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Treatment of hyperphosphatemia in chronic kidney disease Authors Robert E Cronin, MD L Darryl Quarles, MD Section Editor Jeffrey S Berns, MD Deputy Editor Alice M Sheridan, MD Disclosures All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: May 2012. | This topic last updated: Apr 20, 2012. BACKGROUND A tendency toward phosphate retention begins early in renal disease, due to the reduction in the filtered phosphate load. Although this problem is initially mild with hyperphosphatemia being a relatively late event, phosphate retention is intimately related to the common development of cardiovascular disease risk in CKD, increased fibroblast growth factor (FGF)-23 levels, and secondary hyperparathyroidism (figure 1) [1-6]. These adaptive endocrine alterations are a potential concern because high circulating levels of parathyroid hormone (PTH) play an important role in the development of renal osteodystrophy [1,2,7], and elevated circulating FGF-23 concentrations are strongly associated with increased cardiovascular mortality and renal failure [7,8]. (See "Pathogenesis of renal osteodystrophy".) From the viewpoint of calcium and phosphate balance, the hypersecretion of FGF-23 and PTH reflect the development of phosphate retention, and are initially appropriate. FGF-23 appears to be the initial hormonal abnormality leading to increased urinary phosphate excretion and suppression of 1,25(OH)2D. PTH increases in response to reductions in 1,25(OH)2D. By increasing bone turnover and calcium phosphate release from bone and enhancing urinary phosphate excretion (via a decrease in proximal reabsorption), PTH can correct both the hypocalcemia and the hyperphosphatemia. FGF-23 is also important in the renal adaptation to maintain phosphate excretion. The effect on renal phosphate handling is manifested by a progressive reduction in the fraction of the filtered phosphate that is reabsorbed, from the normal value of 80 to 95 percent to as low as 15 percent in advanced renal failure [9]. As a result, phosphate balance and a normal serum phosphate concentration are generally maintained (at the price of elevated FGF-23 and hyperparathyroidism) until the glomerular filtration rate (GFR) falls below 25 to 40 mL/min [2,10]. At this relatively late stage, dietary phosphate restriction may still reduce the serum concentration of phosphate, FGF-23, and PTH, although not usually to normal [2,11]. As a result, oral phosphate binders are frequently required. This problem is exacerbated once maintenance dialysis is required; in this setting, there is essentially no phosphate excretion and oral phosphate binders must be given to limit phosphate absorption [2]. In addition, levels of FGF-23 become extremely elevated, and the secondary hyperparathyroidism may contribute to the hyperphosphatemia by continuing to enhance the release of calcium phosphate from bone [12].

Hyperphosphatemia alone or in combination with a high serum calcium is associated with increased mortality in dialysis patients [13,14]. This relationship also exists in patients with less advanced kidney disease [15]. (See"Patient survival and maintenance dialysis", section on 'Disorders of mineral metabolism'.) When both calcium and phosphate levels are high (due in part to the increased intake of calcium [via calcium-based phosphate binders]), heterotopic deposition of hydroxyapatite in arteries, joints, soft tissues, and the viscera develops; when small arterioles are affected, tissue ischemia and calciphylaxis may occur [2,16]. Tumoral collections of calcium phosphate crystals may also be a consequence of hyperphosphatemia and increased calcium levels [17]. (See "Vascular calcification in chronic kidney disease" and "Calciphylaxis".) Increased coronary arterial calcification is associated with coronary atherosclerosis, and is also related to the presence and/or consequences of elevated serum phosphorus, calcium, FGF-23 and parathyroid hormone levels [18]. If the oral phosphate binders described below are ineffective, parathyroidectomy may be required to control both the hyperparathyroidism and that part of the hyperphosphatemia that is due in part to PTH-induced release from bone [2,12]. (See "Indications for parathyroidectomy in endstage renal disease".) The remainder of this topic will review the recommended goals for serum phosphate at different levels of glomerular filtration rate and the issues that need to be considered in the treatment of hyperphosphatemia of chronic kidney disease. Many such patients are also treated with calcitriol or a vitamin D analog or calcimimetic in an attempt to suppress PTH release. However, calcitriol and other vitamin D analogs also increase intestinal phosphate absorption and can exacerbate the hyperphosphatemia unless bone remodeling is reduced due to inhibition of PTH secretion. High doses of vitamin D analogs also stimulate vascular calcification. Thus, such therapy should NOT be started until the serum phosphate concentration is under reasonable control. (See "Management of secondary hyperparathyroidism and mineral metabolism abnormalities in adult predialysis patients with chronic kidney disease" and "Management of secondary hyperparathyroidism and mineral metabolism abnormalities in dialysis patients".) A review of the overall management of the patient with chronic kidney disease is presented separately. (See "Overview of the management of chronic kidney disease in adults".) GUIDELINE TARGET LEVELS K/DOQI guidelines The 2003 K/DOQI practice guidelines made the following recommendations for goal serum phosphate at different levels of severity of chronic kidney disease [19]: At an estimated glomerular filtration rate between 15 and 59 mL/min per 1.73 m2 (stage 3 and 4 chronic kidney disease), the serum phosphate should be between 2.7 and 4.6 mg/dL (0.87 and 1.49 mmol/L) At an estimated glomerular filtration rate below 15 mL/min per 1.73 m2 (stage 5 chronic kidney disease), the serum phosphate should be between 3.5 and 5.5 mg/dL (1.13 and 1.78 mmol/L)

(See "Overview of the management of chronic kidney disease in adults", section on 'Definition and classification'.)

KDIGO guidelines The 2009 KDIGO practice guidelines were developed to provide recommendations for the evaluation and management of chronic kidney disease-mineral and bone disorder (CKD-MBD) [20]. With respect to phosphate, the guidelines recommend the following: Among patients with stage 3 to 5 CKD not yet on dialysis, the serum phosphate should be maintained in the normal range Among dialysis patients, the phosphate level should be lowered toward the normal range.

GOAL SERUM PHOSPHATE Although the optimal levels are unclear, our target goals for phosphate levels have been chosen based upon attempts to prevent and manage the morbidity and mortality associated with hyperphosphatemia associated with CKD: Among patients with stage 3 to 5 CKD not yet on dialysis, we suggest maintaining serum phosphate levels in the normal range; these levels are consistent with the KDIGO guidelines. Among dialysis patients, we suggest maintaining serum phosphate levels between 3.5 and 5.5 mg/dL (1.13 and 1.78 mmol/L), which is consistent with the K/DOQI guidelines. By comparison, the KDIGO guidelines only recommend lowering levels toward the normal range. We feel that this is not a practical goal since specific levels are not specified, and a phosphate level of 5.5 mg/dL is a reasonable inflection point at which increased mortality has been observed.

No randomized study has evaluated whether achieving these goal serum phosphate targets with phosphate lowering therapy has any bearing on important clinical outcomes. Observational studies in dialysis patients and in non-dialysis CKD patients have examined whether the use of phosphate binders is associated with improved survival: In a prospective observational study of incident dialysis patients followed for one year, the use of phosphate binders was significantly associated with a 25 percent lower one-year mortality [21]. In a retrospective cohort of non-dialysis CKD patients in a single center study, a lower risk of mortality was noted with phosphate binder therapy (23 percent decrease) [22]. However, this apparent benefit could stem from unequal periods of follow up; the median period of follow up was approximately four years for patients not given phosphate binders compared to just two years for patients treated with phosphate binders.

However, a retrospective cohort study of 7076 patients dialyzed in the United Kingdom from 2002 to 2004 suggested that patients who attained the 2003 KDOQI targets for phosphate (3.5 to 5.5 mg/dL), calcium (8.4 to 9.5 mg/dL) and PTH (150 to 300 pg/mL) did not have better survival compared to those who did not [23]. This study did not include any information about the use of medication, vitamin D and alkaline phosphatase levels or dialysate calcium concentration. Randomized trials are needed to determine whether phosphate lowering in CKD impacts important clinical endpoints. A significant amount of epidemiologic and observational evidence suggests that higher than normal phosphate levels, including those in the upper levels of the normal range, may increase the risk of cardiovascular disease and death in patients with normal kidney function as well as those with CKD stages 3 to 5 not yet on dialysis [15,24-26]. With respect to patients with chronic kidney disease who are not yet dialysis dependent, this was perhaps best shown in a study of 3490 patients with CKD [15]. At a median follow-up of two years, an increased mortality risk was observed in those with serum phosphate

levels greater than 3.5 mg/dL (0.81 mmol/L). The mortality risk also increased as serum phosphate levels increased, with each 1 mg/dL (0.32 mmol/L) positive increment being associated with a 23 percent enhanced risk of death. A sustained elevation in serum phosphate alone is also associated with increased mortality among patients with end-stage renal failure [14,27-32]. This was best shown in a meta-analysis of 12 studies that included 92,345 patients with CKD, over 97 percent of whom were on dialysis [32]. The overall mortality risk increased 18 percent for every 1 mg/dl increase in the serum phosphorus (RR 1.18, 95% CI 1.121.25). TREATMENT OPTIONS Two principal modalities are used in an attempt to prevent and/or reverse the hyperphosphatemia of renal failure [20,33]: Restricting dietary phosphate intake The administration of different agents, named phosphate binders, to bind ingested phosphate in the gut

Phosphate restriction We suggest a moderate restriction of phosphate intake in patients with CKD, providing this can be done without compromising nutritional status; approximately 900 mg per day is a level that at least some patients will find acceptable. Phosphate restriction should primarily include processed foods and colas and NOT high biologic value foods such as meat and eggs. However, different considerations are present in maintenance dialysis. A large fraction of dialyzed patients have either overt or borderline malnutrition. Thus, protein supplementation rather than protein restriction is the goal. In this setting, the patient should be encouraged to avoid unnecessary dietary phosphate (as in phosphorus-containing food additives, dairy products, certain vegetables, many processed foods, and colas) while increasing the intake of high biologic value sources of protein (such as meat and eggs) [34,35]. Food additives are an under-appreciated source of dietary phosphorus and patient instruction to read food labels and avoid these is very important [35]. In addition to the phosphate content of a food, measures aimed at lowering phosphate levels also depend upon an understanding of the ability to absorb phosphorus within the gastrointestinal tract. Thus, phosphorus contained in highly processed food is easily absorbed; by comparison, plant-derived phosphorus is less easily absorbed because it is in the form of phytate phosphorus, and the human intestine does not secrete phytase, the enzyme required for absorption [34]. There is a paucity of data examining the efficacy of dietary phosphate restrictions on patient important outcomes. In one randomized study that evaluated the effect of dietary restriction on vascular calcification, a low phosphate diet alone failed to prevent progression of such calcification among patients with CKD not yet on dialysis [36]. In a post hoc analysis of data from the HEMO study, prescribed phosphate restriction was not associated with improved survival of hemodialysis patients [37]. In fact, there was a stepwise trend toward better survival with less restrictive prescribed phosphate intake in this study. Major findings from the HEMO study are discussed elsewhere. (See "Kt/V and the adequacy of hemodialysis", section on 'HEMO study'.) A few small studies have found that phosphate restriction does not compromise nutrition [38-40], although in the HEMO study cohort, phosphate restriction tended to be associated with poorer nutritional indices on baseline analysis and a persistently greater need for nutritional supplementation [37]. These recommendations are consistent with the K/DOQI and KDIGO guidelines [19,20].

Phosphate binders Overview and choice of binder Many patients with CKD not yet on dialysis and nearly all dialyzed patients (undergoing conventional dialysis) require administration of oral phosphate binders to control serum phosphate levels [19,20,41,42]. Thus, among patients with CKD and hyperphosphatemia, we suggest the administration of phosphate binders. At present, the major modalities to lower phosphate levels are the administration of: Calcium-containing phosphate binders. Non-calcium containing phosphate binders. The two principal options are sevelamer and lanthanum.

As shown in a systematic review, these phosphate binders are all effective in lowering phosphate [19]. There is no evidence suggesting that the use of one agent rather than another provides significant clinical benefits related to mortality or bone fractures among dialysis patients. Limited data suggest that sevelamer compared withcalcium carbonate may decrease mortality among CKD patients who are not on dialysis [43]. (See 'Sevelamer' below.) A strategy that relies principally upon calcium-containing phosphate binders increases the risk of positive calcium balance, particularly in the setting of concomitant vitamin D therapy. Compared with the use of non-calcium-containing phosphate binders, this may increase the risk of vascular calcification and arterial disease and is associated with decreased serum PTH levels and increased serum calcium levels. We therefore favor an overall strategy that limits the intake of calcium. This is consistent with both the K/DOQI and KDIGO guidelines. We keep daily elemental calcium intake from binders to less than 1500 mg, and total elemental calcium from diet and binders to less than 2000 mg in patients on concurrent therapy with active vitamin D analogues. Higher doses of calcium may be tolerated in patients not receiving vitamin D analogues or who have hypocalcemia while being treated with calcimimetics. The choice between the two types of binders varies based upon a range of factors. These include the presence of vascular calcification, levels of calcium and PTH, administration of other agents to help control secondary hyperparathyroidism, adverse effects, and others. Among hyperphosphatemic patients, for example, the dose of calcium-containing phosphate binders should be restricted in the setting of hypercalcemia, arterial calcification, adynamic bone disease, and/or persistently low parathyroid hormone (PTH) levels. Calcium salts The following is an overview of the use of calcium salts as phosphate binders. The specific evidence in terms of clinically relevant outcomes with calcium-containing phosphate binders versus other agents is discussed in sections below. (See 'Sevelamer' below and 'Lanthanum' below.) For many years, aluminum hydroxide was the phosphate binder of choice. This regimen, however, created a new problem, aluminum intoxication due to the gradual tissue accumulation of absorbed aluminum. (See 'Other phosphate binders' below.) The problems with aluminum led to the preferential administration of calcium salts to bind intestinal phosphate [1,2,44]. Initial studies with calcium salts revealed that adequate control of the hyperphosphatemia was achieved in approximately 70 percent of patients treated with calcium salts [44]; the remaining patients required the addition of some aluminum-containing antacid [44].

Most patients are administered the calcium-containing phosphate binders, calcium carbonate or calcium acetate [1,44,45]. Calcium acetate may be a more efficient phosphate binder than calcium carbonate [4648]. The latter dissolves only at an acid pH and many patients with advanced renal failure have achlorhydria or are taking H2-blockers [45]. Calcium acetate, on the other hand, is soluble in both acid and alkaline environments. The net effect is that only one-half as much calcium is required with calcium acetate. However, this difference does not appear to be clinically important, since the incidence of hypercalcemia is similar to that seen with higher doses of calcium carbonate [1,47,48]. Therapy of elevated phosphate levels that is refractory to diet and/or dialysis can therefore be initiated with calcium-based phosphate binders. The dose of calcium-containing phosphate binders is generally increased until the serum phosphate falls to normal values for patients with stage 3 to 5 CKD not yet on dialysis or between 4.5 and 5.5 mg/dL (1.5 and 1.8 mmol/L) for dialysis patients or hypercalcemia ensues. There is no known harm in maintaining plasma calcium levels at the lower end of the normal range (8.4 to 9.5 mg/dL [2.1 to 2.35 mmol/L]), especially in patients treated with calcimimetics. However, a serum calcium in the upper limit of a normal population may be acceptable in patients treated with active vitamin D analogues, provided that serum phosphate is <5.5 mg/dL. One potential complication of calcium therapy is that absorption of some of the administered calcium may promote the development of coronary arterial calcification, which is postulated to be associated with coronary atherosclerosis [49-52]. To help decrease this possibility, we suggest that the total dose of elemental calcium (including dietary sources) should not exceed 2000 mg/day [19], and the amount of elemental calcium should be no more than 1.5 grams per day. Even these doses of calcium result in positive calcium balance in the setting of vitamin D therapy, which may have untoward long-term consequences. (See "Management of secondary hyperparathyroidism and mineral metabolism abnormalities in adult predialysis patients with chronic kidney disease" and "Vascular calcification in chronic kidney disease".) Phosphate binders are most effective if taken with meals [53]. This regimen has the advantages of binding dietary phosphate and therefore of leaving less free calcium available for absorption. In comparison, administration between meals only binds the phosphate present in intestinal secretions and results in a greater degree of calcium absorption. Although not generally desirable, the combination of more calcium absorption and less phosphate binding may be preferred in patients who remain hypocalcemic despite a normal or low plasma phosphate concentration. Although generally well tolerated, hypercalcemia is a common complication of this regimen; as previously mentioned, this problem is most likely to occur if a vitamin D preparation is also given [54] or if patient has decreased bone turnover due to osteomalacia or adynamic bone disease, thereby limiting uptake of the extra calcium by bone [1,55]. (See "Pathogenesis of renal osteodystrophy", section on 'Adynamic bone disease'.) To limit calcium loading, it is also reasonable to restrict the dose of calcium-based phosphate binders in patients with evidence of vascular calcification. (See "Vascular calcification in chronic kidney disease".) We therefore recommend that calcium-based phosphate binders not be used in patients with hyperphosphatemia who are also hypercalcemic. In addition, we also suggest that the dose of calciumbased phosphate binders be limited in patients with suspected adynamic bone disease, vascular calcification, and persistently low plasma PTH levels. Adynamic bone disease can be suspected in patients with a low plasma PTH level who develop hypercalcemia on calcium based phosphate binders or active vitamin D therapy. A bone biopsy is the only way to definitively diagnose this disorder.

Thus, careful monitoring of the serum calcium concentration is essential with the chronic administration of calcium salts, particularly in patients on hemodialysis where the dialysate calcium concentration can vary and therefore impact the ability to administer calcium-containing phosphate binders: To help reduce calcium loads, the 2003 K/DOQI guidelines suggested that the dialysate calcium concentration in hemodialysis or peritoneal dialysis should be 2.5 meq/L (1.25 mmol/L) [19]. The 2009 KDIGO guidelines suggest that the dialysate calcium concentration in hemodialysis or peritoneal dialysis should be between 2.5 and 3.0 meq/L. We suggest using a dialysate calcium concentration of 2.5 meq/L, a concentration in which there is no net calcium flux in most patients [56]. By comparison, a dialysate calcium concentration between 3 and 3.5 meq/L (1.50 to 1.75 mmol/L) is much higher than that in the plasma, resulting in a positive calcium balance and increasing the risk of hypercalcemia in patients also taking calcium supplements [56]. It is estimated that, during a four-hour dialysis session, patients gain almost 900 mg of calcium when dialyzed against a 3.5 meq/L dialysate [56].

Among patients treated with continuous ambulatory peritoneal dialysis (CAPD), a low calcium bath (2.0 meq/L) has also been used [57]. However, extended treatment with low calcium peritoneal dialysate fluids may be associated with an increased risk of severe hyperparathyroidism [58,59]. Serum PTH levels and bone metabolism must be closely monitored if low calcium peritoneal dialysate fluids are utilized [60]. Sevelamer Sevelamer hydrochloride (Renagel) and the newer sevelamer carbonate (Renvela) are nonabsorbable agents that contain neither calcium nor aluminum. These drugs are cationic polymers that bind phosphate through ion exchange. Since sevelamer carbonate does not lower serum bicarbonate, it is likely that it will become the preferred binder in this class (see below). As noted with other phosphate binding agents, a significant number of trials have found that sevelamer is effective in lowering serum phosphate levels [61-70]. Although conventional dosing of sevelamer is effective, compliance with the requirement for thrice daily dosing with any phosphate binder can be problematic. A small crossover study found that thrice daily and once daily dosing were equally effective [69]. Although further study is required, once daily dosing may simplify the dosing regimen, thereby resulting in increased compliance and overall efficacy. The important issues with respect to the choice of sevelamer versus other agents are their relative effects on mortality, vascular calcification, bone disease, and biochemical effects, particularly hypercalcemia. The following sections will address some of the evidence evaluating the relative effects of sevelamer on mortality, vascular calcification, and biochemical indices. Mortality Calcium- and non-calcium-based phosphate binders appear to have similar effects on all-cause or cardiovascular mortality in hemodialysis patients. A small number of randomized trials and a meta-analysis have evaluated mortality with sevelamer versus calcium-based phosphate binders [66,67,71-76]. The following is a brief review of the largest studies: A meta-analysis of five trials consisting of 2429 patients (2103 from the DCOR study, next paragraph) reported a similar risk difference for all-cause mortality between sevelamer and calcium-based phosphate binders (-2 percent, 95% CI -6 to +2 percent) [74]. The three-year Dialysis Clinical Outcomes Revisited (DCOR) trial evaluated mortality and morbidity outcomes among 2103 prevalent hemodialysis patients randomly assigned to either sevelamer or calcium-based phosphate binders [73]. At up to 45 months, there was no

significant difference in all-cause mortality (RR 0.93, 95% CI 0.79-1.11) and cardiovascular mortality (RR 0.93, 95% CI 0.74-1.17). A secondary analysis reported no differences in mortality, but there were benefits with sevelamer on all cause hospitalizations and hospital days [76]. In the prospective randomized RIND trial, there was relatively less progression of coronary artery calcification in 109 incident hemodialysis patients randomly assigned to sevelamer versus calcium-based phosphate binders [71]. In a post-hoc analysis of this study, mortality at a median follow-up of 44 months was (borderline) significantly lower with sevelamer (5.3/100 patient-years versus 10.6/100 patient-years) [72]. With multivariate analysis, there was a greater risk for death with calcium-based phosphate binders (hazard ratio 3.1, CI 1.23-7.61). In addition, the baseline coronary artery calcium level was a significant predictor of mortality. Among CKD patients who are not on dialysis, one limited study has suggested that sevelamer compared with calcium carbonate may decrease mortality [43]. In a randomized nonblinded study that included 212 patients, fewer deaths were associated with sevelamer compared with calcium carbonate at 36 months (12 versus 22). The composite endpoint of death or initiation of dialysis was lower among patients on sevelamer compared with calcium carbonate (43 versus 64, respectively). The decreased mortality associated with sevelamer may have been related in part to its greater efficacy in reducing serum phosphorus and decreased risk of hypercalcemia compared with calcium carbonate; although the proportion of patients who achieved the targeted phosphorus concentration (2.7 to 4.6 mg/dl for patients with stage 4 CKD and 3.5 to 5.5 mg/dl for those with stage 5 CKD), the average phosphorus concentration was lower among patients treated with sevelamer compared with calcium carbonate (4.37 versus 4.85 mg/dl, respectively). The average calcium concentrations and the incidence of hypercalcemia were lower in the sevelamer compared with calcium carbonate group (8.6 versus 9.4 mg/dl, and 5 versus 78 percent, respectively). The apparent survival benefit may also have been related to decreases in Creactive protein, total cholesterol and LDL cholesterol, also observed with greater frequency in association with sevelamer. Although larger randomized studies are required to confirm these data, sevelamer is a good option for CKD patients who are not on dialysis and who require a phosphate binder. However, calcium-containing binders would be an acceptable therapy in many non-dialysis CKD patients, particularly if cost is an issue, providing such patients are not hypercalcemic.

Effect on calcification Although the data are not consistent, there appears to be relatively less progression of vascular calcification with sevelamer versus calcium-containing phosphate binders among patients with CKD. However, it is unclear whether this benefit is associated with improvements in morbidity and mortality from cardiovascular disease. The prospective and randomized "Treat-to-Goal" and RIND trials both reported relatively less progression of coronary artery calcification with sevelamer versus calcium-containing phosphate binders [66,71,72,77]. By comparison, the Calcium Acetate Renagel Evaluation (CARE)-2 trial found similar progression of coronary artery calcification with sevelamer and calcium acetate [78]. The differences observed between the "Treat-to-Goal", RIND, and the CARE-2 trial may be due, in part, to study limitations and the inclusion of a higher proportion of diabetic patients in the

CARE-2 trial. This last finding may have resulted in a substantially greater progression of calcification. In the randomized study cited above, de novo coronary artery calcification detected by multi-slice computed tomography was lower at 36 months among patients treated with sevelamer compared with calcium carbonate (13 versus 82 percent, respectively) [43]. Given these findings, calcium-containing phosphate binders remain a cost-effective first-line treatment option for the control of hyperphosphatemia, although the risk of long-term calcium exposure remains a concern. Limiting calcium-containing phosphate binder use and the early use of sevelamer in patients with persistent hyperphosphatemia, even in combination with calciumcontaining binders, may be most appropriate. Bone histology There appears to be no major difference between sevelamer and calciumbased phosphate binders in terms of bone histology. A few randomized prospective studies have been performed that found varying outcomes in different patients, with a consistent finding of improved bone volume with calcium therapy [79-81]. Although the evidence is somewhat inconsistent, there appears to be a correlation between increased calcium intake and an increased incidence of both adynamic bone disease and vascular calcification [79,82,83]. The increased calcium intake was most commonly the result of the use of calcium-containing phosphate binders compared with either sevelamer or lanthanum. (See 'Lanthanum' below.) Calcium and PTH levels A number of randomized prospective studies have found that sevelamer compared with calcium-based phosphate binders is associated with lower serum calcium levels and higher phosphate and PTH levels [66,71,72,77,78,84]. In the prospective "Treat-to-Goal" trial, 200 patients undergoing maintenance hemodialysis were randomly assigned to sevelamer or calcium-based phosphate binders [66]. At one year, although serum phosphate control was similar with both agents (5.1 mg/dL [1.65 mmol/L]), sevelamer was associated with the following: Lower incidence of hypercalcemia (5 versus 16 percent) A minimal decrease in the serum calcium concentration (9.5 versus 9.7 mg/dL [2.35 and 2.43 mmol/L]) Decreased incidence of low PTH levels (30 versus 57 percent) Metabolic acidosis One problem associated with sevelamer hydrochloride is the possible induction of metabolic acidosis. As a result, a buffered form of sevelamer, sevelamer carbonate (Renvela), has been developed. It is associated with higher serum bicarbonate levels than Renagel, but these agents appear to be equivalent in their ability to control phosphate levels. This was shown in a double-blind randomized trial of 79 hemodialysis patients in which patients were administered eight weeks of sevelamer carbonate or sevelamer hydrochloride and then crossedover to the other agent for an additional eight weeks [85]. Both agents similarly controlled mean serum phosphate levels, while bicarbonate levels were significantly higher with sevelamer carbonate (+1.3 meq/L). The induction of metabolic acidosis with sevelamer hydrochloride is discussed separately. (See"Pathogenesis and treatment of metabolic acidosis in chronic kidney disease".) Economic impact There is a large difference in cost between sevelamer and calcium based phosphate binders, with sevelamer being much more expensive. As examples:

To address the possible economic impact of the K/DOQI guidelines, one 2004 study performed a systematic review of the use of this agent in the over 50 percent of Canadian and United States dialysis patients who would fulfill K/DOQI criteria for its administration [86]. It was estimated that, in the United States, approximately 780 million dollars would be required per year for sevelamer alone to meet these recommendations. An economic evaluation of the use of sevelamer for all dialysis patients found that the cost per quality-adjusted life year was economically unattractive [87]. This was particularly true given that sevelamer was associated with uncertain clinical benefits. Lanthanum Lanthanum, a rare earth element, has significant phosphate binding properties. This agent has been shown to be effective in multiple studies that have assessed the effectiveness in lowering phosphate levels of different dosing regimens among dialysis patients [88-95]. Because of a high daily cost when compared to calcium-based binders, lanthanum carbonate is generally restricted to the same population of dialysis patients that now receives sevelamer. This principally involves patients with hypercalcemia, or as an adjunct to a regimen supplying a maximum dose of 1500 mg of elemental calcium from calcium-based phosphate binders. A relative advantage with lanthanum, compared with other phosphate binders, may be a reduced daily tablet burden [96]. Compared with calcium-containing phosphate binders and sevelamer, the relative effects of lanthanum on mortality and vascular calcification have not been evaluated. The principal evaluated outcomes have been the relative effects on bone and biochemical parameters. Bone histology The relative effects on bone histology with lanthanum compared with calciumcontaining phosphate binders have been evaluated in several randomized prospective studies. In general, there were no consistent benefits or adverse effects observed with lanthanum [82,9799]. However, compared with the use of lanthanum, there appears to be a correlation between increased calcium intake via calcium-containing phosphate binders and a relatively increased incidence of both adynamic bone disease and vascular calcification. Biochemical parameters and adverse effects As observed with sevelamer, lanthanum appears to be associated with a lower incidence of hypercalcemia and decreased PTH levels versus calcium-containing phosphate binders. This has been shown in multiple randomized prospective studies that have evaluated the effectiveness of lanthanum [88-90,92,94,95,97,98,100]. In a multicenter European trial, 800 dialysis patients were randomly assigned to lanthanum carbonate (Fosrenol, 750 to 3,000 mg/day) or calcium carbonate (1,500 to 9,000 mg/day), with the dose titrated to achieve serum phosphate levels of less than 5.58 mg/dL (1.80 mmol/L) [92]. At six months, adequate phosphate control was achieved in approximately 65 percent of both groups. However, hypercalcemia was significantly more common with calcium carbonate (20.2 versus 0.4 percent).

Among dialysis patients, no significant clinical adverse effects have yet been reported with lanthanum [88-90,92,94,95,97,98,100]. This was best studied in a report in which the long-term safety of lanthanum carbonate administered for up to two years was evaluated in 1359 hemodialysis patients randomly assigned to lanthanum (maximum dose of 3,000 mg/day) or their pre-study phosphate binder [94]. Average exposure to standard therapy was higher than that with lanthanum (401 and 370 days, respectively). The incidence of adverse effects was similar in both groups, which principally consisted of

gastrointestinal effects. No evidence of hepatic toxicity was observed. Control of phosphorus was similar in both arms, although serum calcium levels were lower with lanthanum. However, the long-term safety of lanthanum, particularly its possible effect on bone and other organs, remains unclear [101,102]. In a short-term animal model, for example, there was progressive accumulation of lanthanum in several organs of animals fed lanthanum for up to 110 days [103]. This was observed particularly in the liver, in which there were nearly 100 fold higher levels measured in uremic rats fed lanthanum versus uremic rats fed a control diet. Lanthanum shares biochemical properties with gadolinium, an agent associated with the development of nephrogenic systemic fibrosis in patients with severe renal dysfunction [104]. However, an association with this disorder and lanthanum has not been reported. Long term clinical studies are currently ongoing. Preliminary evidence suggests the absence of hepatotoxicity with exposure of up to four years [95]. Practically all studies have evaluated the efficacy and safety of lanthanum in dialysis patients. Among individuals with stage 3 and 4 chronic kidney disease, a phase 2 placebo-controlled study found that lanthanum reduced phosphate levels and was well tolerated over an eight-week period [105]. Long-term studies are required to better assess the efficacy and tolerability of this agent. Until more studies and experiences with each agent are available, cost and patient tolerability are the only factors that can be used to determine whether to use sevelamer or lanthanum. Other phosphate binders Aluminum hydroxide was, for many years, the phosphate binder of choice, forming insoluble and nonabsorbable aluminum phosphate precipitates in the intestinal lumen. This regimen, however, created a new problem, aluminum intoxication due to the gradual tissue accumulation of absorbed aluminum. The major manifestations of this problem develop in the bone, skeletal muscle, and the CNS, leading to vitamin D-resistant osteomalacia, a refractory, microcytic anemia, bone and muscle pain, and a dementia. There appears to be no safe dose of aluminum in chronic kidney disease that is also large enough to control the serum phosphate concentration. (See "Aluminum toxicity in end-stage renal disease".) Magnesium-containing antacids (such as magnesium hydroxide) have also generally been avoided in patients with kidney dysfunction. This is because of the risk of hypermagnesemia and the frequent development of diarrhea. Increased and/or extended hemodialysis Standard dialysis is limited in its ability to remove phosphate. Although dialysis membranes are relatively efficient, there is only a slow efflux of phosphate from the large intracellular stores into the extracellular fluid, which is undergoing dialysis [56]. Thus, lengthening dialysis (within standard dialysis regimens) or using larger, high efficiency dialyzers is unlikely to substantially increase phosphate removal. The average standard dialysis removes approximately 900 mg of phosphate. By comparison, extremely long and/or frequent dialysis clears a larger amount of phosphate. (See "Short daily hemodialysis", section on 'Frequent Hemodialysis Network (FHN) Daily Trial'.) In some patients, control of serum phosphate can be achieved without the use of any phosphate binders. For patients with refractory hyperphosphatemia and who are willing to accept this form of dialysis, this form of dialysis may be the best approach. This is discussed separately (see "Technical aspects of nocturnal hemodialysis").

APPROACH TO HYPERPHOSPHATEMIA To optimally manage elevated phosphate levels in patients with CKD, it is important to first assess the presence or absence of other mineral abnormalities, vascular calcifications, and note the administration of concurrent therapies. We therefore obtain phosphate, calcium, and PTH levels initially and then on an ongoing basis, particularly after changes in therapeutic measures. Dialysis patients Among dialysis patients, we aim to maintain serum phosphate levels between 3.5 and 5.5 mg/dL (1.13 and 1.78 mmol/L). Our initial step is to restrict dietary phosphate to 900 mg per day. Among dialysis patients with elevated phosphate levels that are refractory to maintenance dialysis therapy and diet, we recommend the administration of phosphate-binding agents. Our specific approach varies based upon the serum calcium level: Among patients with calcium >9.5 mg/dL (>2.37 mmol/L), we recommend the administration of a non-calcium containing phosphate binder rather than calcium containing binders. Either sevelamer or lanthanum can be given. Among patients with calcium levels between 8.4 and 9.5 mg/dL (2.10 and 2.37 mmol/L), management varies based upon the presence of adynamic bone disease, low PTH levels, and/or vascular calcification: Among those without such comorbidities, we suggest first titrating a calcium-based phosphate binder (up to 1500 mg of elemental calcium from binders alone). Higher doses of calcium may be tolerated in patients not receive vitamin D analogues or who have hypocalcemia while being treated with calcimimetics. If phosphate remains above 5.5 mg/dL (>1.78 mmol/L) despite this strategy, we then add a non-calcium containing phosphate binder. Either sevelamer or lanthanum can be given. Among those with adynamic bone disease, low PTH levels, and/or vascular calcification, a noncalcium based phosphate binder is preferred rather than a calcium-containing phosphate binder. Either sevelamer orlanthanum carbonate can be given in this setting. Among patients with calcium levels <8.4 mg/dL (2.10 mmol/L), we recommend a calcium-based phosphate binder.

Some patients do not achieve the recommended serum phosphate goals with the above regimen due in part to the use of various agents to help control PTH levels. (See 'Goal serum phosphate' above.) Vitamin D analogs may contribute, raising both phosphate and calcium concentrations. A possible alternative is the use of cinacalcet, which acts by a different mechanism and produces significant reductions in PTH, calcium, and phosphate levels. The data supporting these conclusions and our approach to such patients are presented elsewhere. (See "Management of secondary hyperparathyroidism and mineral metabolism abnormalities in dialysis patients", section on 'Calcimimetics'.) More frequent and more intensive dialysis can also lower phosphate levels [19]. Extremely long and/or frequent dialysis, such as that provided by nocturnal hemodialysis, clears a large amount of phosphate. Among patients with refractory hyperphosphatemia, nocturnal hemodialysis is an option among those who are willing to accept this form of dialysis. (See 'Increased and/or extended hemodialysis' above.) We avoid aluminum hydroxide except for short-term therapy (four weeks for one course only) of severe hyperphosphatemia. Many such patients are candidates for parathyroidectomy. (See "Indications for parathyroidectomy in end-stage renal disease".)

Stage 3 to 5 CKD not yet on dialysis Our initial step in the management of hyperphosphatemia in patients with stage 3 to 5 CKD not yet on dialysis is the restriction of dietary phosphate to 900 mg/day. Among patients with serum phosphate levels greater than target levels despite dietary phosphorus restriction after one month, we suggest the administration of phosphate binders. The two principal options for phosphate binder therapy are calcium and non-calcium based phosphate binders. Among patients with calcium >9.5 mg/dL (>2.37 mmol/L), we recommend the administration of a non-calcium containing phosphate binder rather than calcium containing binders. Either sevelamer or lanthanum can be given. Since hypercalcemia is unusual in CKD stage 3 to 5, evaluation for secondary non-PTH mediated causes should be undertaken if PTH values are not significantly elevated and patients are not receiving active vitamin D therapy. Primary hyperparathyroidism can occur in this setting, but distinguishing this disorder from secondary hyperparathyroidism can be difficult. Primary hyperparathyroidism might be suspected in hypercalcemic patients with stage 3 to 4 CKD and a low serum phosphate level in the absence of phosphate binders. Among patients with calcium levels between 8.4 and 9.5 mg/dL (2.10 and 2.37 mmol/L), management varies based upon the presence of adynamic bone disease, low PTH levels, and/or vascular calcification: Among those without such comorbidities, we suggest a calcium-based phosphate binder. The dose of calcium-containing phosphate binders is generally increased until the serum phosphate falls to normal values or hypercalcemia ensues. The safe dose of calcium is not known in stage 3 and 4 CKD but likely exceeds the 1500 mg/day limit in end stage renal disease patients suggested by the K/DOQI work group. Among those with adynamic bone disease, low PTH levels, and/or vascular calcification, we suggest a non-calcium based phosphate binder rather than a calcium-containing phosphate binder. Either sevelamer orlanthanum carbonate can be given in this setting. Among patients with calcium levels <8.4 mg/dL (2.10 mmol/L), we recommend a calcium-based phosphate binder.

Among all patients with CKD, we avoid aluminum hydroxide except for short-term therapy (four weeks for one course only) of severe hyperphosphatemia. (See "Aluminum toxicity in end-stage renal disease".) Approach to hypercalcemia The combination of hypercalcemia (calcium >10.2 mg/dL corrected for serum albumin) and persistent hyperphosphatemia may be a particular problem with calcium therapy and active vitamin D analog administration, possibly leading to extraskeletal calcium phosphate deposition. In this setting, we suggest that the dose of calcium-based phosphate binders should be decreased or therapy discontinued, and/or therapy should be switched to sevelamer to control phosphate [19]. In addition, the dose of active vitamin D sterols should be lowered or therapy should be discontinued until calcium levels return to 8.4 to 9.5 mg/dL (2.10 to 2.37 mmol/L). NOVEL THERAPIES Given that the current approach to management of hyperphosphatemia is not optimal, a number of alternative therapies are undergoing evaluation. Nicotinamide, a metabolite of nicotinic acid (niacin, vitamin B3), inhibits the Na/Pi co-transport system in the gastrointestinal tract and kidneys and may be effective in lowering phosphate levels in dialysis patients by reducing gastrointestinal tract phosphate absorption:

In a pilot study of 20 dialysis patients, Niaspan (prolonged-release nicotinic acid) was administered in slowly increasing doses, with 17 patients eventually tolerating >1000 mg/day [106]. Among such patients, treatment for 12 weeks significantly lowered serum phosphate values (7.2 to 5.9 mg/dL) and increased serum HDL cholesterol levels. A randomized placebo-controlled cross-over trial of 33 patients found that niacinamide (titrated from 500 to 1500 mg/day) significantly lowered phosphate levels (6.26 to 5.47 mg/dL) [107]. Adverse effects were similar with both groups.

Further study is required to better understand the efficacy and safety of these and related agents in this setting. CITRATE AND ALUMINUM Calcium citrate has also been used as a phosphate binder. This preparation, however, should be AVOIDED in patients with renal failure, since citrate can markedly increase intestinal aluminum absorption [108,109] and possibly induce aluminum neurotoxicity or the rapid onset of symptomatic osteomalacia [110]. Citrate appears to enhance aluminum absorption both by keeping aluminum soluble (via the formation of aluminum citrate) in the intestinal lumen and by complexing with luminal calcium; the ensuing decrease in free calcium then leads to increased permeability of the tight junctions between the cells, a change that can markedly enhance passive aluminum absorption (figure 2) [108,109]. In comparison, acetate does not enhance aluminum absorption and therefore can be safely given, even with the concurrent administration of aluminum hydroxide [109]. Similar considerations apply to the administration of aluminum-containing antacids with sodium citrate (Bicitra), which has been used to treat uremic acidosis. Sodium bicarbonate is preferred in advanced kidney disease even if the patient is not being treated with aluminum, since many foods and medications contain some aluminum (such as buffered aspirin and sucralfate) [108]. However, if such items are assiduously avoided, sodium citrate can be used in some patients unable to tolerate sodium bicarbonate, since it does not produce the bloating associated with bicarbonate therapy [111]. These considerations related to aluminum are also likely to apply to the novel phosphate binder, ferric citrate. SUMMARY AND RECOMMENDATIONS A tendency toward phosphate retention begins early in renal disease. However, phosphate balance and a normal serum phosphate concentration are generally maintained (at the price of elevated PTH and FGF23 levels) until the glomerular filtration rate (GFR) falls below 25 to 40 mL/min. At this relatively late stage, dietary phosphate restriction may still minimize positive phosphate balance and may reduce the serum concentration of both phosphate and PTH, although not usually to normal. As a result, oral phosphate binders are frequently required. (See 'Background' above.) Both K/DOQI and KDIGO have published guidelines concerning the management of hyperphosphatemia in patients with chronic kidney disease (CKD). (See 'Guideline target levels' above.) Restricting dietary phosphate intake and the administration of phosphate binders are the two principal modalities used to reverse the hyperphosphatemia of CKD. To optimally manage elevated phosphate levels in all patients with CKD, it is important to first assess the presence or absence of other mineral abnormalities, vascular calcifications, and note the administration of concurrent therapies, particularly vitamin D and vitamin D analogs. (See'Treatment options' above.)

Dialysis We suggest maintaining serum phosphate levels between 3.5 and 5.5 mg/dL (1.13 and 1.78 mmol/L) among dialysis patients (Grade 2C). (See 'Goal serum phosphate' above.) Among dialysis patients with phosphate levels above target levels, we first suggest restricting dietary phosphate (Grade 2C). Our initial step is to restrict dietary phosphate to 900 mg per day. The patient should be encouraged to avoid unnecessary dietary phosphate (as in phosphoruscontaining food additives, dairy products, certain vegetables, many processed foods, and colas) while maintaining the intake of high biologic value sources of protein. Among dialysis patients with elevated phosphate levels that are refractory to maintenance dialysis therapy and diet, we suggest the administration of phosphate-binding agents (Grade 2B). Our approach varies based upon calcium levels and the presence of comorbid conditions. (See 'Dialysis patients' above.) Despite dietary restriction, optimal doses of phosphate binders, and conventional dialysis, some dialysis patients do not achieve the recommended serum phosphate goals. This may be due in part to the use of various agents to help control parathyroid hormone levels, particularly vitamin D analogs, and well as other issues. The approach in these patients is discussed in detail separately. (See "Management of secondary hyperparathyroidism and mineral metabolism abnormalities in dialysis patients" and 'Dialysis patients' above.) Among dialysis patients with persistent hyperphosphatemia, we suggest increasing phosphate removal via hemodialysis (Grade 2C). Among patients with refractory hyperphosphatemia, nocturnal hemodialysis is an option among those who are willing to accept this form of dialysis. (See 'Increased and/or extended hemodialysis' above.) Among all patients with CKD, we recommend NOT administering aluminum hydroxide except for short-term therapy (four weeks for one course only) of severe hyperphosphatemia (Grade 1B). (See 'Other phosphate binders' above.)

Stage 3 to 5 CKD not yet on dialysis We suggest maintaining serum phosphate levels in the normal range among patients with stage 3 to CKD not yet on dialysis (Grade 2C). Among patients with stage 3 to 5 CKD not yet on dialysis with hyperphosphatemia, we first suggest restricting dietary phosphate (Grade 2C). Our initial step is to restrict dietary phosphate to 900 mg per day. Among patients with serum phosphate levels greater than target levels despite dietary phosphorus restriction after 4 weeks, we suggest the administration of phosphate binders (Grade 2C). Our specific approach varies based upon calcium levels and the presence of comorbid conditions. (See 'Stage 3 to 5 CKD not yet on dialysis' above.) Among all patients with CKD, we recommend NOT administering aluminum hydroxide except for short-term therapy (four weeks for one course only) of severe hyperphosphatemia ( Grade 1B). (See 'Other phosphate binders' above.) Use of UpToDate is subject to the Subscription and License Agreement.

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Patient survival and maintenance dialysis Authors Lionel U Mailloux, MD, FACP William L Henrich, MD, MACP Section Editor Jeffrey S Berns, MD Deputy Editor Alice M Sheridan, MD Disclosures All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: May 2012. | This topic last updated: Apr 13, 2012. OVERVIEW Although maintenance dialysis prevents death from uremia, patient survival remains an important issue. Once renal replacement therapy is initiated, the range of the expected remaining life span in the United States Renal Data System report was approximately 8 years (varies with race) for dialysis patients aged 40 to 44, and approximately 4.5 years for those 60 to 64 years of age [1]. These values in older patients are only slightly better than those in patients with lung cancer and are much worse than the general population (which is 30 to 40 years for those aged 40 to 44, and 17 to 22 years for individuals aged 60 to 64). Despite this, some evidence suggests that mortality rates among incident dialysis patients have decreased over the last few years, suggesting that improvements in therapy may provide beneficial results [1]. It is well established that inadequate dialysis is a contributor to lower overall survival. This has important implications since more intensive dialysis, particularly above a certain threshold value, may improve survival, as possibly with nocturnal hemodialysis. Additional factors associated with the dialysis procedure may also correlate with decreased survival. As examples: An increased length of time on dialysis alone is associated with an enhanced risk of death (eg, vintage), with each year of dialysis treatment increasing the risk of death by approximately 6 percent [2]. Potassium levels less than 4.0 or greater than 5.6 meq/L are associated with increased mortality in hemodialysis patients, compared with serum levels between 4.6 and 5.3 meq/L [3]. In the United States, some, but not all, studies have reported that mortality may be lower among dialysis patients being treated in not-for-profit facilities compared to those undergoing dialysis in for-profit facilities [4-8].

A review of those factors associated with mortality among dialysis patients, with an emphasis upon those characteristics related to dialysis itself, will be presented here.

CAUSES OF DEATH Before discussing the different factors underlying mortality in dialysis patients, it is helpful to briefly review the major causes of death in this patient population: cardiovascular disease, infection, and withdrawal from dialysis [1,9-11]. Cardiovascular disease accounts for approximately 50 percent of deaths. While a decline in cardiovascular deaths has occurred in the general population, a similar trend has not been observed in dialysis patients [1]. This discrepancy is in part due to the demographics of patients about to be started on dialysis: about 40 percent are diabetic; the average age is now approximately 60 years and about 20 percent are over 75 years; and many patients have underlying cardiac disease. (See 'Risk factors not related to dialysis' below and "Evaluation of sudden cardiac arrest and sudden cardiac death in dialysis patients".) Infections, which are the second most common cause of death, are usually due to common organisms (such as Staphylococcus aureus) and are frequently related to the hemodialysis vascular access [12]. (See"Nonthrombotic complications of chronic hemodialysis arteriovenous vascular access" and "Tunneled, cuffed hemodialysis catheter-related bacteremia" and "Nonaccess related infections in chronic dialysis patients".) Withdrawal from dialysis accounts for approximately 15 to 25 percent of patient deaths. (See "Withdrawal from and withholding of dialysis".)

RISK FACTORS NOT RELATED TO DIALYSIS A large number of risk factors for decreased survival that are unrelated to the dialysis procedure have been identified, making prognostic evaluation of a single patient more accurate. Comorbid conditions The presence of comorbid disease is an increasingly common problem, being much more prevalent in new patients started on dialysis today than previously [1,11,13-19]. As noted in the 2007 United States Renal Data System Annual Report, diabetes mellitus was the leading cause of end-stage renal disease in those initiating hemodialysis (44 percent) [1]. Extended survival at ten years appears to be less likely for diabetic as compared to nondiabetic patients (4 versus 11 to 14 percent). Heart disease is also very common in the dialysis population. Approximately 80 percent of all patients enrolled in the HEMO study were noted to have some form of heart disease, with nearly 40 percent having ischemic heart disease [20]. It has also been estimated that only 27 percent of patients about to enter a dialysis regimen have a normal echocardiogram, while 19 percent already have severe left ventricular hypertrophy [21,22]. In addition, as many as 75 percent of the total end-stage renal disease population have at least a 50 percent narrowing of at least one coronary artery. Even patients with mild to moderate chronic renal failure are at markedly increased cardiovascular risk, with chronic renal disease alone currently considered a coronary heart disease risk equivalent. (See "Risk factors and epidemiology of coronary artery disease in end-stage renal disease (dialysis)" and "Chronic kidney disease and coronary heart disease".) In addition to antecedent coronary artery disease, additional factors common in dialysis patients may promote the development of coronary disease and enhanced cardiovascular mortality: Hypertension, which is present in approximately 80 percent of patients at the onset of dialysis and, with effective fluid control, about 25 to 30 percent at the end of the first year. (See "Hypertension in dialysis patients".) Metabolic abnormalities, particularly hyperphosphatemia, an elevated calcium phosphorous product, and increased parathyroid hormone levels. These extremely common abnormalities are increasingly recognized as possibly important unique risk factors for dialysis patients. (See "Risk

factors and epidemiology of coronary artery disease in end-stage renal disease (dialysis)" and "Vascular calcification in chronic kidney disease" and'Disorders of mineral metabolism' below.) Left ventricular hypertrophy, due in part to hypertension, chronic anemia, and perhaps decreased renal function. (See "Myocardial dysfunction in end-stage renal disease".) Hyperlipidemia. (See "Lipid abnormalities in nephrotic syndrome" and "Chronic kidney disease and coronary heart disease".) Diabetes mellitus, which is a major risk factor for coronary artery disease (in patients with and without renal failure) and is common among patients requiring dialysis. (See "Prevalence of and risk factors for coronary heart disease in diabetes mellitus".)

The concurrent presence of other life-threatening conditions will also affect overall survival [17,19,23-25]. In an extensive analysis of DOPPS data, 17 comorbid conditions accounted for nearly all of the total variance that predicted survival among hemodialysis patients [19]. Underlying renal disease Five year survival among dialysis patients is best with chronic glomerular diseases and polycystic kidney disease, intermediate with hypertension-induced renal disease, and worst with diabetic nephropathy [1,26]; five year survival of the patient with diabetic nephropathy is only 20 percent [1,26]. Age Survival declines with increasing age, with patients under age 45 doing best [1,13,26,27]. Elderly patients with renal vascular disease appear to have the worst prognosis, with such patients having 5 and 10 year survival rates of only approximately 15 and 5 percent, respectively. In one prospective study from Canada, these elderly patients were frequently not offered dialysis as possible therapy [28,29]. Country Survival among dialysis patients has been substantially lower in the United States than in Europe and Japan [13,17,27,30,31]. Some evidence suggests that this is due in part to general differences in mortality (particularly that due to cardiovascular disease) among the general population in various countries [32,33]. In one European study that adjusted for age, gender, and diabetes, for example, approximately 25 percent of the difference in mortality among dialysis patients between the Northern and Southern areas of Europe could be attributed to differences in mortality in the general population of these areas [33]. Differences in mortality in various countries and geographic regions therefore cannot be entirely explained by differences among patients that are unrelated to dialysis itself. These include variations among comorbid conditions (with increased incidence of diabetes, psychiatric diseases, and cardiovascular disease [heart failure and peripheral vascular disease] in the United States), patient age (which tends to be higher in the United States), racial or genetic differences, other demographic factors, or differences in transplantation rate (low rate in Japan) [17,31]. Other factors that may contribute to the differences in survival include variations in underlying renal disease (such as increased incidence of IgA nephropathy in Japan) and differences in thresholds for accepting patients for dialysis [31]. A decline in the relative mortality rates in the United States may reflect the consistent widespread improvement in the overall quality of the national dialysis prescription [1]. (See 'Improved survival with more intensive dialysis' below.) Race As a group, African-Americans and Asian-Americans have a lower mortality rate than whites [1,34-36]. In one study, the survival rates of black, white, and other races at five years were 35, 25, and 32 percent, respectively. Similar relative results were observed in a single center study, which reported 47 and 36 percent survival rates at five years for black and white patients, respectively [37]. In initial studies,

this survival advantage appeared to persist after adjustment for patient characteristics, comorbidities, and laboratory abnormalities [34,38]. However in subsequent studies, the survival advantage was markedly attenuated or lost in multivariate analyses that adjusted for other patient variables [39,40]. As an example, in an analysis of outcomes of 1,330,007 patients identified in the United States Renal Data System, although the survival of black patients as a group was better compared to white patients, this advantage was modified by age [40]. Whereas a survival advantage persisted for black patients over 50, black patients younger than 50 had higher mortality compared to white counterparts, particularly when transplantation was factored in as a competing risk. The underlying reasons for increased survival among older blacks are unclear. One possibility is that mortality among blacks with predialysis chronic kidney disease (CKD) is much higher than among whites with predialysis kidney disease, resulting in the selection of relatively "healthier" patients who eventually require dialysis. This, in turn, would result in an apparent survival advantage among blacks with ESRD. Support for this hypothesis was provided by a study of participants of the Third National Health and Nutrition Examination Survey in which a higher risk for death in early stages of CKD was observed among blacks [41]. Another possibility is that black dialysis patients may have a relatively greater use of activated vitamin D therapy, a modality indirectly linked with improved survival [42]. Psychosocial factors Psychosocial factors also appear to significantly affect mortality, independent of the presence of other comorbid conditions. Increased levels of social support, enhanced behavioral compliance, and positive perceptions of the effects of illness are all associated with a decreased risk of dying [43]. Their effect on mortality appears to be equivalent to those of medical risk factors. (See "Psychiatric illness in dialysis patients".) Nutrition There is greater medical risk and increased mortality in undernourished patients, particularly those with hypoalbuminemia. Although these observations have primarily been made in patients on maintenance hemodialysis and are related to the dialysis dose (see 'Malnutrition' below), the presence of malnutrition prior to the initiation of dialysis is strongly predictive of increased mortality with the onset of dialysis [44]. Others The effect on mortality of a number of additional patient characteristics has been assessed. Inflammation Dialysis patients with evidence of an ongoing inflammatory state have an enhanced mortality. This is discussed in detail separately. (See "Inflammation in renal insufficiency" and "C-reactive protein in cardiovascular disease".) Serum cardiac enzymes Elevations of cardiac troponin T among asymptomatic chronic dialysis patients are associated with decreased survival. The exact source of cTnT in this setting and the reasons for the correlation between elevated levels and a poor prognosis are unknown. This is discussed in detail separately. (See "Serum cardiac enzymes in patients with renal failure" and "Clinical manifestations and diagnosis of coronary heart disease in end-stage renal disease (dialysis)".) Sleep disorder The presence of a sleep disorder enhances the risk of death in patients without renal failure. (See "Overview of obstructive sleep apnea in adults".) A paucity of data exists concerning their effect upon survival in patients undergoing maintenance dialysis. Limited observational evidence suggests that the presence of periodic limb movements in sleep, the total number of arousals, and a decline in sleep quality during the first year on dialysis may strongly and independently correlate with near-term mortality [45,46].

Predialysis care An increasing number of studies, although all observational and retrospective, suggest that patients referred late to a nephrologist for predialysis medical care, compared with those referred early in the disease course, have an enhanced mortality risk once dialysis is initiated. (See "Overview of the management of chronic kidney disease in adults" and "Late referral to nephrologists of patients with chronic kidney disease".) There is marked variability in the quality of predialysis care based upon the medical center and geographic area. In the United States, there also appears to be geographic clustering of centers with increased mortality and less than adequate predialysis care [47]. Hemoglobin levels A discussion of the role of low hemoglobin levels in association with mortality among patients with renal disease is discussed in detail separately. (See "Anemia of chronic kidney disease: Target hemoglobin/hematocrit for patients treated with erythropoietic agents".) There is also some evidence that variability in hemoglobin levels increases mortality in ESRD [4850]. This was shown in a retrospective cohort study of 34,963 hemodialysis patients in which survival analysis found that each 1 g/dL increase in hemoglobin variability (defined by the residual standard deviation) was associated with a 33 percent increase in the death rate [48]. Fractures Patients with ESRD who fall and have hip fractures have an increased risk of death, which is higher than that observed in those without fracture [51,52]. This was shown in a study from the United States Renal Systems Database in which dialysis patients with a hip fracture had a two-fold higher risk of death than those matched controls with a fracture [52]. Risk factors for falling include older age, diabetes, high number of prescribed oral drugs, antidepressant use, and inability to walk without significant help [51]. Frailty Frailty is defined by the presence of three or more of the following: weight loss, muscle weakness, fatigue or exhaustion, low physical activity, and slow gait. Independent of age, increased mortality is noted among frail dialysis patients. As an example, based upon data from 2275 adults from the dialysis Wave 2 study, a higher risk of death was noted among those defined as frail (adjusted hazard ratio 2.24, 95% CI 1.60-3.15) [53]. Noncompliance Noncompliance, which can be defined in part by regularly skipping hemodialysis sessions and poor adherence to dietary restrictions, is associated with increased mortality [54]. In a study of 739 patients of whom 67 were classified as skippers (absent >3 percent of treatments), increased mortality was associated with skipping (hazard ratio 1.69, 95% CI, 1.23-2.3) [54]. Additional features A large number of additional patient characteristics and/or agents are reportedly associated with mortality. These include periodontal disease, rosiglitazone, warfarin, clopidogrel, and aspirin, and high blood lead levels [55-58].

The remainder of this topic review will focus upon those factors largely unique to the dialysis procedure that affect patient mortality. ADEQUACY OF DIALYSIS The higher mortality rate in the United States was thought to be related at least in part to inadequate dialysis. The weekly dialysis times declined progressively in the United States from 25 to 40 hours in the 1960s to 12 to 15 hours in the 1970s and 1980s to as low as seven to eight hours in the 1990s [59,60]. Studies in both Germany and the United States have documented the relationship between shorter dialysis time and poorer outcome [61,62]. Patients dialyzed fewer than 3.5 hours three times per week

have approximately twice the mortality risk compared to patients dialyzed four or more hours three times per week [61]. The group from Tassin, France has reported one of the best dialysis survival estimates of any program or registry, with a 15-year survival rate of 65 percent in 445 patients followed from 1970 through 1990 (figure 1) [27]. These patients, who were dialyzed very intensively (Kt/V of 1.67), also had a high incidence of full rehabilitation and almost all patients were rendered normotensive on no antihypertensive medications. Similar benefits with longer times on dialysis have been observed among patients undergoing nocturnal hemodialysis. (See "Technical aspects of nocturnal hemodialysis".) Historic overview of survival and Kt/V The utilization of urea kinetic modeling and the Kt/V index was in part responsible for the decreasing hemodialysis time and concomitant increase in mortality in the United States. Urea kinetic modeling became widely applied after the results of the National Cooperative Dialysis Study (NCDS) were published [63-65]. The NCDS found that a Kt/V urea above 0.9 with thrice weekly treatment provided an "adequate" dialysis prescription in that the patient failure rate of 13 percent was substantially below that in patients with a lower Kt/V. (See "Kt/V and the adequacy of hemodialysis".) Although the NCDS included no diabetic patients or those with other important comorbid conditions, a Kt/V of 1.0 was widely accepted as representing adequate dialysis. Shorter dialysis times were permitted as long as the goal Kt/V was attained. However, this goal was quite arbitrary, since no attempt was made in the NCDS to determine whether a higher Kt/V might be associated with further clinical, biochemical, or rehabilitative improvement. Improved survival with more intensive dialysis Subsequent observational data suggested that a higher Kt/V was beneficial. Excellent survival rates have been reported in Tassin, France (Kt/V >1.6) and Minnesota, United States (Kt/V >1.3) where patients, even those in high-risk groups, were more intensively dialyzed [27,66]. Urea kinetic modeling was utilized, but attention was paid to all the details involved in delivering a more optimal dialysis prescription. This improvement in survival occurred despite a striking increase in comorbidity, which itself would have decreased survival [66]. Similar findings were reported in a retrospective analysis of 13,473 patients in which patient outcome was compared to dialysis intensity. Patient survival was significantly reduced at urea reduction ratios below 60 percent (Kt/V below 1.20) [67]. A definition of the urea reduction ratio can be found elsewhere. (See "Kt/V and the adequacy of hemodialysis".) A number of observational studies were compatible with the hypothesis that more intensive dialysis leads to improved survival. In one study, increasing the mean Kt/V from 0.82 (pre-1988) to 1.33 led to a reduction in the gross mortality rate from 22.8 down to 9.1 percent per year [68]. This was associated with increases in protein catabolic rate from 0.83 to 1.0 (an index of protein intake (see "Protein catabolic rate in maintenance dialysis")) and in plasma albumin concentration from 3.5 to 3.9 g/dL (35 to 39 g/L). Thus, enhanced nutrition probably contributed to the improvement in survival (see below). However, increasing the degree of dialysis was associated with the use of biocompatible hemodialysis membranes; it is therefore possible that the observed benefits were due at least in part to avoidance of bioincompatible membranes (see 'Hemodialysis membranes' below). In another report, increasing the mean Kt/V from 1.18 (pre-1989) to 1.46 (and the urea reduction ratio from 61 to 70 percent) led to a reduction in the gross mortality rate from 22.5 down to 18.1 percent per year [69]. This improvement was achieved with standard cellulosic bioincompatible membranes.

A national sample in the United States suggested a 7 percent reduction in mortality for each 0.1 unit increase in Kt/V (figure 2) [70]. Although no statistically significant benefit was noted above a Kt/V of 1.3, a projected trend favoring an increased benefit with increasing dialysis was observed above this dialysis level.

A difficulty concerning the optimal dialysis dose was that some [71,72], but not all [73], studies observed an increased relative risk of death among patients with extremely high values for Kt/V (greater than 1.6) or the urea reduction ratio (URR between 75 and 79 percent). Since these values reflect increased urea clearance and/or an extremely low body volume (which may represent poor nutrition), the increased death rate may have been due to the effects of marked malnutrition. Support for this hypothesis comes from a study that evaluated the correlation between mortality, dialysis dose, and body volume in over 3000 dialysis patients [72]. Consistent with previous reports, patients with a Kt/V or URR value in the highest (or fifth) quintile had an increased relative risk of death (19 percent greater than those in the third quintile). However, a higher Kt alone was not associated with an increased relative risk of death, as there was a 2 percent decrease in mortality risk per liter increase in clearance. These observations, in combination with the finding that patients in the fifth quintile suffered from more severe protein-calorie malnutrition, suggest that the increased mortality associated with very high Kt/V or URR values may reflect poor nutrition. Such findings support the use of alternative measures of dialysis adequacy, such as the Kt alone. (See "Kt/V and the adequacy of hemodialysis".) Based upon these observational studies, the optimal level of hemodialysis and the best measure of hemodialysis adequacy were therefore undefined. Statistical analysis of the previous studies as well as others by Gotch et al suggested that faulty methodology may have supported the conclusion that increasing dialysis equals increasing survival [74]. The above studies were also retrospective in design and ignored the wide variation in dialysis delivery. HEMO study In an attempt to overcome these difficulties concerning survival and dialysis dose (as well as survival and low and high flux dialysis membranes), a large prospective clinical trial, called the Hemodialysis (HEMO) Study, was performed [75]. In this study, 1846 patients were randomly assigned to a standard or high dose of dialysis and a low- or high-flux dialyzer. The standard dose goal was an equilibrated Kt/V of 1.05, which is equivalent to a urea reduction ratio of 65 percent or a single-pool Kt/V of 1.25. The high dose goal was an equilibrated Kt/V of 1.45, which is the same as a ratio of 75 percent or a single-pool Kt/V of 1.65. The primary outcome was death from any cause, while the main secondary outcomes were the rate of all hospitalizations (but excluding those related to access), and the composite outcomes of the first hospitalization for a cardiac problem or death from any cause, the first hospitalization for an infectious cause or death, and the first decline of greater than 15 percent of the serum albumin from baseline value or death. The following results concerning dialysis dose were reported at a mean follow-up of 4.5 years: Impressive separation was obtained. The standard dose group received an equilibrated Kt/V of 1.16, a single-pool Kt/V of 1.32, and a urea reduction ratio of 66.3 percent, while the high dose group had values of 1.53, 1.71, and 75.2 percent, respectively. The risk of death from any cause, the primary outcome, was the same in the high and standard dose groups (RR of 0.96 for high versus standard dose, CI of 0.84-1.10). The risk of the main secondary outcomes (as previously delineated) was also the same for both dialysis doses.

Subgroup analysis revealed a significant survival benefit for women receiving a high dialysis dose (19 percent lower risk of death than women in the standard dose group). However, men receiving high dose dialysis had a 16 percent higher risk of death than those receiving standard dose dialysis.

Subsequent analysis found that differences in dialysis dose also had no effect upon the incidence of infection-related deaths [76]. Thus, hemodialysis patients do not appear to derive a major benefit from a higher than standard dialysis dose, as recommended by the K/DOQI guidelines. (See "Kt/V and the adequacy of hemodialysis" and 'Summary and recommendations' below.) Some data suggest that mortality among patients in dialysis centers with the highest percentage of patients who exceed current K/DOQI guidelines (urea reduction ratios of greater than 65 percent) is lower than those with fewer patients who achieve these ratios. As an example, based upon data from 2858 United States dialysis facilities from 1999 to 2002, those centers in the lowest quintile for the percentage of patients with higher than recommended urea reduction ratios had 22 percent higher mortality rates than those in the highest quintile [77]. Peritoneal dialysis Among patients treated with PD, a similar correlation between the degree of solute clearance (measured weekly either by Kt/V or the creatinine clearance) and survival was also postulated to exist. This hypothesis was supported by the results of a prospective, cohort, multicenter study in Canada and the United States (CANUSA) which evaluated the relationship of the adequacy of dialysis and nutritional status to mortality, morbidity, and technique failure. However, survival in this study was related to residual renal function (which changed over time) and not to peritoneal clearance alone (which did not change). Confirmation that an increase in peritoneal clearance alone (beyond a minimum threshold value) is not a principle factor underlying survival was provided by the ADEMEX trial. Instead, subsequent analysis of this trial found that measures of healthrelated quality of life significantly predicted patient survival [78]. (See "Adequacy of peritoneal dialysis".) HEMODIALYSIS MEMBRANES Survival, dialysis adequacy, and the biocompatibility of hemodialysis membrane may all be closely interrelated. This is discussed separately. (See "Clinical consequences of hemodialysis membrane biocompatibility".) Differences in survival may also be due to variations in the ability of hemodialysis membranes to remove molecules larger than urea, the so-called middle molecules. High flux membranes are better able to remove such substances compared to that observed with low flux membranes. Whether survival differs upon exposure to high and low flux membranes was also evaluated in the HEMO Study, in which nearly 2000 patients were randomly assigned to a standard or high dose of dialysis and a low- or high-flux dialyzer (based on clearance of beta-2-microglobulin) [75]. The primary outcome was death from any cause, while the main secondary outcomes were the rate of all hospitalizations (but excluding those related to access), and the composite outcomes of the first hospitalization for a cardiac problem or death from any cause, the first hospitalization for an infectious cause or death, and the first decline of greater than 15 percent of the serum albumin from baseline value or death. The results and discussion relating to survival and dialysis dose can be found elsewhere in this topic. (See 'HEMO study' above.) With respect to dialysis membranes, the following results were reported at a mean follow-up of 4.5 years: Impressive separation was obtained as the low and high flux groups had clearances of beta-2microglobulin of 3 and 34 mL/min, respectively.

The risk of death from any cause, the primary outcome, was the same in the high and low flux groups (RR of 0.92). The risk of the main secondary outcomes (as previously delineated) was also the same for both flux groups. In the high flux group, there were significant reductions, compared with the low flux group, in the risk of death from cardiac causes and the combined outcome of first hospitalizations or death from a cardiac cause [20]. However, as previously mentioned, total mortality was the same in both flux groups. Subgroup analysis revealed a significant survival benefit for patients with more than 3.7 years of dialysis receiving high flux dialysis (32 percent lower risk than the low flux group). However, men receiving high dose dialysis had a 16 percent higher risk of death than those receiving standard dose dialysis, and the strength of the interaction between flux and years of dialysis was weakened when years of dialysis was treated as a continuous variable.

Subsequent analysis found that differences in dialysis membrane also had no effect upon the incidence of infection-related deaths [76]. Thus, as noted in the HEMO study, survival was the same in patients chronically dialyzed with either high or low flux dialysis membranes. This was also found in the Membrane Permeability Outcome (MPO) study, in which 738 incident hemodialysis patients, separated by serum albumin levels 4 and >4 g/dL, were randomly assigned to high or low flux dialysis membranes [79]. Overall, there was no difference in survival with either membrane, although there was a nonsignificant trend for increased survival with high flux (RR 0.76, 95% 0.56-1.04). Among the subgroup of patients with serum albumin 4 g/dL, survival was significantly higher in the high flux group (HR 0.63, 95% CI 0.45-0.90). This is less likely to be a spurious finding given that this was a prespecified subgroup [80]; nevertheless, this result was not observed in the HEMO trial and should be confirmed by additional studies. Although not directly applicable to the chronic setting, the relative risk for mortality (and recovery of renal function) also appears to be the same with both high and low flux membranes among those with acute renal failure [81]. HEMODIALYSIS SESSION LENGTH The effect of hemodialysis session length on mortality independent of conventional markers of dialysis adequacy is unclear among patients undergoing standard three times per week dialysis therapy. Some observational studies of large databases suggest that increased session length improves survival [82,83]: Based upon data from the Dialysis Outcomes and Practice Patterns Study of 22,000 hemodialysis patients, treatment time that was greater than 240 minutes per session was significantly associated with decreased risk of mortality (RR of 0.81) [83]. In addition, a seven percent lower relative risk of death was observed with each additional one-half hour time on dialysis. In a study of 6593 patients in the Australian/New Zealand registry, the lowest mortality risk was observed in patients with hemodialysis session lengths of 4.5 to 4.9 hours [82].

A discussion of the effect of prolonged dialysis session length on outcomes, including survival, with nocturnal hemodialysis is presented separately. (See "Technical aspects of nocturnal hemodialysis".) CONTROL OF FLUID BALANCE AND HYPERTENSION Adequate fluid removal depends upon the technical ability to remove excess fluid, the patient's tolerance to the fluid removal rate, and the patient's adherence to fluid-intake restrictions. Shorter dialysis necessitates more rapid fluid removal, which is

more likely to induce episodes of hypotension that are treated with fluid administration. The net effect is that "dry weight" is never achieved, leading to persistent volume expansion, hypertension, and possible deterioration in left ventricular function. These complications may contribute to the high cardiac mortality in dialysis patients. (See "Hemodynamic instability during hemodialysis: Overview".) Dry weight has been defined as not merely the absence of edema, but the minimal body sodium content and volume of body water that can be tolerated without inducing hypotension. Gradual fluid removal with longer dialysis permits a greater degree of total fluid loss and more likely attainment of dry weight. As an example, slow dialysis, such as with nocturnal hemodialysis, commonly results in normotensive patients who do not require the use of antihypertensive medications. The ability to discontinue drug therapy may be an important component of this regimen, since it further minimizes the risk of hypotension as the excess fluid is removed. The ability to remove adequate fluid also depends upon the ability of the patient to adhere to fluid-intake restrictions. Some data suggest that psychologic interventions may improve the ability to adhere to such restrictions, although the quality of the medical literature is generally poor [84]. Inadequate total body fluid removal may increase the overall risk of death. In one study of over 3,000 hemodialysis patients, the relative risk of death was correlated with ultrafiltration status [85]. In this study, soft tissue hydration was determined via bioelectric impedance analysis and impedance vector length; a shorter vector length, which was associated with inadequate ultrafiltration, was associated with a increased relative risk of death. A similar correlation between survival and ultrafiltration was observed in a study from the Netherlands [86]. Better volume management via intradialytic blood volume monitoring may improve outcomes, including mortality. This was evaluated in a six month study in which 443 patients were randomly assigned to an intradialytic blood volume monitoring device and conventional monitoring [87]. Mortality and non-access related hospitalizations were significantly higher with the device; this result may have been due in part to the atypically low hospitalization and mortality rates for the conventionally monitored group. INTERDIALYTIC INTERVAL Long interdialytic intervals that occur over a weekend among patients who are dialyzed on a three times weekly schedule likely contribute to mortality and morbidity. This was suggested by a retrospective analysis of 32,065 hemodialysis patients who participated in the End Stage Renal Disease Clinical Performance Measures Project [88]. This analysis demonstrated an increase in all-cause mortality on the day following the long interval compared to other days (22.1 versus 18.0 deaths per 100 person-years). After the long interval there was also an increase in the following (per 100 patientyears): Mortality from cardiac causes (10 versus 7.5) Mortality from infection (2.5 versus 2.1) Mortality from cardiac arrest (1.3 versus 1.0) Mortality from myocardial infarction (6.3 versus 4.4) Admissions for myocardial infarction (6.3 versus 3.9) Congestive heart failure (29.9 versus 16.9) Stroke (4.7 versus 3.1) Dysrhythmia (20.9 versus 11.0) Any cardiovascular event (44.2 versus 19.7)

The authors were unable to determine whether adverse events occurred before, during or after the first weekly dialysis sessions.

These data suggest that the two-day interval is a time of increased risk for cardiovascular and noncardiovascular mortality and morbidity for patients who are on a three times weekly dialysis schedule. Potential reasons for the increased risk were not addressed in this study but fluid accumulation, hemodynamic changes, and electrolyte abnormalities or changes may contribute at least to the cardiovascular events. MALNUTRITION Studies have demonstrated greater medical risk and increased mortality in undernourished and small dialysis patients (as noted by a low body mass index) with hypoalbuminemia and lower plasma levels of urea nitrogen and creatinine than expected from the intensity of dialysis [67,89-91]. As an example, a plasma albumin concentration below 4 g/dL (40 g/L) is the single laboratory finding most closely associated with an increased probability of death. The increase in risk is dosedependent, rising modestly at a plasma albumin concentration of 3.5 to 3.9 g/dL (35 to 39 g/L) but being much greater at values below 3.0 g/dL (30 g/L) (figure 3) [67,89,90]. These observations have primarily been made in patients on maintenance hemodialysis and may overestimate the effect of hypoalbuminemia, since some measurements taken in the weeks to months before death were included. However, a similar relationship between hypoalbuminemia and increased mortality has been demonstrated with peritoneal dialysis and, although less pronounced than in Figure 1, with plasma albumin concentrations measured within six weeks of starting dialysis (figure 4) [92]. (See "Nutritional status and protein intake in continuous peritoneal dialysis".) The presence of malnutrition prior to the initiation of dialysis is also strongly predictive of increased mortality [44]. Despite this, the presence of associated conditions, particularly comorbid conditions, significantly contributes to mortality, independent of nutritional status. In one study, for example, the outcomes of a total of 153 consecutive peritoneal dialysis patients were analyzed based upon the presence or absence of malnutrition, with or without comorbid conditions [93]. The combined presence of malnutrition plus a comorbid condition was associated with a high mortality, while there is a trend with malnutrition alone for an increase in mortality. Conversely, measures of good nutritional status, such as high body mass index (BMI) in combination with normal or high muscle mass, are associated with increased survival [94,95]. As an example, in a study of incident peritoneal dialysis patients, the best survival was observed in those with high BMI and normal or high muscle mass [94]. As with hypoalbuminemia, a similar incidence of undernutrition has been noted with the use of creatinine production to assess lean body mass in stable patients on maintenance dialysis. In one study, estimated lean body mass was below normal in 47 and 66 percent of hemodialysis and peritoneal dialysis patients, respectively [96]. There was a significant correlation between lean body mass and the plasma albumin concentration in the group as a whole; however, there was substantial variability in individual patients. Another marker of malnutrition, a low ratio of body weight for height, also predicts mortality in hemodialysis patients. In an analysis of data from nearly 13,000 patients, there was a highly significant inverse relationship between mortality rates and the ratio of body weight for height among those with ratios below the 50th percentile [97]. The association between markers of malnutrition and reduced patient survival does not prove a causeand-effect relationship. Nevertheless, it constitutes the rationale for attempting to improve nutrition via diet and more intensive dialysis. (See "Pathogenesis and treatment of malnutrition in maintenance dialysis".) The meaning of a low plasma albumin concentration may also differ among hemodialysis and peritoneal dialysis patients, due in part to variations in volume status. The serum albumin among hemodialysis

patients is often measured predialysis, a time when volume expansion is maximum; by comparison, the concentration of albumin in the peritoneal dialysis population should not vary acutely. Differences in mortality among these two modalities that appear to correlate with albumin levels may therefore instead be due to variations in intravascular volume. Although poor nutrition is a common cause of hypoalbuminemia in dialysis patients, a number of chronic inflammatory conditions can also reduce the serum albumin concentration [98]. This effect appears to be mediated by cytokines, such as interleukin-1 and tumor necrosis factor-alpha, which suppress hepatic albumin synthesis [99]. Thus, the presence of an untreated underlying inflammatory process may contribute to the decreased survival observed among chronic hemodialysis patients with hypoalbuminemia. (See "Inflammation in renal insufficiency".) Unlike the general population, some, but not all, studies have shown that being overweight (perhaps a surrogate for "overnutrition") may enhance survival among hemodialysis patients [95,100-106]. In one study of over 1300 hemodialysis patients, every one unit increase in the body mass index (BMI) was associated with a reduction of 30 percent in the relative risk of dying [100]. This result may be confounded in part by race and gender, since African-American females have the highest BMI [107]. The apparent survival benefit conferred by higher body weight may be limited to older adults (>65 years). This was suggested by a prospective analysis of 1749 patients who were stratified by age and BMI [108]. Among 984 patients younger than 65 years, the age-standardized mortality rate was 1.7 times higher for obese patients compared with those with a normal BMI. By contrast, among 765 patients older than 65 years, there was no difference in mortality between obese individuals and those with normal BMI. However this study included both peritoneal and hemodialysis patients, and a larger percentage of patients younger than 65 years were on peritoneal dialysis (50 versus 22 percent in patients older than 65 years). Obesity has been associated with worse survival outcomes among peritoneal dialysis patients in other studies [103,109]. CHRONIC HEMODIALYSIS ACCESS Arteriovenous fistulas have advantages over arteriovenous grafts and central venous catheters, with some evidence suggesting a survival benefit with fistulas. (See "Chronic hemodialysis vascular access: Types and placement".) DISORDERS OF MINERAL METABOLISM A number of reports have delineated an increased risk of all-cause and cardiovascular mortality in patients with disorders of mineral metabolism [110-113]. Although not found in all studies, the association with decreased survival primarily involves increased phosphate, calcium, calcium x phosphate product, and/or parathyroid hormone levels. These in turn may be associated with accelerated atherosclerosis, arterial calcification, and an increased risk of adverse cardiovascular outcomes and death. This was shown in a retrospective analysis of a database of over 40,000 hemodialysis patients in which the relative risks of death were determined for multiple categories of serum phosphate, calcium, calcium x phosphate product, and parathyroid hormone [110]. After multivariate adjustments, the lowest relative risks of death were observed among patients with serum phosphate concentrations between 3 to 5 mg/dL (0.97 to 1.61 mmol/L), serum calcium concentrations less than 8.0 mg/dL (2.0 mmol/L), a calcium x phosphate product of less than 45 to 50 mg2/dL2, and intact parathyroid hormone levels less than 600 pg/mL (600 ng/L). Concentrations of these substances that were above each of these levels were significantly associated with decreased survival. Compared to serum phosphate concentrations between 4.0 to 5.0 mg/dL (1.29 to 1.61 mmol/L), for example, an increased relative risk of death was noted for serum phosphate levels

greater than 5.0 mg/dL (1.61 mmol/L): the relative risk increased gradually from 1.07 to 2.02 at serum phosphate levels of 5.0 to 6.0 and 9.0 mg/dL, respectively. Given that the calcium result may have been confounded by the tendency of calcium levels to increase or decrease with reciprocal changes in serum phosphate, the risk of death was also determined for calcium levels measured within serum phosphate categories of 4 to 5, 5 to 6, 6 to 7, and 7 to 8 mg/dL. Within each phosphate category, higher calcium levels were associated with significant increases in mortality risk. Analyses of similar large databases have also found that increased levels of calcium, phosphate, and/or PTH had significant adverse effects upon survival [111-115]. As examples: Among 25,588 patients participating in the Dialysis Outcomes and Practice Patterns Study, the highest mortality was noted for those with calcium levels above 10.0 mg/dL, phosphorus levels greater than 7.0 mg/dL, and PTH levels above 600 pg/mL [115]. Among 1,629 incident hemodialysis and peritoneal dialysis patients from the Netherlands, phosphate and calcium X phosphate levels above K/DOQI guideline levels were associated with increased mortality risks in both patient groups [113].

However, other studies have noted that low PTH and calcium levels are associated with an increase or no effect on mortality [116-119]. A possible explanation for these disparate findings include variations in study design, differences in population evaluated, and the use of only single measurements of calcium, phosphate, and PTH. To better assess the association between mortality and changes in calcium, phosphate, and PTH over time, two studies have been performed to assess survival compared with differences over time in changes in bone mineral elements [120,121]. One prospective study, for example, was performed of 1006 incident hemodialysis and peritoneal dialysis patients, in whom longitudinal changes in bone mineral parameters were assessed [120]. PTH levels decreased over the course of one year, while calcium and phosphate levels, and the calcium x phosphate product increased over the first six months and then remained stable. After adjustment for comorbidity and other confounding variables, an increased risk of death was observed with the highest quartile for phosphate levels using both baseline and timedependent values (hazard ratio of 1.57, 95% CI 1.07-2.30). By comparison, an increased mortality risk with the highest quartile for calcium, calcium x phosphate product, and PTH levels was only observed with the time-dependent values. In addition to phosphate, calcium, calcium x phosphate product, and parathyroid hormone levels, additional serum laboratory values related to bone disease are associated with survival among dialysis: Fibroblast growth factor 23 (FGF-23) is an osteoblastic hormone involved in the regulation of phosphate and vitamin D. With increasing phosphate levels in those with increasing kidney dysfunction, elevations in FGF-23 levels stimulate the renal excretion of phosphate and inhibit the synthesis of 1,25-dihydroxyvitamin D. As with increased phosphate levels, elevated FGF-23 levels are associated with increased mortality among patients with end-stage renal disease. This was shown in a nested case-control study of 200 patients who died and 200 patients who survived the first year of hemodialysis [122]. Based upon multivariable analysis, increasing FGF23 levels were associated with an increasing risk of death when analyzed via either a continuous scale or quartiles. As an example, the risk of death was significantly higher in patients with the highest FGF-23 levels (quartile 4) compared with the group with the lowest FGF-23 levels

(quartile 1) (odds ratio of 5.7 95% CI 2.6-12.6). FGF-23 has also been associated with cardiovascular events and mortality in pre-dialysis CKD patients [123,124], renal transplant patients [125] and in non-CKD patients [126]. Further studies are needed to define the role of FGF-23. Increased mortality is described in dialysis patients with elevated serum alkaline phosphate levels [127,128]. In one study, levels of alkaline phosphatase greater than or equal to 120 units/L were associated with an increased risk of death (hazard ratio 1.25, 95% CI 1.21-1.29) [127].

These observational studies suggest that the many interventions currently utilized to maintain target calcium, phosphate, and PTH levels must be adequately assessed in rigorous trials to help determine their effect upon survival in patients with end-stage renal disease. These interventions include low phosphate diets, calcium and non-calcium based phosphate binders, vitamin D analogs, and/or calcimimetics. Some of these issues are discussed in detail separately. (See "Treatment of hyperphosphatemia in chronic kidney disease" and "Management of secondary hyperparathyroidism and mineral metabolism abnormalities in adult predialysis patients with chronic kidney disease" and "Management of secondary hyperparathyroidism and mineral metabolism abnormalities in dialysis patients" and "Vascular calcification in chronic kidney disease".) ACHIEVING MULTIPLE CLINICAL PERFORMANCE MEASURES Meeting specific goals for some clinical parameters has a beneficial impact upon survival in dialysis patients. Prominent examples include attaining and maintaining target levels for either hemodialysis dose or hemoglobin concentration. (See 'Adequacy of dialysis' above.) Practically all studies that have examined the effect upon survival of achieving clinical performance goals have evaluated benefits due to a single measure of clinical care. There is evidence that achieving multiple clinical targets may be associated with superior survival outcomes versus that observed with attaining fewer clinical targets or only one [129-134]. As examples: Among nearly 200,000 patients, the risk of death during the first year of hemodialysis correlated with having met zero, one, two, or three of the following guideline goals at initiation of hemodialysis: use of an arteriovenous fistula graft at initiation, hemoglobin level 11 g/dL, and goal albumin level [134]. Compared with those who met no goal, the risk of death was significantly lower among those who met one (0.81, 0.80 to 0.83), two (0.53, 0.41 to 0.56), or three goals (0.34, 0.30 to 0.39). A lower mortality rate was also observed in those who met each individual goal. During a 12 month follow-up period in a retrospective study of 15,287 hemodialysis patients, death or hospitalization were compared with achie ving target levels for hemoglobin (11 g/dL), serum albumin levels (3.7 g/dL by bromocresol purple laboratory method), use of a fistula for vascular access, and a single pool Kt/V urea of 1.2 [ 129]. Seven, 24, 39, 24, and 6 percent of patients met 4, 3, 2, 1 and zero targets, respectively. There was a significantly increased risk of death and hospitalization among those in whom targets were not met, which increased with each specific target that was not achieved. Compared with meeting all four targets: Adjusted hazard ratios for death were 1.9 (95% CI 1.4-2.6), 2.6 (95% CI 1.9-3.5), 3.5 (95% CI 2.6-4.7), and 4.6 (95% CI 3.3-6.4) for those who met 3, 2, 1, and zero targets, respectively.

Adjusted hazard ratios for hospitalization were 1.1 (95% CI 0.98-1.3), 1.3 (95% CI 1.1-1.5), 1.5 (95% CI 1.3-1.7), and 1.6 (95% CI 1.4-1.9), respectively. A retrospective analysis of 13,792 incident hemodialysis patients evaluated the correlation between survival and achieving K/DOQI clinical practice guidelines for single-pool Kt/V, hematocrit, serum albumin, calcium, phosphate, and PTH level [131]. Compared with not achieving any one target, the adjusted hazard ratios for mortality were 0.11 (95% CI 0.06-0.19), 0.19 (95% CI 0.15-0.25), 0.30 (95% 0.24-0.37), 0.39 (95% CI 0.31-0.49), 0.52 (95% CI 0.420.65), and 0.74 (95% CI 0.49-0.93) for those who met 6, 5, 4, 3, 2, and 1 target, respectively. By comparison, an increased mortality was associated with achieving the blood pressure goal (predialysis<140/90 mmHg) (1.90, 95% CI 1.73-2.10).

These studies are limited in part because of their design, underreporting of comorbid conditions, and unknown incidence of disease severity. However, these results are generally consistent with other, primarily observational, studies showing increased risk of death and hospitalization with decreased dialysis dose or hemoglobin levels, low serum albumin concentration, abnormal mineral metabolism, and hemodialysis with a vascular access other than an arteriovenous fistula. This suggests that quality improvement measures should be implemented to increase the number of those who meet multiple performance measures. HEMODIALYSIS VERSUS PERITONEAL DIALYSIS The data described above were almost entirely from patients treated with maintenance hemodialysis. Survival of hemodialysis versus peritoneal dialysis patients is presented in detail separately. (See "Dialysis modality and patient outcome".) With peritoneal dialysis, there is increasing evidence that increased survival is associated with centers that are relatively more experienced with peritoneal dialysis [135-137]. In one observational study of outcomes in large dialysis organizations, an increased mortality risk was observed in patients being treated in organizations with the lowest rates of peritoneal dialysis use [137]. HOME HEMODIALYSIS Home hemodialysis is generally associated with good survival rates. Improved survival had been thought to be due to selection bias since fewer older and sicker patients are treated with home hemodialysis. However, adjustments for age, diagnosis, comorbidity, and gender in large dialysis databases did not alter the decreased risk of death among home hemodialysis patients. (See "Home hemodialysis".) ALTERNATIVE FORMS OF HEMODIALYSIS Although currently undergoing intense study, no significant conclusions can be drawn concerning the effect on survival of nocturnal hemodialysis or short daily hemodialysis. (See"Technical aspects of nocturnal hemodialysis" and "Short daily hemodialysis".) SUMMARY AND RECOMMENDATIONS The Kt/V as a measure of urea kinetic modeling quantifies the delivery of dialysis and verifies the dialysis prescription [67-70,75,138,139]. Current recommendations are presented separately. (See "Kt/V and the adequacy of hemodialysis".) Increasing dialysis time is the most certain way to increase the dialysis prescription, but a modest benefit can be obtained with more efficient membranes and higher blood flow rates. (See "Dialysis modality and patient outcome".) It is important to appreciate, however, that there may be a significant difference between the dialysis prescription and the amount of dialysis actually delivered to the patient. In particular, problems with cardiovascular and access recirculation can substantially reduce dialysis delivery. (See "Prescribed versus delivered dialysis: Importance of dialysis time".)

There are similar issues among patients undergoing peritoneal dialysis. Minimal weekly total target clearance values in terms of Kt/V and creatinine clearance have been published over the last several years by United States and International Societies. There is a general consensus that some previously recommended target weekly dialysis doses are inconsistent and probably unattainable for many patients, particularly low-average and low transporters. The net effect is an unnecessary increase in the number of patients transferred to hemodialysis because of perceived inadequate dialysis with PD. (See "Adequacy of peritoneal dialysis".) An optimal dialysis prescription, whether for hemodialysis or peritoneal dialysis, also must take into account other factors, such as the patient's symptoms, mineral metabolism status, nutritional status (as estimated in part from the plasma albumin concentration and protein catabolic rate), and degree of rehabilitation toward a fully active life. (See "Protein catabolic rate in maintenance dialysis".) Another important goal is a normotensive patient (without antihypertensive medications) who is maintained at estimated dry weight to minimize any dialysis-induced cardiovascular risk factors. Use of UpToDate is subject to the Subscription and License Agreement. REFERENCES