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Secondary hyperparathyroidism in chronic kidney disease: clinical consequences and challenges.

Secondary hyperparathyroidism (HPT) is an insidious disease that develops early in the course of chronic kidney disease (CKD) and increases in severity as the glomerular filtration rate deteriorates. Virtually all patients are affected by the time end stage renal disease (ESRD) (stage 5 CKD) ensues and dialysis is initiated (National Kidney Foundation [NKF], 2002; Tortes et al., 1995). Several studies have demonstrated that the severity of secondary HPT correlates directly with increased morbidity and mortality in the dialysis population (Block, Hulbert Shearon, Levin, & Port, 1998). The most commonly cited morbidity associated with secondary HPT is renal osteodystrophy, which leads to characteristic skeletal complications. However, the alterations in mineral metabolism reach far beyond these commonly recognized complications and can cause significant effects including soft tissue calcification, alterations in lipid metabolism and glucose utilization, anemia, and an increased risk of cardiac-related death (Angelis, Wong, Myers, & Wong, 1997; Block et al., 1998; Block & Port, 2000; Bro & Olgaard, 1997; Chiu et al., 2000; Drueke, 1991; Fine & Zacharias, 2002; Massry & Smorgorzewski, 1994; Rao, Shih, & Mohini, 1993; Slatopolsky & Delmez, 1996).

Due to the clinical significance of these complications, optimal control of the factors that contribute to secondary HPT has become a primary quality-of-care goal for nephrology clinicians. However, despite ongoing and intensive clinical interventions, secondary HPT is often not adequately controlled in dialysis patients (Block et al., 1998). Therefore, the potential for adverse clinical out comes related to the disease persists and often may be exacerbated by currently available therapies (Malluche & Mawad, 2002; Martin & Gonzalez, 2001; Steddon, Schroeder, & Cunningham, 2001). This article reviews secondary HPT in the dialysis population and includes a brief overview of the pathophysiology of the disease, the consequences of inadequately controlled secondary HPT, the clinical challenges associated with current therapeutic interventions, and newer management approaches.

Pathophysiology of Secondary HPT

Normal bone and mineral metabolism. To understand the interrelated series of events leading to secondary HPT, it is first necessary to review normal physiology. In the absence of CKD, bone and mineral metabolism are influenced by the interaction of four primary factors: parathyroid hormone (PTH), calcium, vitamin D, and phosphorus (see Table 1). The primary role of PTH is to maintain the extracellular concentration of calcium within a narrow physiologic range. PTH acts directly on the bone to increase bone resorption, resulting in the release of calcium and phosphorus into the blood. PTH also acts indirectly by stimulating an increase in vitamin D, which in turn increases intestinal absorption of both calcium and phosphorus. In addition, PTH acts directly on the kidney to increase both phosphorus excretion and calcium reabsorption (thereby helping to maintain normal serum calcium levels) (Potts, 2002; Slatopolsky, 1998).

The second major factor that affects bone and mineral metabolism is the interrelationship between calcium and the calcium-sensing receptors (CaR). Secretion of PTH is controlled by the CaRs located on the surface of chief cells within the parathyroid glands. These receptors are extremely sensitive to changes in extracellular calcium, resulting in the secretion of PTH secretion within seconds or minutes. As the calcium concentrations increase, the CaRs are activated, thereby inhibiting the secretion of PTH from the parathyroid glands. Conversely, when serum calcium levels are low, the CaRs are inactivated, thereby increasing secretion of PTH from the parathyroid glands to maintain normal calcium homeostasis (Goodman, 2002; Goodman & Turner, 2002; Slatopolsky, 1998).

The third major factor, vitamin D, fulfills an essential role in maintaining skeletal integrity. Vitamin D helps maintain calcium and phosphorus homeostasis by modulating dietary absorption of calcium and phosphorus throughout the small intestine. In the presence of low levels of calcium, vitamin D levels increase, thereby increasing calcium and phosphorus absorption in the small intestine. Vitamin D also induces bone resorption and the release of calcium and phosphorus and decreases the excretion of these substances in the urine. In the parathyroid glands, vitamin D controls the synthesis of PTH. Vitamin D is derived both from the diet and from the action of sunlight on the skin. However, when vitamin D is taken into the body, it is inert and must be converted to the active form through a series of reactions in the liver and kidneys before it can exert its effect (Brown, Dusso, & Slatopolsky, 1999).

Phosphorus, the central component of bone, is another factor that contributes to control of bone and mineral metabolism. Approximately 85% of phosphorus in a normal adult is located in the skeleton. The interrelationship between phosphorus and vitamin D is well recognized. Studies have shown that vitamin D levels increase dramatically when serum phosphorus levels are low, thereby promoting increased intestinal absorption. Conversely, in the presence of hyperphosphatemia, the parathyroid glands may be resistant to the action of vitamin D. The normal route of excretion for phosphorus is primarily through the kidneys. When serum phosphorus levels are elevated, PTH acts directly on the kidneys to increase phosphorus excretion and normalize serum phosphorus levels (Brown et al., 1999; Potts, 2002; Slatopolsky & Delmez, 1996).

Bone and mineral metabolism disruptions in secondary HPT, PTH, calcium, vitamin D, and phosphorus normally act in concert to maintain optimal levels of phosphorus and calcium and ensure bone integrity. In patients with CKD, the mechanisms that maintain homeostasis are disrupted. As the number of functioning nephrons decrease, the failing kidneys are unable to excrete phosphorus and a progressive in crease in serum phosphorus levels and a consequential suppression of vitamin D activation ensues. In combination, these effects lead to a deficiency in biologically active vitamin D that, in turn, results in reduced absorption of calcium from the gastrointestinal tract, ultimately causing hypocalcemia (NKF, 2002).

Because the CaRs are the major regulator of PTH, the series of events leading to hypocalcemia is crucial to the development of secondary HPT. Hypocalcemia causes inactivation of the CaRs on the parathyroid glands and results in an increase in PTH secretion. PTH, in turn, stimulates the release of calcium and phosphorus from the bone and increased activation of vitamin D, resulting in increased intestinal absorption of calcium as the body attempts to maintain normal calcium homeostasis. The ongoing inability to excrete phosphorus leads to continual over-stimulation of the parathyroid glands, tissue hyperplasia, and over secretion of PTH (Goodman, 2002; Goodman & Turner, 2002; Slatopolsky, 1998). This series of events leads to secondary HPT.

Clinical Consequences of Secondary HPT

The consequences of uncontrolled secondary HPT manifest in multiple systems, with potentially devastating consequences on patient outcomes. Common clinical problems associated with secondary HPT include renal osteodystrophy, cardiovascular calcification, extraskeletal calcification, endocrine disturbances, and altered erythropoiesis (see Table 2).

Skeletal complications of secondary HPT. High-turnover bone disease is the classic skeletal complication observed in patients with secondary HPT. Bone is a dynamic tissue that is constantly being remodeled. The action of osteoclasts (bone resorbing cells) to remove "old" bone is tightly balanced with the functions of osteoblasts (bone forming cells) that deposit "new bone" at sites where old bone was removed. PTH is the major stimulator of bone remodeling (both bone formation and bone resorption). PTH interacts with receptor cells found on osteoblasts, leading to an increase in the number and activity of these bone-forming cells and the consequential formation of new bone tissue. One action of osteoblasts is the release of cytokines and growth factors that increase the number and activity of osteoclasts. Thus, PTH indirectly stimulates bone resorption (Hamdy, 1995).

As CKD progresses and PTH levels rise, the rates of bone resorption and formation increase, leading to the deposition of an immature, structurally inferior woven bone. As the severity of secondary HPT increases, fibrous tissue accumulates within the marrow space and adjacent bony trabeculae, leading to the characteristic pattern of bone marrow fibrosis that is often referred to as osteitis fibrosa cystica (Goodman, 2001; Hamdy, 1995).

In the past, most patients with CKD experienced high turnover bone disease. However, in recent years an increasing number are now experiencing low-turnover bone disease, characterized by reductions in osteoclasts and osteoblasts and decreased bone remodeling. The most common type of low-turnover bone disease, adynamic bone disorder, is actually not a manifestation of secondary HPT, but is usually an unwanted side effect of the therapeutic interventions prescribed to treat it. Adynamic bone disorder is typically caused by the oversuppression of PTH with vitamin D and/or the con current administration of calcium-based phosphate-binding agents that increases calcium levels and further inhibits PTH secretion. Since the bone is not actively being remodeled, patients with adynamic bone disorder often experience hypercalcemia--it is believed that excess calcium is deposited in soft tissue and vasculature, thereby increasing the risk of calcification (Fukagawa, Kazama, & Shigematsu, 2001; Sherrad et al., 1993). Regardless of the etiology of bone disease, skeletal changes that occur in patients with secondary HPT decrease the structural integrity of the bone, leading to a weakened bone matrix and increasing the risk of fracture, hypercalcemia, vascular calcification, and calcific uremic arteriolopathy (Braun et al., 1996; Ganesh, Stack, Levin, Hulbert Shearon, & Port, 2001; Parfrey & Foley, 1999).

Cardiovascular complications of secondary HPT. Dialysis patients are exposed to a number of cardiovascular risk factors, including advanced age, obesity, extracellular fluid volume overload, hypertension, diabetes, dyslipidemia, and alterations in homocysteine metabolism. The mortality rate secondary to cardiovascular disease in dialysis patients is alarmingly high and accounts for approximately 50% of all deaths (United States Renal Data System [USRDS], 2002; Zocalli, 2000).

Data indicate that the metabolic changes induced by secondary HPT or its treatment, including elevations in PTH, phosphorus, Ca x P, and calcium, are all independently associated with cardiac causes of death. In a study by Ganesh et al. (2001), the relative risk of sudden death increased significantly in patients whose PTH levels exceeded 495 pg/mL compared with those whose PTH levels were in the range of 91 to 197 pg/mL The same analysis found that hyperphosphatemia was independently associated with an increased risk of sudden cardiac-related death-patients whose serum phosphorus was greater than 6.5 mg/dL had a 41% increased risk of death from coronary artery disease and a 20% increased risk of sudden death compared with those whose serum phosphorus was between 2.4 and 6.5 mg/dL.

Similarly, in a study conducted by Block et al. (1998), patients whose serum phosphorus was greater than 6.5 mg/dL had a 27% increased risk of mortality compared with patients whose phosphorus was 2.4 to 6.5 mg/dL (P < 0.001). This study also found there was a significantly increased risk of mortality in patients with an elevated Ca x P. Patients whose Ca x P was between 42 and 52 mg2/dL2 had a 34% decreased risk of mortality compared with those whose serum Ca x P was greater than 72 [mg.sup.2]/[dL.sup.2] (P < 0.01).

Elevations in serum calcium levels are also associated with an increased risk of mortality. A retrospective analysis found that serum calcium levels greater than 9.5 mg/dL are associated with an 18% to 38% increased risk of death compared with patients with calcium levels of 8.5 to less than 9.5 mg/dL (n = 37,169). Point estimates also suggest that calcium levels less than 8.5 mg/dL may be associated with additional reductions in the risk of death (Block, Klassen, Kim, LaBrecque, & Danese, 2003).

Further, elevated serum calcium levels leading to uremic calcification have been linked to myocardial dysfunction in dialysis patients (Goodman et al., 2000; Guerin, London, Marchais, & Metivier, 2000). One representative study used electron beam computed tomography to determine the extent of calcification of the heart, vasculature, and tissues in 34 hemodialysis patients. Results from this study showed that the mitral and aortic valves were calcified in 59% and 55% of the population, respectively (Braun et al., 1996). The potential negative ramifications of cardiac calcification are numerous and include valvular dysfunction, myocardial fibrosis, left ventricular dysfunction, conduction defects, and cardiac arrhythmias.

Soft tissue calcification. Metabolic disorders associated with secondary HPT, including hypercalcemia, hyperphosphatemia, and increased Ca x P, are important risk factors for soft tissue calcification (Bro & Olgaard, 1997). Recent data indicate that hypercalcemia from sources such as calcium based phosphate-binding agents and vitamin D sterols can also contribute to soft-tissue calcification in dialysis patients. The potential roles of other factors that may contribute to soft-tissue calcification, including elevated PTH and expression of regulating genes and proteins, are still being elucidated (Mawad, Sawaya, Sarin, & Malluche, 1999; Proudfoot, Shanahan, & Weissberg, 1998; Schinke, McKee, Kiviranta, & Karsenty, 1998).

The calcification process can spread throughout the body, affecting areas such as the cornea and conjunctiva, muscle, lung, gastrointestinal tract, skin and subcutaneous tissue, and cardiovascular system (Bro & Olgaard, 1997; Coates et al., 1998; Hsu, 1997). In addition to the increased risk of cardiovascular disease associated with multisystem calcification, peripheral artery calcification can complicate future vascular access surgeries and compromise options for preserving vascular access. In addition, calcification of renal blood vessels may decrease the success rate for kidney transplantation (Norris, 1998).

Calcific uremic arteriolopathy (CUA). CUA, previously called calciphylaxis, is a complication of ESRD that is characterized by calcification in medium-sized and small arteries, particularly those in subcutaneous tissue. The painful, mottled skin lesions that manifest in patients with CUA often progress to ulcers and tissue necrosis, which can ultimately lead to amputation, sepsis, and death (Fine & Zacharias, 2002). Although this relatively rare condition occurs in only 4.5% of dialysis patients (compared with an estimated prevalence of 1% in 1993), it is associated with an extremely high rate of death (Fine & Zacharias, 2002; Levin, Mehta, & Goldstein, 1993). Overall, 39% of patients with CUA die within 6 months of diagnosis, and mortality rates exceeding 80% have been reported in patients who develop skin ulcerations (Fine & Zacharias, 2002).

In addition to elevated serum phosphorus and Ca x P levels, risk factors for CUA include Caucasian ethnicity, female gender, low serum albumin levels, and obesity. While the increase in the prevalence of CUA can be attributed in part to improved detection, increased use of calcium-containing phosphate binding agents and the increased use of large doses of vitamin D (both of which can lead to increased serum Ca x P levels) have also been implicated. Treatment with warfarin has also been repeatedly identified as a risk factor for CUA. Although PTH levels are not always elevated in patients with CUA, reports have shown dramatic improvements in symptoms after parathyroidectomy, suggesting that excess PTH secretion may also play a role in the etiology (Angelis, Wong, Myers, & Wong, 1997; Fine & Zacharias, 2009; Massry & Smorgorzewski, 1994).

Endocrine disturbances. Alterations in calcium metabolism and elevated PTH levels have both been implicated as factors that can adversely affect lipid metabolism and glucose utilization in patients with CKD. These metabolic disturbances in calcium and PTH lead to all increase in intracellular or cytosolic calcium con centrations that have been linked to abnormal lipid metabolism and impaired glucose utilization and insulin secretion (Gadallah et al, 2001). Insulin sensitivity in healthy subjects has also been shown to be inversely related to plasma PTH concentrations (Chin et al., 2000). The abnormal lipid metabolism, insulin resistance, and glucose intolerance that result can represent distinct risk factors for cardiovascular disease in patients with CKD.

Altered erythropoiesis. Anemia is a common comorbidity in patients with CKD and has been identified as an independent risk factor for left ventricular hypertrophy and for hospitalization due to cardiac and noncardiac causes. High PTH levels may contribute to anemia by directly inhibiting the production of red blood cells and increasing their fragility, thereby shortening cell survival (Drueke, 1991). Secondary HPT can also cause marrow fibrosis, further decreasing the production of red blood cells. Data indicate that the response to Epoetin alfa therapy in these patients depends largely on the extent of bone marrow fibrosis (Drueke, 1991; Rao et al., 1993).

Therapeutic Interventions: Strategies and Challenges

A three-pronged approach has traditionally been employed for the management of secondary HPT: pre venting hyperphosphatemia, maintaining normal serum calcium, and replacing physiologic levels of vita min D. The primary management strategies used to achieve these goals include control of dietary phosphorus and calcium intake, administration of phosphate binders to prevent phosphorus absorption, and administration of vitamin D therapy to suppress PTH and modify calcium absorption (see Table 3).

Dietary restriction of phosphorus. Dietary restriction of phosphorus is an essential but extremely challenging component of controlling secondary HPT. Restricting phosphorus is difficult because virtually all dairy dietary sources of protein have a high phosphorus content. The NKF's Guidelines on Nutrition in maintenance hemodialysis patients recommend a minimum protein intake of 1.2 g/kg/day. Thus, virtually all well-nourished dialysis patients have a positive phosphorus balance (Goodman, 2001; NKF, 2000).

Dietary calcium supplementation. Historically, providing supplemental calcium to suppress PTH secretion has been a cornerstone in the treatment of secondary HPT. Calcium intake should be limited to about 1,500 to 2,000 mg/day, including calcium from dietary intake, calcium in the dialysate bath, and calcium from calcium-based phosphate binders. Higher doses may exacerbate the risk of cardiovascular calcification, especially in patients with low-turnover bone disease (who often have high calcium levels secondary to ongoing administration of calcium-based phosphate binders) or in those with calcific vascular disease (NKF, 2000).

Phosphate binder therapy. Most patients require phosphate binders to decrease or prevent phosphorus absorption and control hyperphosphatemia. All phosphate binders work through the stone mechanism of action of binding phosphorus in the diet, thereby decreasing absorption of dietary phosphorus in the gastrointestinal tract. Aluminum-based phosphate binders were used for decades, but it was eventually recognized that long-term administration was associated with numerous negative effects, including microcytic anemia, aluminum deposits in bone (osteomalacia), and an increased risk for encephalopathy. As a result, aluminum-based binders are now typically recommended only for short-term use in patients who otherwise have poor control of phosphorus (Delmez & Slatopolsky, 1992).

The most commonly used phosphate binders are calcium carbonate or calcium acetate. While these binders effectively bind phosphorus in the intestine and limit its absorption, effective binding of dietary phosphate requires large daily doses of calcium that often lead to hypercalcemia. This increased calcium load is accentuated by the co-administration of vitamin D sterols, which enhance the intestinal absorption of calcium and phosphorus. While both calcium acetate and calcium carbonate salts lead to similar control of phosphorus levels, studies have shown that the average amount of elemental calcium is lower with calcium acetate than with calcium carbonate (Llach & Yudd, 1998; Malluche & Mawad, 2002). In recent years, concern has arisen over the use of calcium based phosphate binders because of the potential for hypercalcemia and progressive metastatic calcification. An alternative phosphate-binding option is sevelamer, which binds phosphorus in the gastrointestinal tract through ion exchange and hydrogen binding mechanism and does not contain either calcium or aluminum. Studies have documented the effectiveness of sevelamer in lowering both phosphorus and Ca x P without significantly increasing serum calcium; however, treatment may also be associated with gastrointestinal side effects (including GI upset and diarrhea) and worsening acidosis (Chertow, Burke, Dillon, & Slatopolsky, 1999; Cizman, 2003; Slatopolsky, Burke, & Dillon, 1999).

Poor patient adherence, secondary to gastrointestinal upset, unpleasant taste, and the significant number of pills required each day are a common management challenge for all patients receiving phosphate binders. Some patients also have difficulty swallowing large pills and must balance the need for copious amounts of fluid during pill ingestion with fluid restrictions aimed at preventing detrimental fluid weight gain. In addition, timing the ingestion of phosphate binders in relationship to ingestion of phosphorus-containing foods is very important but problematic for some patients, as the phosphate binder dose should be adjusted for the amount of phosphorus in the meal (Rocco, Easter, & Makoff, 1999).

Vitamin D therapy. Administration of active vitamin D sterols inhibits PTH production and increases intestinal calcium and phosphorus absorption, thereby indirectly de creasing PTH secretion. Calcitriol is effective in reducing serum PTH levels; however, the accompanying rise in serum calcium and phosphorus levels is also the principal toxicity that limits its effectiveness (Martin & Gonzalez, 2001).

The fact that calcitriol increases levels of calcium and phosphorus, which has been associated with increased morbidity and mortality in dialysis patients, led to the development of two second-generation vitamin D sterols, paricalcitol and doxercalciferol. These second generation agents were developed in an attempt to reduce the risk of hypercalcemia and hyperphosphatemia while maintaining PTH control. To date, neither of these newer vitamin D sterols has been shown to actually prevent hypercalcemia and hyperphosphatemia, although they may cause a lower relative increase in calcium compared with calcitriol (Steddon et al., 2001).

Further studies are required to fully elucidate the mechanism of action and comparative long-term efficacy and safety of these vitamin D sterols. One recently published study attempted to shed light on this issue by comparing paricalcitol with calcitriol. In this retrospective analysis, patients undergoing long-term hemodialysis were evaluated over 36 months to determine whether treatment with paricalcitol (n = 29,021) compared with calcitriol (n = 38,378) conferred any survival benefits. After 12 months, calcium and phosphorus had increased by 6.7% and 11.9%, respectively, in the paricalcitol group, compared with 8.2% and 13.9%, respectively, in the calcitriol group. The authors reported a mortality rate of 18% in patients receiving paricalcitol compared with a rate of 22.3% in those receiving calcitriol, a reduction of approximately 4% in mortality for those receiving paricalcitol (P < 0.001) (Teng et al., 2003).

While these data suggest that paricalcitol may offer improved patient survival compared with calcitriol, an accompanying editorial by Drueke and McCarron (2003) pointed out several shortcomings of the study that limit interpretation of the results. First, because the study used an uncontrolled, retrospective design, no causality can be concluded from the results. Second, the fact that the patients in the paricalcitol group were on dialysis 3 months longer than those in the calcitriol group before being enrolled in the study highlights a major weakness in the study design: the lack of prestudy clinical and treatment data that only could be acquired in a prospective, randomized trial. Third, the 8% greater representation of African-American patients in the paricalcitol group may have biased the results as well, because this group as a whole is at increased risk for severe secondary HPT and cardio vascular disease, and data suggest that the greater the severity of secondary HPT, the greater the benefit from treatment. Finally, the authors point out that the only prospective head-to-head study that compared paricalcitol and calcitriol found no differences in achieving the primary end points between the two treatment groups, that is, an elevated Ca x P or a single episode of hypercalcemia (although the results did suggest that paricalcitol more rapidly corrects secondary HPT and is associated with fewer hypercalcemic episodes). Similarly, two unpublished studies comparing these two vitamin D products showed no clinically significant differences in Ca x P, PTH levels, or plasma calcium levels (Drueke & McCarron, 2003). While the design of the study by Teng et al. (2003) does not provide conclusive evidence that paricalcitol is superior to calcitriol, it does suggest the need for a prospective trial to evaluate the comparative efficacy and safety of vitamin D sterols and also raises the question of whether aggressive management of calcium and phosphorus disturbances can help prevent/attenuate the most serious risk of secondary HPT (Drueke & McCarron, 2003).

Regardless of the vitamin D sterol that is administered, the metabolic changes that result from ongoing use of these medications must be monitored carefully. The tendency toward hypercalcemia in patients receiving vitamin D, especially in those receiving concomitant calcium-containing phosphate binders, may require ongoing modification to prevent or attenuate the potential risks associated with coronary or soft-tissue calcification. In addition, it is important to monitor patients with high-turnover bone disease frequently to ensure that PTH is not over suppressed, possibly resulting in adynamic bone disease. In those with documented adynamic bone disease, vitamin D should be used with caution to avoid the risk of further suppressing PTH and aggravating or inducing hypercalcemia. It is recommended that vitamin D therapy be temporarily discontinued in patients with elevated Ca levels, depressed PTH levels, or Ca x P greater than 75 [mg.sup.2]/[dL.sup.2] (Abbott Laboratories, 2003; Malluche, Mawad, & Koszewski, 2002; Sherrard et al., 1993).

NKF Bone Metabolism Guidelines

Management of secondary HPT has historically been hampered by the absence of universally accepted recommendations to guide clinical assessments and interventions. This issue has recently been addressed by the publication of the NKF's Kidney Disease Outcomes Quality Initiative (NKF-K/DOQI[TM]) Clinical Practice Guidelines for Bone Metabolism and Disease in Chronic Kidney Disease. These guidelines highlight the need for aggressive management of HPT, including the importance of achieving PTH, C[A.sup.2+], P[O.sub.4.sup.3-], and Ca x P levels that are more physiologically normal to prevent bone disease, uremic calcification, vascular disease, and cardiac death. The guidelines recommend target ranges for each of these key parameters (Table 4), including: (a) [Ca.sup.2+] of 8.4 to 9.5 mg/dL, (b) P[O.sub.4.sup.3-] of 3.5 to 5.5 mg/dL, (c) Ca x P below 55 [mg.sup.2]/[dL.sup.2], and (d) iPTH of 150 to 300 pg/mL. Analyses conducted by NKF-K/DOQI[TM] indicate that many patients have serum laboratory levels well above the recommended guidelines, providing a tremendous opportunity for improving patient care and outcomes (National Kidney Foundation, 2003).

Effectiveness of Current Therapeutic Approaches and Future Directions

Current therapeutic approaches frequently have limited effectiveness in simultaneously maintaining PTH, phosphorus, and calcium control in patients with secondary HPT and potentially contribute to the cardio vascular morbidity that predominates in the dialysis population. Analyses have shown that 60% of dialysis patients have phosphorus levels greater than 5.5 mg/dL, and 39% have levels greater than 6.5 mg/dL. Similarly, Ca x P is greater than 60 [mg.sup.2]/[dL.sup.2] in 40% of dialysis patients and above 72 [mg.sup.2]/[dL.sup.2] in 20% of these patients. Despite ongoing therapeutic interventions, about 10% of patients also continue to have PTH levels in excess of 975 pg/mL (Block et al., 1998; Block & Port, 2000). Overall, approximately 60% of patients are currently not achieving adequate control of PTH, phosphorus, and/or Ca x P (Chertow et al., 1999). These data illustrate the limitations of current therapeutic options and highlights the need for ongoing research to improve the treatment of secondary HPT.

Dialysis has traditionally not been an effective method for controlling phosphorus levels. The majority of the body's excess phosphorus resides in the bone and other intracellular compartments, and it is, therefore, extremely difficult to remove adequate amounts of phosphorus during a conventional dialysis session (Delmez & Slatopolsky, 1992). Several investigations have been undertaken to determine whether innovative approaches in the delivery of dialysis may improve control of secondary HPT. Because phosphorus egresses very slowly from intracellular compartments, increasing dialysis length will probably do little to improve phosphorus removal. Some data indicate that increasing the frequency of dialysis through daily or nocturnal dialysis may improve phosphorus levels. Studies in patients using daily nocturnal hemodialysis have shown that phosphorus can be well controlled with lower doses of phosphate binders, even when protein and phosphorus intake are increased (Musci et al., 1998; Pierratos et al., 1998). However, some of these studies also reported an increase in PTH that may have been related to more efficient removal of calcium, leading to hypocalcemia. Further study is required to determine how to optimize renal replacement therapy to improve management of secondary HPT.

Because of its role in regulating PTH secretion, the calcium-sensing receptors have become a target for drug development to identify agents that will provide alternative therapeutic options for the treatment of secondary HPT. Calcimimetic agents are small organic molecules that activate the CaRs oil the membrane of the parathyroid cell, thereby inhibiting the release of PTH. They represent a novel and direct approach to managing excess PTH secretion because their mechanism of action differs fundamentally from that of vitamin D sterols (Goodman & Turner, 2002; Horl, 2003; Lindberg et al., 2003).

In contrast to vitamin D therapy, patients receiving calcimimetic therapy experience a decrease in PTH as well as a decrease in serum phosphorus and calcium levels. In two recently published studies, patients undergoing 18 weeks of calcimimetics therapy experienced a 26% to 33% decrease in mean iPTH levels 24-hours after dosing. Simultaneously, serum calcium levels decreased by 4.7% to 4.6%, mean serum phosphorus decreased by 7.5%, and mean Ca x P decreased by 7.9% to 11.9% over the course of the study (Lindberg et al., 2003; Quarles et al., 2003). Use of calcimimetics may therefore provide the benefit of PTH control while avoiding the high phosphorus and calcium levels associated with cardiac, soft tissue, and vascular calcification. If these results are confirmed in subsequent clinical trials, they could broaden the appeal of using calcimimetic agents to treat secondary HPT (Goodman & Turner, 2002; Horl, 2003; Lindberg et al., 2003).

Conclusion

Ongoing clinical investigations have led to significant improvements in our understanding of the pathophysiology and treatment of secondary HPT over the past decade. However, treatment of secondary HPT continues to be less than optimal, and only 7% of patients achieve NKF-K/DOQI[TM] target levels for all four of the primary laboratory values --PTH, calcium, phosphorus, and Ca x P (Walters, Danese, Kim, & Klassen, 2003). Further, the ongoing elevations in calcium, phosphorus, and Ca x P that can result from current therapeutic options represent a serious concern that may be contributing to the risk for morbidity aim mortality in the dialysis population. Innovative dialytic approaches and application of novel therapeutic approaches such as calcimimetics offer the potential for alternative therapies and possible improvements in patient outcomes in the future.
Table 1
Primary Factors That Control Bone and Mineral Metabolism

Factor      Function                       Normal Mechanism(s) of
                                           Action

PTH         * Maintain serum calcium       * Acts directly on bone to
              levels                         increase bone resorption
            * Stimulate bone resorptions     resulting in release of
              Increase calcium               calcium and phosphorus
              reabsorption                 * Acts indirectly by
              from the kidney                stimulating an increase in
            * Increase phosphorus            Vitamin D by the kidney
              excretion from the kidney

Calcium     * Important for bone           * High levels activate CaR,
              integrity                      blocking PTH secretion
            * Modulates PTH secretion      * Low levels inactivate CaR,
                                             allowing PTH secretion

Phosphorus  * Central component of bone    * Low levels stimulate
            * Regulates vitamin D            increase in activated
                                             vitamin D
                                           * High levels may cause
                                             parathyroid
                                             gland-resistance
                                             to vitamin D

Vitamin D   * Important for bone           * Induces bone resorption of
              integrity                      calcium and phosphorus
            * Helps modulate calcium,      * Regulates synthesis of PTH
              phosphorus, and PTH          * Increases absorption of
              levels                         calcium and phosphorus in
                                             the intestinal tract

Table 2
Clinical Complications Associated With Secondary HPT

Complication                       Potential Consequences

Renal osteodystrophy            * Weak/unstable bone
                                * Increased risk of fractureo
                                  Hypercalcemia in adynamic bone
                                  disease

Cardiovascular calcification    * Myocardial dysfunction
                                * Valvular dysfunction
                                * Myocardial fibrosis
                                * Left ventricular dysfunction
                                * Conduction defects
                                * Cardiac arrhythmia
                                * Increased cardiac-related death

Soft-tissue calcification       * Increased risk of heart disease
                                * Complications of access surgeries
                                * Decreased success rate for kidney
                                  transplantation
                                * Calcific uremic arteriolopathy (CUA)
                                * Painful skin lesions, tissue necrosis
                                * Amputation, sepsis, and death

Endocrine disturbances          * Impaired lipid metabolism, insulin
                                  resistance, and glucose intolerance
                                * Increased cardiovascular risk

Marrow fibrosis                 * Altered erythropoiesis
                                * Aggravation of anemia

Table 3
Limitations of Current Treatment Options for Secondary HPT

Therapy                  Indication             Limitations

Dialysis               * Control of calcium    * Limited ability to
                         and phosphorus          remove phosphorus

Dietary restrictions   * Hyperphosphatemia     * May lead to inadequate
                                                 protein intake
                                               * Poor patient adherence

Aluminum-based         * Hyperphosphatemia     * Aluminum toxicity
phosphate binders                              * Poor patient adherence
                                               * Encephalopathy
                                                 dementia

Calcium-based          * Hyperphosphatemia     * Cardiac and soft
phosphate binders      * Hypocalcemia            tissue calcification
                                               * Hypercalcemia
                                               * Over-suppression
                                                 of PTH
                                               * Poor patient adherence
                                               * Multiple pill
                                                 ingestion

Aluminum/calcium-free  * Hyperphosphatemia     * GI upset, diarrhea,
phosphate binders                                acidosis
                                               * Poor patient adherence
                                               * Multiple pill
                                                 ingestion

Vitamin D sterols      * Suppression of PTH    * Over suppression
                       * Hypocalcemia            of PTH
                       * Replacement therapy   * Hyperphosphatemia
                                               * Hypercalcemia
                                               * Increased risk of
                                                 calcification
                                               * Elevated Ca x P

Parathyroidectomy      * Parathyroid           * Irreversible
                         hyperplasia           * Hypoparathyroidism
                       * Uncontrolled          * Mineral imbalances
                         secondary HPT           (e.g., hypocalcemia)

Table 4
NKF-K/DOQI[TM] Guidelines for Bone Metabolism and Disease

Parameter                 Target Range

[Ca.sup.2+]              8.4 to 9.5 mg/dL
P[O.sub.4.sup.-3]        3.5 to 5.5 mg/dL
Ca x P                   <55 [mg.sup.2]/d[L.sup.2]
iPTH                     150 to 300 pg/mL

Note: From National Kidney Foundation. (2003). Clinical practice
guidelines for bone metabolism and disease in chronic kidney disease.
American Journal of Kidney Diseases, 42, S1-S202.


References

Abbott Laboratories. (2003). Zemplar (paricalcitol). Package insert. North Chicago, IL: Abbott Laboratories.

Angelis, M., Wong, L.L., Myers, S.A., & Wong, L.M. (1997). Calciphylaxis in patients on hemodialysis: a prevalence study. Surgery, 122,1083-1090.

Block, G.A., Hulbert-Shearon, T.E., Levin, N.W., & Port, F.K. (1998). Association of serum phosphorus and calcium x phosphate product with mortality risk in chronic hemodialysis patients: A national study. American Journal of Kidney Diseases, 31, 607-617.

Block, G., Klassen, P., Kim, J., LaBrecque, J., & Danese, M. (2003). Relationship between serum calcium and mortality risk in hemodialysis patients. Poster presented at the National Kidney Foundation's Clinical Nephrology Meeting, Dallas, TX.

Block, G.A., & Port, F.K. (2000). Re-evaluation of risks associated with hyperphosphatemia and hyperparathyroidism in dialysis patients: Recommendations for a change in management. American Journal of Kidney Diseases, 35,1226-1237.

Braun, J., Oldendorf, M., Moshage, W., Heidler, R., Zeitler, E., & Luft, F.O. (1996). Electron beam computed tomography in the evaluation of cardiac calcifications in chronic dialysis patients. American Journal of Kidney Diseases, 27, 394-401.

Bro, S., & Olgaard, K. (1997). Effects of excess PTH on nonclassical target organs. American Journal of Kidney Diseases, 30, 608-620.

Brown, A.J., Dusso, A., & Slatopolsky, E. (1999). Vitamin D. American Journal of Physiology, 277, F157-F175.

Chertow, G.M., Burke, S.K., Dillon, M.A., & Slatopolsky, E., for the RenaGel[R] Study Group. (1999). Long term effects of sevelamer hydrochloride on the calcium x phosphate product and lipid profile of haemodialysis patients. Nephrology Dialysis and Transplantation, 14, 2907-2914.

Chiu, K.C., Chuang, L-M., Lee, N.P., Ryu, J.M., McGullam, J.L., Tsai, G.P., & Saad, M.F. (2000). Insulin sensitivity is inversely correlated with plasma intact parathyroid hormone level. Metabolism, 49,1501-1505.

Cizman, B. (2003). Hyperphosphatemia and treatment with sevelamer in haemodialysis patients. Nephrology, Dialysis, Transplantation. 18, v47-v49.

Coates, T., Kirldand, G.S., Dymock, R.B., Murphy, B.F., Brealey, J.K., Mathew, T.H., & Disney, A.P. (1998). Cutaneous necrosis from calcific uremic arteriolopathy. American Journal of Kidney Diseases, 32, 384-391.

Delmez, J.A., & Slatopolsky, E. (1992). Hyperphosphatemia: Its consequences and treatment in patients with chronic renal disease. American Journal of Kidney Diseases, 19, 303-317.

Drueke, T.B. (1991). Modulating factors in the hematopoietic response to erythropoietin. American Journal of Kidney Diseases, 18, 87-92.

Drueke, T.B, & McCarron, D.A. (2003). Paricalcitol as compared with calcitriol in patients undergoing hemodialysis. The New England Journal of Medicine, 349, 496-499.

Fine, A., & Zacharias, J. (2002). Calciphylaxis is usually non-ulcerating: Risk factors, outcome, and therapy. Kidney International, 61, 2210-2217.

Fukagawa, M., Kazama, J.J., & Shigematsu, T. (2001). Skeletal resistance to PTH as a basic abnormality underlying uremic bone diseases. American Journal of Kidney Diseases, 38, S152-S155.

Gadallah, M.F., El-Shahawy, M., Andrews, G, Ibrahim, M., Ramdeen, G., Hanna, D., Gorospe, W., Morkos, A., Abbassian, M., & Moles, K. (2001). Factors modulating cytosolic calcium. Role in lipid metabolism and cardiovascular morbidity and mortality in peritoneal dialysis patients. Advances in Peritoneal Dialysis, 17, 29-36.

Ganesh, S.K., Slack, A.G., Levin, N.W., Hulbert-Shearon, T., & Port, F.K. (2001). Association of elevated serum P[O.sub.4], Ca x P[O.sub.4] product, and parathyroid hormone with cardiac mortality risk in chronic hemodialysis patients. Journal of the American Society of Nephrology, 12, 2131-2138.

Goodman, W.G. (2001). Recent developments in the management of secondary hyperparathyroidism. Kidney International, 59, 1187-1201.

Goodman, W.G. (2002). Calcimimetic agents and secondary hyperparathyroidism: Treatment and prevention. Nephrology Dialysis and Transplantation, 17, 204-207.

Goodman, W.G., Goldin, J., Kaizon, B.D., Yoon, C., Gales, B., Sider, D., Wang, Y., Chung, J., Emerick, A., Greaser, L., Elashoff, R.M., & Salusky, LB. (2000). Coronary-artery calcification in young adults with end stage renal disease who are undergoing dialysis. New England Journal of Medicine, 342,1478-1483.

Goodman, W.G., & Turner SA. (2002). Future role of calcimimetics in end stage renal disease. Advances in Renal Replacement Therapy, 9, 200-208.

Guerin, A.P, London, G.M., Marchais, S.J., & Metivier, F. (2000). Arterial stiffening and vascular calcifications in end stage renal disease. Nephrology Dialysis and Transplantation, 15, 1014-1021.

Hamdy, N.A.T. (1995). The spectrum of bone disease. Nephrology Dialysis and Transplantation, 10, 14-18.

Horl, W.H. (2003). Renal osteodystrophy: Role of calcimimetics. American Journal of Kidney Diseases, 47, S104-S107.

Hsu, C.H. (1997). Are we mismanaging calcium and phosphate metabolism in renal failure? American Journal of Kidney Diseases, 29, 641-649.

Levin, A., Mehta, R.L., & Goldstein, M.B. (1993). Mathematical formulation to help identify the patient at risk of ischemic tissue necrosis--A potentially lethal complication of chronic renal failure. American Journal of Nephrology, 13, 448-456.

Lindberg, J.S., Moe, S.M., Goodman, W.G., Coburn, J.W., Sprague, S.M., Liu, W., Blaisdell, P.W., Brenner, R.M., Turner, S.A., & Martin, K.J. (2003). The calcimimetic AMG 073 reduces parathyroid hormone and calcium x phosphorus in secondary hyperparathyroidism. Kidney International, 63, 248-254.

Llach, F., & Yudd, M. (1998). The importance of hyperphosphatemia in the severity of hyperparathyroidism and its treatment in patients with chronic renal failure. Nephrology Dialysis and Transplantation, 13, 57-61.

Malluche, H.H., & Mawad, H. (2002). Management of hyperphosphataemia of chronic kidney disease: Lessons from the past and future directions. Nephrology Dialysis and Transplantation, 17, 1170-1175.

Malluche, H.H., Mawad, H., & Koszewski, N.J. (2002). Update on vitamin D and its newer analogues: Actions and rationale for treatment in chronic renal failure. Kidney International, 62, 367-374.

Martin, K.J., & Gonzalez, E.A. (2001). Vitamin D analogues for the management of secondary hyperparathyroidism. American Journal of Kidney Diseases, 38, S34-S40.

Massry, S.G., & Smorgorzewski, M. (1994). Mechanisms through which parathyroid hormone mediates its deleterious effects on organ function in uremia. Seminars in Nephrology, 14, 219-231.

Mawad, H.W., Sawaya, B.P., Satin, R., & Malluche, H.H. (1999). Calcific uremic arteriolopathy in association with low turnover uremic bone disease. Clinical Nephrology, 52, 160-166.

Musci, I., Hercz, G., Uldall, R., Ouwendyk, M., Francoeur, R., & Pierratos, A. (1998). Control of serum phosphate without any phosphate binders in patients treated with nocturnal hemodialysis. Kidney International, 53, 1399-1404.

National Kidney Foundation (NKF). (2000). K/DOQI Clinical Practice Guidelines on nutrition ha chronic renal failure. American Journal of Kidney Diseases, 35(Suppl. 2).

National Kidney Foundation (NKF). (2002). K/DOQI Clinical Practice Guidelines for Chronic Kidney Disease: Evaluation, classification, and stratification. American Journal of Kidney Disease, 39, S1143-S155.

Norris K.C. (1998). Toward a new treatment paradigm for hyperphosphatemia in chronic renal disease. Dialysis and Transplantation. 27, 767-772.

Parfrey, P.S., & Foley, R.N. (1999). The clinical epidemiology of cardiac disease in chronic renal failure. Journal of the American Society of Nephrology, 10, 1606-1615.

Pierratos, A., Ouwendyk, M., & Fancoeur, R., Vas, R., Rai, D.S., Ecclestrone, A.M., Langos, V., & Uldall, R. (1998). Nocturnal dialysis: 3-year experience. Journal of the American Society of Nephrology, 9, 859-868.

Potts, J.T. (2002). Diseases of the parathyroid gland and other hyper- and hypocalcemic diseases. In E. Braunwald, A.S. Fauci, D.L. Kasper, S.L. Hauser, D.L. Longo, & J.L. Jameson (Eds.), Harrison's principles of internal medicine, 15th ed. (pp. 2205-2226). New York: McGraw-Hill.

Proudfoot, D., Shanahan, C.M., & Weissberg, P.L. (1998). Vascular calcification: New insights into an old problem. Journal of Pathology, 185, 1-3.

Quarles, L.D., Sherrard, D.J., Adler, S., Rosansky, S.J., Mccary, L.C., Liu, W., Turner, S.A., & Bushinsky, D.A. (2003). The calcimimetic AMG 073 as a potential treatment for secondary hyperparathyroidism of end stage renal disease. Journal of the American Society of Nephrology, 14, 575-583.

Rao, D.S., Shih, M-S., & Mohini, R. (1993). Effect of serum parathyroid hormone and bone marrow fibrosis on the response to erythropoietin in uremia. New England Journal of Medicine, 328, 171-175.

Rocco, M.V., Easter, L., & Makoff, R. (1999). Management of hyperphosphatemia with calcium-based binders. Seminars in Dialysis, 12, 195-201.

Schinke, T., McKee, M.D., Kiviranta, R., & Karsenty, G. (1998). Molecular determinants of arterial calcification. Annals of Internal Medicine, 30, 538-541.

Sherrard, D.J., Herez, G., Pei, Y., Maloney, N.A., Greenwood, C., Manuel, A., Saiphoo, C., Fenton, S.S., & Segre, G.V. (1993). The spectrum of bone disease in end-stage renal failure--an evolving disorder. Kidney International, 43, 436-442.

Slatopolsky, E. (1998). The role of calcium, phosphorus, and vitamin D metabolism in the development of secondary hyperparathyroidism. Nephrology Dialysis and Transplantation, 13, 3-8.

Slatopolsky, E.A., Burke, S.K., Dillon, M.A., and the RenaGel[R] Study Group. (1999). RenaGel[R], a nonabsorbed calcium- and aluminum-free phosphate binder, lowers serum phosphorus and parathyroid hormone. Kidney International, 55, 299-307.

Slatopolsky, E., & Delmez, J.A. (1996). Pathogenesis of secondary hyper parathyroidism. Nephrology Dialysis and Transplantation, 11, 130-135.

Steddon, S.J., Schroeder, N.J., & Cunningham, J. (2001). Vitamin D analogues: How do they differ and what is their clinical role? Nephrology, Dialysis, and Transplantation, 16, 1965-1967.

Teng, M., Wolf, M., Lowrie, E., Ofsthun, N., Lazarus, M., & Thadhani, R. (2003). Survival of patients undergoing hemodialysis with paricalcitol or calcitriol therapy. The New England Journal of Medicine, 349, 446-456.

Tortes, A., Lorenzo, V., Hernandez, D., Rodriguez, J.C., Concepcion, M.T., Rodriguez, A.P., Hernandez, A., de Bonis, E., Darias, E., & Gonzalez Posada, J.M. (1995). Bone disease in predialysis, hemodialysis, and CAPD patients: Evidence of a better bone response to PTH. Kidney International, 47, 1434-1442.

U.S. Renal Data System (USRDS). (2002). USRDS 2002 Annual Data Report: Atlas of end stage renal disease in the United States. Bethesda, MD: National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases.

Walters, B.A.J., Danese, M.D., Kim, J.J., & Klassen, P.S., (2003). Patient prevalence within proposed NKFK/DOQI Guidelines for bone metabolism and disease. Journal of the American Society of Nephrology, 14, SA-PO799. Abstract.

Zocalli, C. (2000). Cardiovascular risk in uraemic patients--is it fully explained by classical risk factors? Nephrology Dialysis and Transplantation, 15, 454-457.

Secondary Hyperparathyroidism in Chronic Kidney Disease: Clinical Consequences and Challenges

Maureen Michael, MBA, BSN, CHN and Donna Garcia, RD, LD/N

Posttest--1.8 Contact Hours Posttest Questions

(See posttest instructions on the answer form, on page 196.)

1. The primary role of parathyroid hormone (PTH) is to

A. maintain bone remodeling.

B. increase intestinal absorption of calcium.

C. maintain extracellular concentration of calcium.

D. increase kidney reabsorption of calcium.

2. Calcium sensing receptors (CAR), located on the surface of chief cells within the parathyroid glands, are responsible for the following: as calcium

A. decreases, CaR is activated, increasing PTH secretion.

B. decreases CaR is inactivated, decreasing PTH secretion.

C. increases, CaR is inactivated, increasing PTH secretion.

D. increases, CaR is activated, decreasing PTH secretion.

3. Mr. Hardin is receiving Zemplar (Vitamin D analog). His PTH is not decreasing. What might explain this finding? In the presence of the --, parathyroid gland is resistant to the action of Vitamin D.

A. hypercalcemia

B. hypocalcemia

C. hyperphosphatemia

D. hypophosphatemia

4. What happens first in a patient with chronic kidney disease when the mechanisms of bone and mineral homeostasis are disrupted?

A. Calcium absorption is reduced.

B. Vitamin D is activated.

C. The kidneys are unable to secrete phosphorous.

D. CaR are activated.

5. The most common type of low-turnover bone disease is

A. a manifestation of secondary HPT.

B. caused by oversuppression of PTH.

C. due to concurrent administration of non-calcium based phosphate binders.

D. a manifestation of decreased calcium levels and inhibition of PTH secretion.

6. What metabolic change(s) induced by secondary HPT or its treatment are independently associated with cardiac causes of death?

A. Elevated PTH only.

B. Elevated PTH and elevated phosphorous only.

C. Elevated PTH, elevated phosphorous, and elevated calcium/phosphorous product only.

D. Elevated PTH, elevated phosphorous, elevated calcium/ phosphorous product, and elevated calcium.

7. As plasma PTH concentrations rise, you would expect which disturbance?

A. Hyperglycemia.

B. Hypolipidemia.

C. Hypotriglycerides.

D. Increased insulin sensitivity.

8. The primary management strategies employed to manage secondary (HPT) include:

A. control dietary phosphorous only.

B. control dietary phosphorous and administer phosphorous binders only.

C. control dietary phosphorous, administer phosphorous binders and vitamin D therapy only.

D. control dietary phosphorous, administer phosphorous binders and vitamin D therapy and dietary calcium supplementation.

9. In what patient should vitamin O therapy be temporarily discontinued?

A. Hypercalcemia only.

B. Hypercalcemia and hyperphosphatemia only.

C. Hypercalcemia, hyperphosphatemia and oversuppression of PTH.

D. Hypercalcemia, hyperphosphatemia, oversuppression of PTH and low calcium/phosphorous product.

10. New approaches to decreasing phosphorous include increasing

A. frequency of dialysis.

B. dialysis time.

C. blood flow.

D. dialysate flow.

Maureen Michael, BSN, MBA, CHN, is Executive Director of Central Florida Kidney Centers, Inc., Orlando, FL, and a member of the NKF K/DOQI[TM] Steering Committee. She is a member of ANNA's Sunshine Central Chapter.

Donna Garcia, RD, LD/N, is Renal Dietitian, Central Florida Kidney Centers, Inc., Orlando, FL.
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Title Annotation:Continuing Education
Author:Michael, Maureen; Garcia, Donna
Publication:Nephrology Nursing Journal
Date:Mar 1, 2004
Words:7509
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