COMPLICATIONS OF DIALYSIS - PART 5 potx

340 Boccardo and Remuzzi 114. Vanholder RC, Camez AA, Veys NM, Sovia Y, Mir- shahi M, Soria C, Ringoir S. Recombinant hirudin: a specific thrombin inhibiting anticoagulant for hemodialysis. Kidney Int 1994; 45:1745–1749. 115. van Wijk V, Badenhorst PN, Luus HG, Kotze HF. A comparison between use of recombinant hirudin and heparin during hemodialysis. Kidney Int 1995; 48: 1338–1343. 116. Nurmohamed MT, Hoek JA, Ten Cate JW, Krediet RT, Bu¨ller HR. A randomized cross-over study comparing the efficacy and safety of two dosages dermatan sulfate and standard heparin in six chronic hemodialysis patients. Br J Haematol 1990; 76(suppl):23. 117. Ryan KE, Lane DA, Flynn A, Ireland H, Boisclair M, Shepperd J, Curtis JR. Antithrombotic properties of dermatan sulphate (MF 701) in hemodialysis for chronic renal failure. Thromb Haemost 1992; 68:563– 569. 118. Fernandez F, van Ryn J, Ofosu F, Hirsh J, Buchanan MR. The haemorragic and antithrombotic effects of dermatan sulphate. Br J Haematol 1986; 64:309–317. 119. Lane DA, Ryan K, Ireland H, Ryan K, Ireland H, Cur- tis JR, Nurmohamed MT, Krediet RT, Roggekamp MC, Stevens P, ten Cate JW. Dermatan sulphate in haemodialysis. Lancet 1992; 339:334–335. 120. Nurmohamed MT, Knipscheer HC, Stevens P, Krediet RT, Roggekamp MC, Berckmans RJ, ten Cate JW. Clinical experience with a new anticoagulant (dermatan sulphate) in chronic hemodialysis patients. Clin Nephrol 1993; 39:166–171. 121. Gianese F, Nurmohamed MT, Imbimbo BP, Buller HR, Berckmans RJ, Ten Cate JW. The pharmacody- namics of dermatan sulphate MF 701 during haemodialysis for chronic renal failure. Br J Clin Pharmacol 1993; 35:335–339. 122. Nurmohamed MT, Knipscheer HC, Gianese F, Bu¨ller HR, Stevens P, Roggekamp MC, ten Cate JW. No clin- ically relevant accumulation of dermatan sulfate (DS) during chronic use in hemodialysis (abstr). Thromb Haemost 1993; 69:1118. 123. Boccardo P, Melacini D, Rota S, Mecca G, Boletta A, Casiraghi F, Gianese F. Individualized anticoagulation with dermatan sulphate for haemodialysis in chronic renal failure. Nephrol Dialysis Transpl 1997; 12: 2349–2354. 124. Dawson A, Lawinski C, Weston M. Sulfinpyrazone as a method of keeping dialysis membranes clean. In: Frost TH, ed. Technical aspects of Renal Disease. Bath: Pitman Press, 1978. 125. Shaarshmidt BF, Martin JS, Shapiro CG. The use of calcium chelating agents and prostaglandin E 1 to elim- inate platelet and white blood cell losses resulting from hemoperfusion through charcoal albumin, ara- gose gel and neural and neutral and cation exchange resus. J Lab Clin Nephrol 1985; 24:15–20. 126. Morring K, Sinn H, Schuler HW. Comparative eval- uation of iatrogenic sources of blood loss during main- tenance dialysis. In Proceedings of the 13th Congress of European Dialysis and Transplant Association. Tun- bridge Wells: Pitman Medical, 1976:223. 127. Turney JH, Fewell MR, Williams LC, Person V, Wes- ton MJ. Platelet protection and heparin sparing with prostacyclin during regular therapy. Lancet 1980; 2: 219–222. 128. Arze RS, Ward MK. Prostacyclin safer than heparin in haemodialysis. Lancet 1981; 2:50. 129. Zusman RM, Rubin RH, Cato AE, Cocchetto DM, Crow JW, Tolkoff-Rubin N. Hemodialysis using prostacyclin instead of heparin as the sole antithrombotic agent. N Engl J Med 1981; 304:934–939. 130. Swartz RD, Flamenbaum W, Dubrow A, Hall JC, Crow JW, Cato A. Epoprostenol (PGI, prostacyclin) during high risk hemodialysis: preventing further bleeding complications. J Clin Pharmacol 1988; 28: 818–825. 131. Dubrow A, Flamenbaum W, Mittman N, Hall J, Zinn T. Safety and efficacy of epoprostenol (PGI 2 ) versus heparin in hemodialysis. Trans Am Soc Artif Int Or- gans 1984; 30:52–54. 132. Jacons J, Shoemaker C, Ruderdorf R. Isolation and characterization of genomic and cDNa clones of human erythropoietin-rich plasma in vivo. J Clin Invest 1984; 74:434–441. 133. Ward DM, Mehta RL. Extracorporeal management of acute renal failure patients at high risk of bleeding. Kidney Int 1993; 41:S237–S244. 134. Sanders PW, Taylor H, Curtis JJ. Hemodialysis without anticoagulation. Am J Kidney Dis 1985; 5:32–35. 135. Lin FK, Suggs S, Lin CH. Cloning and expression of the human erythropoietin gene. PNAS USA 1985; 82: 7580–7584. 136. Winearls CG, Oliver DO, Pippard MJ, Reid C, Down- ing MR, Coter PM. Effect of human erythropoietin derived from recombinant DNA on the anaemia of patients maintained by chronic hemodialysis. Lancet 1986; 2:1175–1178. 137. Eschbach JW, Egrie JC, Downing MR, Browne JK, Adamson JW. Correction of the anemia and end-stage renal disease with recombinant human erythropoietin: results of a phase I and II clinical trial. N Engl J Med 1987; 316:73–78. 138. Zwaginga JJ, Ijsseldijk MJW, de Groot PG, Kooistra M, Vos J, van-Es A, Koomans HA, Struyvenberg A, Sixma JJ. Treatment of uraemic anemia with recombinant erythropoietin also reduces the defects in platelet adhesion and aggregation caused by uraemic plasma. Thromb Haemost 1991; 66:638–647. 139. Suraib S, Al-Momen AK, Gader AMA. Effect of recombinant human erythropoietin in chronic hemodialysis patients. Thromb Haemost 1989; 61:117. 140. Triulzi DJ, Blumberg N. Variability in response to cry- oprecipitate treatment for hemostatic defects in uremia. Yale J Biol Med 1990; 63:1–7. Coagulation Problems in Dialysis Patients 341 141. Mannucci PM, Ruggeri ZM, Pareti FI, Capitanio A. 1-Deamino-8D-arginine vasopressin: a new pharma- cological approach to the management of haemophilia and von Willebrand’s disease. Lancet 1977; 1:869– 872. 142. Canavese C, Salomone M, Mangiarotti G, Calitri V. Reduced response of uraemic bleeding time to re- peated doses of desmopressin. Lancet 1985; 1:867– 868. 143. Shapiro MD, Kelleher SP. Intranasal deamino-8-D-arginine vasopressin shortens the bleeding time in uremia. Am J Nephrol 1984; 4:260–261. 144. Rydzewski A, Rowinski M, Mysliwiec M. Shortening of the bleeding time after intranasal administration of 1-deamino-8-D-arginine vasopressin to patients with chronic anemia. Folia Haematol Int Mag Klin Mor- phol Blut Forsch 1986; 113:823–830. 145. Vigano` G, Mannucci PM, Lattuada A, Harris A, Re- muzzi G. Subcutaneous desmopressin (DDAVP) shortens the bleeding time in uremia. Am J Hematol 1989; 31:32–35. 146. Byrnes JJ, Larcada A, Moake JL. Thrombosis following desmopressin for uremic bleeding. Am J Hematol 1988; 28:63–65. 147. Liu YK, Kosfeld RE, Marcum SG. Treatment of uraemic bleeding with conjugated oestrogen. Lancet 1984; 2:887–890. 148. Livio M, Mannucci PM, Vigano GL, Mingardi G, Lombardi R, Mecca G, Remuzzi G. Conjugated estrogens for the management of bleeding associated with renal failure. N Engl J Med 1986; 315:731–735. 149. Vigano` G, Gaspari F, Locatelli M, Pusineri F, Bonati M, Remuzzi G. Dose-effect and pharmacokinetics of estrogens given to correct bleeding time in uremia. Kidney Int 1988; 34:853–858. 150. Sloand JA, Schiff MJ. Beneficial effect of low-dose transdermal estrogen on bleeding time and clinical bleeding in uremia. Am J Kidney Dis 1995; 26:22– 25. 151. Zoja C, Noris M, Corna D, Vigano` G, Perico N, de Gaetano G, Remuzzi G. L-Arginine, the precursor of nitric oxide, abolishes the effect of estrogens on bleeding time in experimental uremia. Lab Invest 1991; 65: 479–483. 343 18 Arthropathies and Bone Diseases in Hemodialysis and Peritoneal Dialysis Patients Alkesh Jani, Steven Guest, and Richard A. Lafayette Stanford University Medical Center, Stanford, California I. INTRODUCTION Renal osteodystrophy refers to a collection of bone disorders that affect virtually all patients with end-stage renal disease (ESRD). The term originally described osteitis fibrosa cystica, a high bone-turnover state. In the 1970s, however, it was recognized that excessive aluminum exposure could cause osteomalacia and a low bone-turnover state referred to as adynamic bone disease. It is now recognized that patients may be af- fected by a combination of these disorders and that mild forms exist. The frequency and pathological findings for each of these disorders are listed in Table 1. This chapter will describe the clinical and pathological features of the bone disorders collectively referred to as renal osteodystrophy. The additive role that metabolic acidosis may play in these disorders is discussed in a separate section. II. OSTEITIS FIBROSA CYSTICA The most common form of renal osteodystrophy is osteitis fibrosa cystica (OFC). This lesion is defined by specific changes in bone architecture, including: 1. Bone marrow fibrosis Special thanks to Henry Jones, M.D., Professor Emeritus, Radiology, Stanford University School of Medicine, Stan- ford, California. 2. A parathyroid hormone (PTH)–stimulated increase in the number and activity of osteoclasts 3. An increase in osteoid and nonlamellar bone which defines OFC as a high-turnover bone disease OFC is typically asymptomatic until end-stage renal disease (ESRD), when bone pain and fractures may occur. However, as discussed in the next section, the changes that result in OFC generally start well before dialysis is initiated. A. Pathophysiology of OFC OFC is due to secondary hyperparathyroidism. The primary event is phosphate retention, which typically occurs when the GFR falls below normal. PTH-dependent enhanced urinary phosphate excretion maintains serum phosphorus levels in the normal range, until the GFR falls below 30 mL/min (2). Phosphate loading in rats with varying degrees of renal failure results in an elevated serum PTH due to reduced calcium levels and a coincident reduction in calcitriol (3,4). Elevated serum phosphate itself may also directly stimulate PTH secretion. Conversely, phosphate restriction in dogs with renal insufficiency prevents the development of secondary hyperparathyroidism despite worsening renal function (5). PTH functions to maintain serum calcium and phosphate within normal range. In early renal failure, its release should therefore be seen as an appro- priate response. PTH maintains calcium-phosphorus (Ca-PO 4 ) homeostasis in three ways: 344 Jani et al. Table 1 Frequency and Pathological Findings Disease Frequency (%) Cause Pathology Osteitis fibrosa cystica 50 Secondary hyperparathyroidism Bone marrow fibrosis Resorption/Remodeling Osteomalacia 7 Aluminum deposition Increased osteoid Mixed disease 13 Secondary hyperparathyroidism and aluminum deposition Mixed features Mild disease 3 Early secondary hyperparathyroidism Increased remodeling Adynamic bone disease 27 Aluminum deposition Hypocellularity and no remodeling Source: Adapted from Ref. 1. 1. It reduces proximal tubule phosphate reabsorb- tion from 75–80% to 15% (6). 2. It increases the activity of osteoclasts, resulting in an increase in the serum calcium (4). 3. It promotes the 1 hydroxylation of 25-hydroxy cholecalciferol, resulting in active vitamin D. As renal failure progresses, excretion of phosphate decreases further, as does production of vitamin D. The resulting hypocalcemia allows for uninhibited PTH secretion and parathyroid gland hyperplasia. Increased osteoclast activity ensues, resulting in bone resorption. Bone marrow fibrosis is thought to occur when stimulated bone marrow mesenchymal cells differentiate into secretory fibroblast-like cells (1). B. Laboratory Findings/Investigations 1. Serum Calcium Serum calcium levels are typically low in patients with ESRD and secondary hyperparathyroidism. However, spuriously low values can result from plasma samples or stored serum samples because of adsorption of calcium to the tube or precipitation within the sample. Errors can be reduced if samples are measured expe- ditiously and if serum is used rather than plasma. Para- thyroid cells in uremic patients have decreased sensitivity to calcium. Therefore, a greater serum calcium is needed to inhibit secretion of PTH. A consensus conference on use of calcitriol in dialysis patients with hyperparathyroidism (7) recommended that serum calcium should be maintained at approximately 10– 11.5 mg/dL. 2. Serum Phosphorus Phosphorus is primarily an intracellular anion, and ef- flux of phosphorus from this compartment to the extra- cellular space is slow. Consequently, phosphate is poorly cleared by dialysis (ϳ25–30% the clearance of urea). This problem may be exacerbated by the use of recombinant human erythropoeitin, which increases hemocrit and therefore reduces the amount of plasma cleared by the dialyzer (8). The recommended dietary phosphate intake in normal individuals is 800 mg/day (9), while dialysis removes 250–350 mg of the anion per session. Most dialysis patients, therefore, remain in positive phosphate balance without additional therapy. 3. Serum Alkaline Phosphate Antigenically different forms of alkaline phosphatase are produced by the liver, intestine, kidney, and pla- centa. Skeletal origin can be confirmed by checking for the specific isoenzyme. In bone, alkaline phosphatase is found anchored to osteoblast cell membranes (10). [In contrast, acid phosphatase is anchored to osteoclast membranes (11).] Increased osteoblastic activity, as occurs with bone remodeling, will lead to an elevation in serum levels of alkaline phosphatase. Serum bone alkaline phosphatase has been found to correlate with the extent of bone osteoblast surface and volume of fibrosis (12). Serum bone alkaline phosphatase can be a useful clinical indicator of the extent of OFC. Levels greater than 20 ng/mL are very suggestive of high-turnover bone disease (13), whereas decreasing values can indicate a response to therapy. Rising serum levels usually indicate progression of OFC, even if the increase is seen within the normal range. However, it is important to note that many patients with abnormal bone architecture have normal levels of alkaline phosphatase (14). 4. Serum PTH Mature PTH is an 84-amino-acid protein made by the chief cells of the parathyroid glands. The biological activity of PTH resides in the N terminus (amino acids Arthropathies and Bone Diseases 345 Fig. 1 Subperiosteal resorption and distal phalangeal tuft erosions in a dialysis patient with secondary hyperparathyroidism. 1–34), while the midportion and C terminus are inac- tive. The liver cleaves the mature hormone into N-terminal fragments as well as C-terminal fragments. The latter accounts for most of the circulating PTH in the serum of patients with renal failure, as it is cleared mainly by the kidney and has a longer half-life. Since N-terminal and C-terminal fragments can accumulate in renal failure, intact PTH levels should be measured to avoid overestimation of the serum level. Immuno- radiometric (IRMA) and immunochemiluminometric (ICMA) assays employ specific two-site antibodies to measure intact hormone and are the preferred tests in patients with renal failure. In dialysis patients, bone marrow fibrosis does not typically occur until PTH levels exceed 250 pg/mL, and severe OFC is seen with levels greater than ϳ500 pg/mL. However, PTH levels below 120 pg/mL are more likely to be associated with adynamic bone disease (15). These observations suggest that the ideal serum PTH in a patient with ESRD is not known, and serial serum measurements are required to prevent undertreatment or overvigorous suppression of PTH. C. Radiological Findings of OFC Radiological abnormalities indicative of secondary hyperparathyroidism are seen in ϳ50% of patients with renal failure, and these patients invariably have increased resorption on bone biopsy. Subperiosteal resorption is the most widely recognized finding of OFC and occurs most commonly in the phalanges and hands (Fig. 1). Resorption can also be seen at the distal ends of the clavicles, as well as in the pelvis, ribs, and man- dible. Skull x-rays in these patients are often described as having a ‘‘salt-and-pepper’’ appearance, indicating widespread mottling (Fig. 2). This is due to alternating areas of increased cortical resorption and enhanced tra- becular density. Other typical findings include erosion of the tufts of the terminal phalanx, cyst formation (Fig. 3), and osteosclerosis. Fig. 4 demonstrates the ‘‘Rug- ger-Jersey’’ spine of secondary hyperparathyroidism. D. Indications for Bone Biopsy As noted previously, serum alkaline phosphatase and PTH levels are useful as correlates of disease severity. They are poor indicators, however, of the type of renal osteodystrophy present. The gold standard for estab- lishing a diagnosis is bone biopsy, but the indications for undertaking this procedure are controversial. Bi- opsies are generally performed for two indications: (1) to assess the extent of aluminum accumulation prior to therapy with desferoxamine, and (2) to diagnose adynamic bone disease in patients who are symptomatic, with a serum PTH level of <100 pg/mL. Whether a biopsy should be performed on a patient with a serum PTH between 150 and 450 pg/mL is unclear. An alter- native approach would be to assume that this most likely represents early OFC and to empirically start calcium supplements, phosphate binders, and, if indicated (i.e., if serum PTH > 400 pg/mL), calcitriol. E. Treatment of Osteitis Fibrosa Cystica 1. The Predialysis Patient Slatopolsky et al. demonstrated that dietary phosphate restriction could entirely prevent the development of secondary hyperparathyroidism in dogs (5). Correction of serum phosphate to 4.5–5.5 mg/dL in children with moderate renal insufficiency (GFR = 45 Ϯ 4 mL/min/ 1.73 m 2 ) has been shown to improve hypocalcemia, 346 Jani et al. Fig. 2 Cyst formation in the carpal bones and distal phalanges in a patient with dialysis-related amyloidosis. hyperparathyroidism, and calcitriol deficiency (16). Similar effects can be seen with calcitriol therapy. Szabo et al. demonstrated that administration of 1,25- (OH) 2 vitamin D 3 could prevent but not cause, regres- sion of parathyroid cell proliferation in experimental uremia (17). The primary limitation to the use of calcitriol in predialysis patients is the development of hypercalcemia, which could hasten progression to ESRD. Hypercalcemia is seen primarily with doses of Ն1 ␮ g/ day. A reduction of serum PTH with improvement of renal osteodystrophy has been shown to occur with as little as 0.25 ␮ g/day of calcitriol (18). These studies suggest that secondary hyperparathyroidism can be effectively prevented by control of serum phosphate and judicious use of calcitriol. Serial monitoring of serum calcium levels is important in this setting to avoid hypercalcemia and its potential complications. It should be noted, however, that predialysis patients require a greater serum PTH to maintain a normal osteoblast surface than dialysis patients (16). This study implies that PTH resistance is severe in predialysis patients and has led a reviewer to suggest withholding calcitriol therapy unless serum PTH levels are greater than 400 pg/mL (19). More studies of this patient population are needed to confirm these initial observations, but based on present findings it would seem prudent to actively treat predialysis patients in the hope of preventing the development of OFC. Treatment recommendations for the predialysis patient are as follows: Serial monitoring of serum phosphorus as the GFR falls below 30 mL/min. Dietary phosphorus restriction and, if necessary, use of phosphate binders once serum phosphorus rises above 5.5 mg/dL. Institution of low-dose calcitriol (0.25 ␮ g/day) therapy if intact serum PTH levels rise above 400 mg/ dL, with close monitoring to prevent hypercalcemia. (Data from ESRD patients suggest this therapy is unlikely to be effective if serum phosphorus is not controlled first.) 2. The Dialysis Patient Slatopolsky et al. recently demonstrated that high phosphate directly stimulated posttranscriptional PTH secretion in tissue culture (20). As with predialysis patients, the first step in management of bone disease in the dialysis population is to control serum phosphate. The following is a discussion of the treatment options available to achieve this goal as well as the other biochemical abnormalities of secondary hyperparathyroidism. a. Control of Dietary Phosphate Phosphorus is particularly abundant in proten-rich foods and cereals. Approximately half of the dietary phosphorus in the United States comes from milk, meat, poultry, and fish. Significantly greater amounts of phosphorus are found in processed cheese and meat than in their natural counterparts. Dialysis patients should ideally be restricted to less than 800 mg/day of phosphorus. This is difficult to achieve since many dialysis patients are already malnourished, and limiting phosphate intake could further limit their protein intake. This problem can be partially offset by increasing the proportion of dietary protein with high biological value, such as meat and eggs. Phosphorus-rich food with low biological value, such as dairy products, co- las, and processed foods, should obviously be avoided. These measures can help reduce serum phosphorus lev- Arthropathies and Bone Diseases 347 Fig. 3 Skull x-ray demonstrating typical ‘‘salt and pepper’’ appearance caused by hyperparathyroidism. els, but almost invariably dialysis patients will require medication to achieve this goal. The treatment recommendation is as follows: Maintain patients on a diet of Յ800 mg/day of phosphorus, derived from high–biological value protein. b. Phosphate Binders Several types of phosphate binders are currently available. All act by forming insoluble complexes with dietary phosphorus, which is then excreted in the stool. The binders differ significantly, however, with respect to their side effects. Magnesium-containing phosphate binders, such as magnesium hydroxide, are infrequently used because of their propensity to cause potentially serious hyper- magnesemia. Furthermore, these agents are effective cathartics, resulting in decreased patient compliance. For many years, aluminum-containing phosphate binders were the phosphate binders of choice. During the 1970s, it was discovered that an accumulation of aluminum, from either the binding agents or the dialysis water supply, could cause bone disease (1). Consequently, binders containing calcium have largely replaced these agents. Aluminum salts also have additional disadvantages (see below). Slatopolsky et al. demonstrated that hyperphosphatemia could be controlled in ϳ70% of dialysis patients using calcium carbonate (21). This agent requires an acid medium to function effectively and is therefore not as useful in patients treated with H 2 blockers. Calcium acetate, however, binds phosphorus more effectively, and its use is not limited by intestinal pH. Both agents 348 Jani et al. Fig. 4 Severe cystic changes affecting the phalangeal bones of a dialysis patient with secondary hyperparathyroidism. bind dietary phosphorus and are therefore given with food. If taken between meals they can serve as a calcium supplement since they are relatively well ab- sorbed. The primary side effect of this class of binders is hypercalcemia. Metastatic calcification can occur if the Ca-PO 4 product is >70, and in this setting the binder should be discontinued. An aluminum salt can be used temporarily in this situation. Once the calcium- phosphorus (Ca-PO 4 ) product decreases, the calcium salt can be started again in addition to a ‘‘low’’ dialysate calcium of 2.5 mg/dL (see below). Treatment recommendations are as follows: Use calcium binders as the agents of choice. Avoid magnesium-based binders. Aim for a serum calcium level of >10 mg/dL and a serum phosphate level of <5.5 mg/dL. Use binders with meals to most efficiently limit phosphate absorption. Avoid hypercalcemia (serum calcium > 11.5 mg/dL) and a Ca-PO 4 product of >70. Should this occur, switch temporarily to an aluminum-based binder, and consider a lower dialysate calcium. Use calcium acetate in patients with H 2 blockers or patients who have achlorhydria. c. New Phosphorus-Binding Agents Cross-linked poly(allylamine hydrochloride), or Rena- gel, is a phosphate binder that does not contain magnesium, aluminum, or calcium. It binds preferentially to trivalent anions such as phosphate and citrate and has no gastrointestinal absorption. Renagel also binds bile acids and increases their excretion. In normal human volunteers, Renagel given in doses of 2.5 and 5 g three times a day significantly reduced urinary phosphate excretion compared to placebo. Mean serum phosphorus and calcium levels did not differ between treatment and placebo groups. Subjects treated with 1, 2.5,and5gofRenagel also had significant reductions of 15–25% in total cholesterol from baseline. This effect was ascribed to bile acid–binding properties (22). Chertow et al. (23) found that Renagel, 3.5 g per day, significantly reduced serum phosphorus (6.6 Ϯ 2.1 mg/ dL to 5.4 Ϯ 1.5 mg/dL) over 2 weeks of treatment. Serum cholesterol was also significantly reduced (from 173 Ϯ 37 to 149 Ϯ 32 mg/dL) when compared to placebo-treated patients. LDL levels were also significantly reduced, but HDL levels remained unchanged. Goldberg et al. (24) evaluated Renagel in 48 hemodialysis patients over an 8-week period. Renagel was dosed to achieve serum phosphorus control. The mean daily dosage was approximately 4.5 g and varied directly with dietary phosphate intake. Renagel produced significantly lower serum phosphorus at the end of the treatment period, and the mean reduction in serum phosphorus was 1.4 mg/dL. d. Calcitriol Therapy Activated vitamin D 3 suppresses PTH synthesis directly, although the exact mechanism for this effect is Arthropathies and Bone Diseases 349 uncertain. Calcitriol causes decreased PTH mRNA concentration in cultured bovine cells (25). The levels of vitamin D 3 typically start to fall when the GFR drops below 30 mL/min (26) and ESRD is characterized as a calcitriol-deficient state. In uremic patients, vitamin D 3 receptor binding (27) and receptor density (28) within the parathyroid gland are reduced, especially in areas of nodular hyperplasia, which are more apt to develop in hyperplastic glands (29). These observations provide the rationale for use of calcitriol in patients with ESRD and secondary hyperparathyroidism. Calcitriol is given either orally or intravenously. Continuous calcitriol refers to daily oral therapy, while intermittent therapy denotes pulse therapy, usually given at the end of dialysis. Controversy exists as to which route of administration and which schedule is superior. Initial observations suggested that pulse intravenous therapy was better than pulse oral therapy, because much higher peak serum levels are obtained with the former (30). However, other studies have failed to show that this effect causes better suppression of PTH (31) or that either route has a greater tendency to hypercalcemia. At this time there are insufficient data to suggest that one route is better than the other. The lit- erature regarding continuous versus pulse therapy is also contradictory, with some investigators able to suggest a difference (32) between the two modes of administration, while others could not. The question is somewhat moot, since most dialysis units prefer to employ pulse intravenous therapy because of convenience, reimbursement issues, and to ensure patient compliance. Not all patients respond successfully to calcitriol therapy. Felsenfeld suggests that high PTH and hyperphosphatemia identify patients who will have a poor response to therapy (19). Consensus conference guide- lines from the American Society of Nephrology annual meeting in 1994 suggest that all patients with a serum PTH > 200 pg/mL be treated with IV calcitriol (7). Furthermore, mild to moderate hyperparathyroidism, defined as a PTH of 200–600 pg/mL in asymptomatic patients, should be treated with an initial dose of 0.5– 1 ␮ g/dialysis. Moderate to severe hyperparathyroidism, with serum PTH levels of 600–1200 pg/mL, should be started on 2–4 ␮ g/dialysis. This dose was found by Cannella et al. (33) to control the hyperparathyroidism of patients with a mean serum PTH of 900 pg/mL. However, Quarles et al. (31) were not able to reproduce these findings in patients with serum PTH > 900 pg/ mL using similar doses of calcitriol. Hyperphospha- temia was well controlled in the former study, whereas patients in the latter group required much higher doses of phosphate binders. As noted, patients who have un- controlled hyperphosphatemia are unlikely to have an optimal response to calcitriol. A markedly elevated serum PTH does not preclude controlling secondary hyperparathyroidism with calcitriol. Dressler et al. (34) showed that severe hyperparathyroidism, defined as a PTH > 1200 pg/mL, can be controlled using a mean dose of 4 ␮ g/dialysis. Six patients required a mean maximum dose of 8 ␮ g/dialysis. These findings suggest that such patients may have nodular hyperplasia and relative vitamin D resistance. The ultimate aim of therapy is to achieve a PTH two to three times the upper limit of normal, or ϳ130–190 pg/mL. As stated, bone marrow fibrosis is not typically seen until serum PTH exceeds ϳ200 pg/mL. Normal- ization and stabilization of serum bone alkaline phosphatase (or total alkaline phosphatase) should parallel the fall in PTH. As mentioned, the most frequent side effects of calcitriol therapy are hypercalcemia and hyperphosphatemia. Calcitriol should not be used unless the serum phosphate level is <6 mg/dL. Hyperphosphatemia can both reduce the efficacy of calcitriol and put the patient at increased risk of metastatic calcification. Treatment recommendations include the following: Control hyperphosphatemia (aim for level of <6 mg/ dL) before initiating calcitriol therapy. For a PTH of 200–600 pg/mL, start calcitriol at a dose of 0.5–1.0 ␮ g/dialysis. For a PTH of 600–1200 pg/mL, start calcitriol at a dose of 2–4 ␮ g/dialysis. For a PTH of >1200 pg/mL, use calcitriol at a dose of 4–8 ␮ g/dialysis only if hyperphosphatemia is well controlled. Aim for a PTH of ϳ130–190 pg/mL. Avoid over- suppression of parathyroid gland activity. Follow serum calcium levels in anticipation of hypercalcemia. e. Concentration of Dialysate Calcium Dialysate calcium usually varies between 2.5 and 3.5 mEq/L in hemodialysis and 1 and 1.75 mmol/L in peritoneal dialysis solutions. The ‘‘correct’’ concentration of dialysate calcium should be determined for each in- dividual patient based on his or her calcium balance. The goal should be to induce positive calcium balance, suppress PTH secretion, and at the same time prevent the attendant effects of hypercalcemia, namely extraosseous calcification. Early reports suggested that a positive calcium balance could be achieved with 2.5 mEq/L hemodialysate calcium concentration (35). 350 Jani et al. More recent studies have shown that use of a 2.5 mEq/ L solution can cause an increase in serum PTH levels over the long term. However, the authors found that this effect could be reversed with 1- ␣ -hydroxyvitamin D (36). Use of a 2.5 mEq/L calcium solution would be reasonable in patients with a low PTH who are taking calcium-based phosphate binders and calcitriol. These patients should be monitored for increases in PTH. Di- alysate solutions containing 3 and 3.5 mEq/L, on the other hand, do cause a positive calcium balance and result in suppression of PTH (37). In these patients care must be taken to avoid hyperalcemia and extraosseous calcification. Weinrich et al. (38) compared the use of a 2.0 mEq/L CAPD bath with a standard 3.5 mEq/L bath. The low-calcium bath resulted in significantly lower serum calcium and less need for aluminum binders. However, severe hyperparathyroidism occurred in 23% of the patients in this group, compared to 10.3% in the patients using the standard calcium bath. Thus, as with hemodialysis patients, use of lower dialysate calcium concentration in CAPD patients must be carried out judiciously and with close monitoring of serum PTH. Treatment recommendations are as follows: Tailor dialysate calcium concentrations to ensure a positive calcium balance and suppression of PTH secretion, while avoiding hypercalcemia. Use calcium-based phosphate binders and calcitriol if a dialysate concentration of 2.5 mEq/L is em- ployed. Be vigilant for changes in serum PTH. Follow serum calcium and Ca ϫ PO 4 product when using dialysate calcium concentrations of >3.0 mEq/L. f. Parathyroidectomy Parathyroidectomy is typically reserved for severe secondary hyperparathyroidism with debilitating OFC, untreatable pruritis, severe persistent hypercalcemia despite medical therapy, calciphylaxis, or severe extraosseous calcification. Adynamic bone disease can mimic OFC and be worsened by parathyroidectomy. One should, therefore, confirm that the serum PTH is severely elevated (typically > 1000 pg/mL, although there are no absolute values) prior to surgery. III. ALUMINUM-INDUCED BONE DISEASE Aluminum gels have been widely used as phosphate- binding agents. The aluminum-phosphate complex was originally thought to be excreted as an insoluble complex in stool, with little gastrointestinal absorbtion. However, absorption of aluminum was subsequently demonstrated in both normal (39) and dialysis-dependent subjects (40). Aluminum toxicity was then impli- cated as a cause of encephalopathy, anemia, debilitating muscle and joint pain, and renal osteodystrophy. The primary sources of aluminum are phosphate- binding gels and local water supplies. Aluminum in dialysate water enters the serum readily and becomes highly protein bound (90%), limiting the degree to which dialysis can remove aluminum from plasma (41). Water purification systems utilizing reverse os- mosis, deionization, and demineralization can effectively prevent aluminum intoxication from dialysate water. Aluminum antacids have for the most part been supplanted by calcium-containing phosphate binders. Aluminum-based gels are still used, however, when hypercalcemia and high–calcium-phosphate products preclude the use of calcium-containing binders. A. Manifestations of Aluminum Toxicity Aluminum toxicity results in a variety of systemic effects, including neurotoxicity, renal osteodystrophy, anemia and bone and muscle pain. Alfrey et al. (40) showed that patients with dialysis-associated encephalopathy have significantly greater gray-matter aluminum deposition than normal controls or dialysis patients without dementia. The majority of patients who develop encephalopathy have been on dialysis for 3– 7 years. The clinical features of this syndrome include focal seizures, dementia, myoclonus, asterixis, and dys- arthria. Abnormal EEG patterns of generalized slowing punctuated by bursts of delta wave activity may pre- cede the clinical findings by 3–6 months (41). Aluminum causes two forms of renal osteodystrophy: osteomalacia and adynamic bone disease (42). The more prevalent form is osteomalacia, which is characterized by an increase in osteoid volume and decreased rate of bone turnover. In contrast, the adynamic form results in a loss of osteoid volume and diminished tetracycline uptake. Andress et al. (43) demonstrated that aluminum deposition occurred more quickly in hemodialysis patients with type 1 diabetes as compared to nondiabetic hemodialysis patients. Decreased serum PTH and a low rate of bone turnover in diabetics (44) may account for the more aggressive disease seen in this population. A similar form of accelerated deposition is seen in patients with aluminum-induced bone disease after parathyroidectomy. [...]... serum aluminum of 50 ␮g/L above baseline and a serum iPTH threshold of < 150 mg/L had a sensitivity of 87% and a specificity of 95% in detecting aluminum-related bone disease C Treatment of Aluminum-Induced Bone Disease DFO can also be used for the treatment of aluminuminduced bone disease Malluche et al ( 45) used a regimen of 14. 25 mg/kg three times a week for hemodialysis patients and 85 mg/kg per week... interaction of parathyroid hormone and aluminum in renal osteodystrophy Kidney Int 1987; 31:842– 854 Cannata Andia JB Aluminum toxicity: its relationship with bone and iron metabolism Nephrol Dial Transplant 1996; 11(suppl 3):69–73 Andress DL, Kopp JB, Norma AM, Coburn JW, Sherrard DJ Early deposition of aluminum in bone in dia- 358 44 45 46 47 48 49 50 51 52 53 54 55 56 Jani et al betic patients on hemodialysis... Hemodialysis in and HCOϪ out during the treatment) that exists for 3 peritoneal dialysis However, given the rapid rates of transfer during hemodialysis, the magnitude of the HCOϪ loss is much greater than in peritoneal dialysis 3 For example, at a blood flow rate of only 200 mL/min, almost 1000 mmol of acetate are added and over 800 mmol of HCOϪ are lost during a 4-hour dialysis treat3 ment (16 ,55 ,56 )... The contribution of acidosis to renal osteodystrophy Kidney Int 19 95: 47:1816–1832 Pellegrino ED, Biltz RM The composition of human bone in uremia Medicine 19 65; 44:397–418 359 86 87 88 89 90 91 92 93 94 95 96 97 98 99 Lee SW, Russell J, Avioli LV 2 5- hydroxy-cholecalciferol conversion to 1, 2 5- dihydroxy-cholecalciferol: Conversion impaired by systemic metabolic acidosis Science 1977; 1 95: 994–996 Kawashima... Metabolic acidosis suppresses 2 5- hydroxyvitamin D 3-1 -alpha-hydroxylase in the rat kidney J Clin Invest 1982; 70: 35 140 Cunningham J, Bikle DD, Avioli LV Acute but not chronic, metabolic acidosis disturbs 2 5- hydroxyvitamin D3 metabolism Kidney Int 1984; 25: 47 52 Krapf R, Vetsch R, Vetsch W, Hulter HN Chronic metabolic acidosis increased the serum concentration of 1, 2 5- dihydroxyvitamin D in humans by... of DFO should be used to treat aluminum-related bone disease High-flux polysulfone hemodialyzers should be used when DFO therapy is started to maximize clearance of DFO-aluminum complexes Baseline and serial audiovisual exams are suggested for the duration of therapy IV DIALYSIS- RELATED AMYLOIDOSIS ␤2-Microglobulin was first identified as the major protein in dialysis- associated amyloidosis in 19 85 (56 )... treated by intermittent dialysis modalities In a study of 690 thrice-weekly hemodialysis patients, the large majority exhibited plasma bicarbonate values well below the normal values of 24 mmol/L (94) In another study, 41% of 129 hemodialysis patients had 356 Jani et al predialysis bicarbonate values of less than 21 mmol/L, and 17% had values less than 19 mmol/L ( 95) Peritoneal dialysis, however, has... Clinical Physiology of Acid-Base and Electrolyte Disorders New York: McGraw-Hill Inc., 1984 Korkor AB Reduced binding of [3H]1, 2 5- dihydroxyvitamin D3 in the parathyroid glands of patients with renal failure N Engl J Med 1987; 316: 157 3– 157 7 Fukuda N, Tanaka H, Tominaga Y, Fukagawa M, Kurokawa K, Seino Y Decreased 1, 2 5- dihydroxyvitamin D3 receptor density is associated with a more severe form of parathyroid... consequences of high mass-transfer hemodialysis Kidney Int 1977; 11:361–378 56 Gennari FJ Comparative physiology of acetate and bicarbonate alkalinization In: Cummings NB, Klahr S, eds Chronic Renal Disease New York: Plenum, 19 85: 453 –461 57 Dolan MJ, Whipp BJ, Davidson WD, Weitzman RE, Wasserman K Hypopnea associated with acetate hemodialysis: carbon dioxide-flow-dependent ventilation N Engl J Med 1981; 3 05: 72– 75. .. dioxide-flow-dependent ventilation N Engl J Med 1981; 3 05: 72– 75 58 Hunt JM, Chappell TR, Henrich WL, Rubin LJ Gas exchange during dialysis Am J Med 1984; 77: 255 – 260 3 75 59 60 61 62 63 64 65 66 67 68 69 70 71 72 73 Vreman HJ, Assomull VM, Kaiser BA, Blaschke TF, Weiner MW Acetate metabolism and acid-base homeostasis during hemodialysis: influence of dialyzer efficiency and rate of acetate metabolism Kidney Int 1980; 18(suppl . aluminum of 50 ␮ g/L above baseline and a serum iPTH threshold of < 150 mg/L had a sensitivity of 87% and a specificity of 95% in detecting aluminum-related bone disease. C. Treatment of Aluminum-Induced Bone. the duration of therapy. IV. DIALYSIS- RELATED AMYLOIDOSIS ␤ 2 -Microglobulin was first identified as the major protein in dialysis- associated amyloidosis in 19 85 (56 ). This form of amyloidosis. treatment of aluminuminduced bone disease. Malluche et al. ( 45) used a regimen of 14. 25 mg/kg three times a week for hemodialysis patients and 85 mg/kg per week for peritoneal dialysis patients.