested in this latter possibility because of previous work performed at our institution with the intravenous 1,25(OH)2D3 (24). Twenty patients undergoing hemodialysis received intravenous 1,25(OH)2D3 (0.5-4.0 ug) following each dialysis. A profound fall in iPTH levels of 70% was noted. In part, the decline was due to raised calcium levels. There was, in addition, a 20% decrement in iPTH concentrations prior to changes in ICa levels. When the percent of control PTH levels was plotted against the increase in ICa levels, the regression line intercepted the ordinate at 80% of the original value. This suggested that IV 1,25(OH)2D3 may directly suppress PTH secretion. We, therefore, sought to detennine if PTH suppression could be achieved by either increasing calcium mass transfer with a high dialysis solution Ca (4 mEq/L) or via intraperitoneal (IP) 1 ,25(OH)2D3 in patients undergoing CAPD. Eleven patients were dialyzed for 2 months with standard Ca dialysate (3.5 mEq/L), followed by two months with 4.0 mEq/L Ca dialysate and then by 3 months of nocturnal dwells containing IP 1,25(OH)2D3 (14). Ionized calcium and total calcium did not change with the higher dialysate calcium. However, both rose significantly with the use of IP 1 ,25(OH)2D3. Phosphorus levels did not change. High dialysate calcium led to a small decrease (P < 0.05) in iPTH levels to 84 ::!:5.5% of control values. With IP 1,25(OH)2D3, however, there was a more profound fall to 54 ::!: 8% of initial levels. As mentioned previously, the high dialysate Ca led to an increase in calcium mass transfer from 38 to 84 mg/d. Calcium mass transfer declined to -5 mg/ d during IP 1,25(OH)2D3 because of the elevated ICa values. Serum 1,25(OH)2D3 levels rose from undetectable values to 47.7 ::!: 7.2 pg/ dl. We then looked at the kinetics of IP 1 ,25(OH)2D3 absorption. Following the instillation of 2 ug of 1,25(OH)2D3, peak levels were seen at 2-4 hours and remained elevated for at least 8 hours. These kinetics are more similar to that which one sees with oral 1,25(OH)2D3 than with intravenous 1 ,25(OH)2D3. When the percent of control iPTH values versus increase in the ionized calcium, was plotted, a highly significant reciprocal relationship was detennined with the y-intercept approaching 100% of control values. These findings suggest that the major, if not sole, effect oflP 1,25(OH)2D3 in suppressing PTH secretion is due to increases in ICa concentrations. Thus, increasing Ca MT leads to only a modest decline in iPTH levels, whereas IP 1 ,25(OH)2D3 causes a rather dramatic fall. Whether the IP administration is superior to oral 1,25(OH)2D3 or calcium carbonate remains to be detennined.

Aluminum

Aluminum related bone disease has been well described in patients on long-tenn hemodialysis. With the institution of virtually aluminum free dialysate, the source of aluminum intoxication is undoubtedly the ingestion of aluminum containing phosphorus binders (ACPB). Aluminum-related bone disease has also been described in patients on CAPD but it is doubtful that dialysate contaminated with A1 currently plays a significant role. Hercz et al (25) found A 1 levels of less than 6 ug/ liter in both DianealR and ImpersolR solutions. In studying 19 patients on peritoneal dialysis with A1 intoxication, the same authors noted a net removal of 200400 ug/ day. How does this compare with A 1 removal during hemodialysis? Milliner (26) studied aluminum removal during hemodialysis in patients with roughly the same A1levels as those described by Hercz. They found a net removal of 200 ::!: 300 ug per treatment. Therefore, on a weekly basis one removes about twice as much aluminum with peritoneal dialysis compared with hemodialysis. It is, nonetheless, likely that long-tenn ACPB ingestion during CAPD would cause aluminum related bone disease in a fashion similar to that seen in hemodialysis patients. In support of this contention are the findings of Rottenbourg et al (27) who noted increasing serum aluminum levels in CAPD patients ingesting ACPD and stable levels in those never receiving these compounds.

Assuming that aluminum-related bone disease may become a problem if peritoneal dialysis patients are treated for long periods with ACPB, questions arise concerning its diagnosis and treatment. For example, Milliner et al (26) found that a plasma aluminum level of greater than 200 J.l-g/L was reliably associated with alumunim related bone disease in chronic hemodialysis patients. Unfortunately, a baseline aluminum level was not particularly sensitive (sensitivity 43% ) .Following an intravenous infusion of deferoxamine most patients with aluminum related bone disease had an increment of greater than 200 g/L. A good correlation could be found with the amount of trabecular bone A1 and the increment in Al levels 24 hours after the chelation challenge. No comparable studies have been perfonned in patients on peritoneal dialysis. However, Hercz et al (25) showed that IP deferoxamine achieved an increment in aluminum levels which was comparable with that following an intravenous infusion. Furthennore, the amount of A1 removed following either IV or IP administration of DFO was similar.

Bone histology

The results of several studies employing serial bone biopsies are summarized in Table II. Gokal et al ( 17) studied bone histology in 20 patients around the time of initiation of CAPD and approximately one year later. Five patients were treated with I-hydroxycholecalciferol and all received between 1.5-3.0 9 of CaCO3 per day. The vast majority of subjects had either an improvement or no change in the degree of osteitis fibrosa. One patient developed osteomalacia following a parathyroidectomy. Zucchelli et al (21 ) compared the changes in bone histology in 17 patients treated with CAPD with those of 19 receiving maintenance hemodialysis. After a little more than a year of followup those patients on CAPD demonstrated a fall in both per cent bone volume and active formation surface which was statistically greater than those on hemodialysis. There were no changes in the amount of osteoid during treatment with CAPD. These authors conclude that CAPD may lead to osteopenia in the absence of worsening osteomalacia or osteitis fibrosa. These findings were not confirmed by Shusterman et al (28) who found that CAPD in 6 patients led to an improvement in osteomalacia but no change in osteitis fibrosa. It is of note that Zucchelli et al did not administer vitamin D to their patients whereas calcitriol was used in the Shusterman study. Buccianti et al (18) felt that all parameters of bone histology deteriorated in 7 patients. Loschiavo et al (29) reported the results of serial bone biopsies in 14 patients who did not receive ACPD or vitamin D. They found no healing of osteomalacia in 5 patients after one year .Unfortunately, quantitative assessment of the biopsy results was not provided. We (30) recently reported the serial bone histology of 12 patients treated with CAPD. All patients received calcium carbonate and ACPB and none was prescribed a vitamin D preparation. We found no significant changes in indices of osteitis fibrosa. This no doubt reflected the variable effects of CAPD on iPTH levels during the study period. There was a close correlation between iPTH concentrations and fibrotic surface (r = 0.585, p = 0.003). The most impressive finding was a decline in the amount of osteoid. Of the eight patients with an increased total osteoid surface at the start of CAPD, seven demonstrated improvement after 12 months. These changes were not associated with changes in bone Al staining. The quantity of osteoid is a reflection of the relative rates of synthesis and mineralization. In order to determine if the decline in unmineralized matrix was due to enhanced mineralization or decreased osteoid production, time-spaced courses of tetracycline as morphological markers of rates of mineralization were employed. We found that the mineralization lag time decreased in seven of eight in whom it was initially elevated. In other words, the bone mineralization rate improved. This indicates that, in general, CAPD has a beneficial effect on calcification of the uremic bone.

Recommendations for managing renal osteodystrophy in CAPD

The avoidance of A I intoxication with concurrent PTH and phosphorus control are the goals of the therapeutic regimen. Restricting dietary phosphorus intake is essential in controlling phosphorus levels in renal failure. Unfortunately, a dietary protein intake of 1.2 gm/kg/day usually results in the use of phosphate binders. We (31) and others (32-35) have reported the efficacy of calcium carbonate as an effective phosphorus binder in hemodialysis patients. Recently, Ramirez et al (36) compared the effects of CaCO3 and Al(OH)3 capsules on the inhibition of phosphorus absorption. Both decreased the net absorption from a baseline of 79% to 60-65%. Thus, both are relatively inefficient but there are few alternatives in the United States. Salusky et al (37) administered calcium carbonateas a phosphorus binder to 15 children. Most of his subjects were on some form of peritoneal dialysis and received concurrent oral calcitriol. Serum phosphorus levels were well controlled during a greater than 9 month followup period. However , asymptomatic transitory hypercalcemia was seen in 92% of patients. For the past year we have been employing CaCO3 as the phosphorus binder of first choice in patients on CAPD. We recently reviewed the results of all patients currently on peritoneal dialysis and not receiving a vitamin D preparation. Over the past six months, 11 of 14 patients did not require ACPB and maintained ICa and P levels of 4.94:t 0.11 and 5.48 :t 0.34mg/dl respectively. The mean dose of elemental calcium employed was 1. 8g1 day. Three patients developed moderately severe hypercalcemia (ICa > 5.5 mg/dl) necessitating the addition of ACPB to their regimen. Thus CaCO3 may be used during peritoneal dialysis but its usefulness may be limited by hypercalcemia. It would seem advisable that peritoneal dialysate containing 2.5 and 3.0 mEq/L calcium be made available for those with a tendency to become hypercalcemic. If this approach is implemented, close monitoring of calcium and phosphorus is mandatory to prevent metastatic calcification during long-term therapy.

Thus, our recommendations are as follows:

  1. Dietary P should be reduced as much as possible within the confines of a 1.2 glkg/day protein diet.
  2. Serum P should be controlled by diet and the ingestion of calcium carbonate. If a patient has severe hyperphosphatemia (P > 8.0mg/dl), P should first be controlled by ACPB and gradually as P decreases to 5-6 mg/dl the ACPB should be replaced by calcium carbonate.
  3. The long term goals are to keep P levels between 4 and 5 mgl dl and ICa concentrations at the upper limits of normal.
  4. Dialysate containing low amounts of calcium should be made available for those patients developing marked hypercalcemia (ICa > 5.5 mg/dl). In the interim, ACPB must be judiciously prescribed.
  5. There is little proof that the routine administration of any form of vitamin D is indicated in patients on CAPD, but it may be advisable to monitor 25-OH D levels periodically.
  6. If PTH levels are high or are rising in the presence of low levels of ICa, calcitriol may be started with close monitoring of PTH, Ca, and P .
  7. If the patient develops evidence of A 1 intoxication, weekly IP deferoxamine (3-4 g) should be considered.
Acknowledgements
This work was supported in part by research funds from the Shriners Hospital for Crippled Children (St. Louis Unit) and CRC grant No. RROO0364.

The authors are indebted to Dr. E. Slatopolsky for his helpful criticisms and suggestions and to Mrs. Donna Morgan for her assistance in the preparation of the manuscript.

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All correspondence should be addressed to:
lames A. Delmez, M.D., Chromalloy American Kidney Center, 4949 Barnes Hospital Plaza, St. Louis, Missouri,63110.