Hyperphosphatemia in CKD
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  • 1. HYPERPHOSPHATEMIA In Chronic Kidney Disease Rehab Aly Rayan & Doaa Ali Hegy Rehab.a.rayan@gmail.com
  • 2. Rehab Aly Rayan & Doaa Ali Hegy 23-May-14 1 HYPERPHOSPHATEMIA | In Chronic Kidney Disease Table of Contents INTRODUCTION ......................................................................................................................................................................2 THE CAUSES OF HYPERPHOSPHATEMIA................................................................................................................................2 Acute or chronic kidney disease ........................................................................................................................................3 Phosphate Retention..............................................................................................................................................................3 GUIDELINE TARGET LEVELS....................................................................................................................................................4 Treatment of Hyperphosphatemia........................................................................................................................................4 1- Phosphate restriction :...............................................................................................................................................5 2- Phosphate binders: categorized as:............................................................................................................................5 1. Aluminum hydroxide :............................................................................................................................................5 2. Magnesium-containing antacids:...........................................................................................................................5 3. Calcium salts :.........................................................................................................................................................5 4. Non-calcium binders ..............................................................................................................................................6 3- NOVEL THERAPIES ......................................................................................................................................................7  Nicotinamide : ........................................................................................................................................................7  Polynuclear iron (III)-oxyhydroxide phosphate (PA21) :.......................................................................................7  Increased and/or extended hemodialysis :...........................................................................................................7 Managing hyperphosphatemis in CKD Patients’...................................................................................................................7 Among dialysis patients:...................................................................................................................................................7 Stage 3 to 5 CKD not yet on dialysis: ..............................................................................................................................7 Summery.................................................................................................................................................................................8 References..............................................................................................................................................................................9
  • 3. Rehab Aly Rayan & Doaa Ali Hegy 23-May-14 2 HYPERPHOSPHATEMIA | In Chronic Kidney Disease INTRODUCTION Phosphate is an inorganic molecule consisting of a central phosphorus atom and four oxygen atoms. In the steady state, the serum phosphate concentration is determined by the ability of the kidneys to excrete dietary phosphate. THE CAUSES OF HYPERPHOSPHATEMIA Phosphate intake above 4000 mg/day (130 mmol/day) causes small elevations in serum phosphate concentrations as long as the intake is distributed over the course of the day. If, however, an acute phosphate load is given over several hours, transient hyperphosphatemia will occur. The diagnostic approach to hyperphosphatemia involves elucidating why phosphate entry into the extracellular fluid exceeds the degree to which it can be excreted or why the renal threshold for phosphate excretion is increased above normal.  There are four general circumstances in which this occurs:
  • 4. Rehab Aly Rayan & Doaa Ali Hegy 23-May-14 3 HYPERPHOSPHATEMIA | In Chronic Kidney Disease Acute or chronic kidney disease The filtered load of phosphate is approximately 4 to 8 g/day (130 to 194 mmol/day). If, for example, the glomerular filtration rate (GFR) is 180 L/day (125 mL/min) and the phosphate concentration is 4 mg/dL (1.3 mmol/L), then the filtered load will be 7.2 g/day. Only 5 to 20 percent of the filtered phosphate is normally excreted, with most being reabsorbed in the proximal tubule. The normal physiologic regulation of renal phosphate excretion, the following factors are involved:  Serum phosphate concentration – Hyperphosphatemia can directly diminish proximal tubular phosphate reabsorption via suppression of sodium-phosphate cotransporters in the luminal membrane that mediate reabsorption of filtered phosphate.  Parathyroid hormone – Parathyroid hormone (PTH) increases phosphate excretion by diminishing activity of sodium-phosphate cotransporters.  Phosphatonins – Phosphatonins such as fibroblast growth factor 23 (FGF23) and secreted frizzled related protein-4 (sFRP-4) decrease phosphate reabsorption by suppressing the luminal expression of sodium phosphate cotransporters. An acute or chronic reduction in GFR will initially diminish phosphate filtration and excretion. Nevertheless, phosphate balance can initially be maintained in such patients by decreasing proximal phosphate reabsorption under the influence of increased secretion of PTH and FGF23. Once the GFR falls below 20 to 25 mL/min, however, phosphate reabsorption is thought to be maximally suppressed, and urinary excretion may no longer keep pace with phosphate intake. At this point, hyperphosphatemia occurs, increasing the filtered load and reestablishing phosphate balance. Phosphate Retention 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 chronic kidney disease (CKD), increased fibroblast growth factor (FGF)-23 levels, and secondary hyperparathyroidism. 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, and elevated circulating FGF-23 concentrations are strongly associated with increased cardiovascular mortality and renal failure.
  • 5. Rehab Aly Rayan & Doaa Ali Hegy 23-May-14 4 HYPERPHOSPHATEMIA | In Chronic Kidney Disease From the viewpoint of calcium and phosphate balance, the hyper secretion 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- dihydroxycholecalciferol (1, 25(OH) D). PTH increases in response to reductions in 1, 25(OH) D. 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 hypocalcaemia 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. 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. Hyperphosphatemia alone or in combination with a high serum calcium has been associated with increased mortality in dialysis patients. 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 . Tumoral collections of calcium phosphate crystals may also be a consequence of hyperphosphatemia and increased calcium levels. Increased coronary arterial calcification is associated with coronary atherosclerosis and is related to the presence and/or consequences of elevated serum phosphorus, calcium, FGF-23, and PTH levels. 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. 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. GUIDELINE TARGET LEVELS 1. K/DOQI guidelines — The 2003 Kidney Disease Outcomes Quality Initiative (K/DOQI) practice guidelines made the following recommendations for goal serum phosphate at different levels of severity of chronic kidney disease (CKD): o At an estimated glomerular filtration rate (eGFR) between 15 and 59 mL/min per 1.73 m (stage 3 and 4 CKD), the serum phosphate should be between 2.7 and 4.6 mg/dL (0.87 and 1.49 mmol/L). o At an eGFR <15 mL/min per 1.73 m (stage 5 CKD), the serum phosphate should be between 3.5 and 5.5 mg/dL (1.13 and 1.78 mmol/L). Treatment of Hyperphosphatemia Both the (K/DOQI) and (KDIGO) have published guidelines concerning the management of hyperphosphatemia in patients with (CKD).Two principal modalities are used in an attempt to prevent and/or reverse the hyperphosphatemia of renal failure:
  • 6. Rehab Aly Rayan & Doaa Ali Hegy 23-May-14 5 HYPERPHOSPHATEMIA | In Chronic Kidney Disease 1- Phosphate restriction : - Approximately 900 mg/day is a level that at least some patients will find acceptable. Phosphate restriction should primarily include processed foods, colas, and not high biologic value foods such as meat and eggs. - A large fraction of dialyzed patients has 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). 2- Phosphate binders: categorized as:  calcium containing (mostly calcium carbonate and calcium acetate)  Non-calcium containing (including sevelamer and lanthanum). o Use of calcium-containing phosphate binders become less frequent because of concerns about toxicity of calcium accumulation. We generally use non-calcium-containing phosphate binders for:  normocalcemic CKD patients  CKD patients who are receiving active vitamin D analogs for parathyroid hormone (PTH) suppression (non-calcium-based phosphate binders decrease mortality among CKD patients). 1. Aluminum hydroxide :  The phosphate binder of choice, forming insoluble and nonabsorbable aluminum phosphate precipitates in the intestinal lumen.  -It has been avoided due to 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 central nervous system (CNS), leading to vitamin D-resistant osteomalacia; a refractory, microcytic anemia; bone and muscle pain; and dementia.  There appears to be no safe dose of aluminum in CKD that is also large enough to control the serum phosphate concentration. 2. Magnesium-containing antacids:  Generally avoided in patients with kidney dysfunction because of the risk of hypermagnesemia and the frequent development of diarrhea. 3. Calcium salts :  The problems with aluminum led to the preferential administration of calcium salts to bind intestinal phosphate they include calcium carbonate and calcium acetate. o Calcium acetate may be a more efficient phosphate binder than calcium carbonate as calcium carbonate dissolves only at an acid pH, and many patients with advanced renal failure have achlorhydria or are taking H2-blockers. 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. o Calcium citrate should be avoided in patients with renal failure since citrate can markedly increase intestinal aluminum absorption and possibly induce aluminum neurotoxicity or the rapid onset of symptomatic osteomalacia. o 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. However, if such items are avoided, sodium citrate can be used in some patients unable to tolerate
  • 7. Rehab Aly Rayan & Doaa Ali Hegy 23-May-14 6 HYPERPHOSPHATEMIA | In Chronic Kidney Disease sodium bicarbonate since it does not produce the bloating associated with bicarbonate therapy.  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 for dialysis patients, or until hypercalcemia ensues.  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.  To help decrease this possibility, the total dose of elemental calcium (including dietary sources) should not exceed 2000 mg/day, and the amount of elemental calcium should be no more than 1.5 grams per day. 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.  Phosphate binders are most effective if taken with meals. 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.  This problem is most likely to occur if a vitamin D preparation is also given or if the patient has decreased bone turnover due to osteomalacia or adynamic bone disease, thereby limiting uptake of the extra calcium by bone.  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 affect the ability to administer calcium-containing phosphate binders. 4. Non-calcium binders a. Sevelamer : o Sevelamer hydrochloride (Renagel®) and sevelamer carbonate (Renvela®) are nonabsorbable agents that contain neither calcium nor aluminum. o These drugs are cationic polymers that bind phosphate through ion exchange. o 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. o There appears to be no major difference between sevelamer and calcium-based phosphate binders in terms of bone histology, 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. o One problem associated with sevelamer hydrochloride is the possible induction of metabolic acidosis. As a result, sevelamer carbonate has been developed. It is associated with higher serum bicarbonate levels than sevelamer hydrochloride, it is likely that it will become the preferred binder in this class, but these agents appear to be equivalent in their ability to control phosphate levels. o Sevelamer is much more expensive than calcium-based phosphate binders are. b. Lanthanum : o It is a rare earth element, has significant phosphate-binding properties. o The risk of lanthanum accumulation and toxicity, however, appears to be quite low with short- term use.
  • 8. Rehab Aly Rayan & Doaa Ali Hegy 23-May-14 7 HYPERPHOSPHATEMIA | In Chronic Kidney Disease o The lower pill burden is one consideration that may favor the use of lanthanum. o Sevelamer is commonly initially used over lanthanum since, although equally effective in lowering phosphate, as the long-term data on safety of lanthanum are more limited. 3- NOVEL THERAPIES The current approach to management of hyperphosphatemia is not optimal; a number of alternative therapies are undergoing evaluation.  Nicotinamide : o 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  Polynuclear iron (III)-oxyhydroxide phosphate (PA21) : o Various doses of polynuclear iron (III)-oxyhydroxide phosphate (PA21) were compared with sevelamer in a randomized, multicenter open-label study, PA21 at doses of 5 and 7.5 g/day produced similar decreases in serum phosphorus to sevelamer dosed at 4.8 g/day. o Further study is required to better understand the efficacy and safety of these and related agents in this setting.  Increased and/or extended hemodialysis : o 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. Thus, lengthening dialysis (within standard dialysis regimens) or using larger, high-efficiency dialyzers is unlikely to substantially increase phosphate removal. o The average standard dialysis removes approximately 900 mg of phosphate. By comparison, extremely long and/or frequent dialysis clears a larger amount of phosphate. o For patients with refractory hyperphosphatemia who are willing to accept this form of dialysis, this form of dialysis may be the best approach. Managing hyperphosphatemis in CKD Patients’  Calcium, and parathyroid hormone (PTH) levels initially and then on an ongoing basis, particularly after changes in therapeutic measures.  Among all patients with CKD, we avoid aluminum hydroxide except for short-term therapy (four weeks for one course only) of severe hyperphosphatemia. Among dialysis patients:  we aim to maintain serum phosphate levels between 3.5 and 5.5 mg/dL 1- Restrict dietary phosphate to 900 mg/day. 2- Among dialysis patients with elevated phosphate levels that are refractory to maintenance dialysis therapy and diet, we recommend the administration of phosphate-binding agents. 3- More frequent and more intensive dialysis can also lower phosphate levels. Extremely long and/or frequent dialysis, such as that provided by nocturnal hemodialysis, clears a large amount of phosphate; it is an option among those who are willing to accept this form of dialysis. Stage 3 to 5 CKD not yet on dialysis: 1- Restrict dietary phosphate to 900 mg/day. 2- Among patients with serum phosphate levels greater than target levels despite dietary phosphorus restriction after one month, we suggest the administration of phosphate binders.
  • 9. Rehab Aly Rayan & Doaa Ali Hegy 23-May-14 8 HYPERPHOSPHATEMIA | In Chronic Kidney Disease Summery  Hyperphosphatemia results when phosphate entry into the extracellular fluid exceeds the rate at which it can be excreted. This occurs when there is a large phosphate load over a short period of time (which may be from endogenous or exogenous sources), cellular shift of phosphate from the cells to the extracellular fluid, acute or chronic kidney disease, and because of a primary increase in proximal phosphate reabsorption.  Renal failure is a common cause of diminished phosphate excretion. Urinary excretion may not keep pace with phosphate intake when the glomerular filtration rate (GFR) falls below 20 to 25 mL/min.  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 parathyroid hormone [PTH] and fibroblast growth factor [FGF]-23 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.  Both the Kidney Disease Outcomes Quality Initiative (K/DOQI) and Kidney Disease: Improving Global Outcomes (KDIGO) have published guidelines concerning the management of hyperphosphatemia in patients with chronic kidney disease (CKD).  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, to assess vascular calcifications, and note the administration of concurrent therapies, particularly vitamin D and vitamin D analogs.  Dialysis o It is suggested maintaining serum phosphate levels between 3.5 and 5.5 mg/dL (1.13 and 1.78 mmol/L) among dialysis patients (Grade 2C). o 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/day. 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 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. o 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 PTH levels, particularly vitamin D analogs, as well as other issues. The approach in these patients is discussed in detail separately. o 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 for those who are willing to accept this form of dialysis. o 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).  Stage 3 to 5 CKD not yet on dialysis o We suggest maintaining serum phosphate levels in the normal range among patients with stage 3 to CKD not yet on dialysis (Grade 2C).
  • 10. Rehab Aly Rayan & Doaa Ali Hegy 23-May-14 9 HYPERPHOSPHATEMIA | In Chronic Kidney Disease o 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/day. Among patients with serum phosphate levels greater than target levels despite dietary phosphorus restriction after four weeks, we suggest the administration of phosphate binders (Grade 2C). Our specific approach varies based upon calcium levels and the presence of comorbid conditions. o 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). References 1. Murer H. Homer Smith Award. Cellular mechanisms in proximal tubular Pi reabsorption: some answers and more questions. J Am Soc Nephrol 1992; 2:1649.18. 2. Murer H, Lötscher M, Kaissling B, et al. Renal brush border membrane Na/Pi-cotransport: molecular aspects in PTH-dependent and dietary regulation. Kidney Int 1996; 49:1769. 3. 12.Martin KJ, González EA. Metabolic bone disease in chronic kidney disease. J Am Soc Nephrol 12. 2007; 18:875. 4. National Kidney Foundation. K/DOQI clinical practice guidelines for chronic kidney disease: evaluation, classification, and stratification. Am J Kidney Dis 2002; 39:S1. 5. Kates DM, Sherrard DJ, Andress DL. Evidence that serum phosphate is independently associated with serum PTH in patients with chronic renal failure. Am J Kidney Dis 1997; 30:809. 6. Hruska KA, Teitelbaum SL. Renal osteodystrophy. N Engl 15. J Med 1995; 333:166. 7. Fournier A, Morinière P, Ben Hamida F, et al. Use of alkaline calcium salts as phosphate binder in uremic patients. Kidney Int Suppl 1992; 38:S50. 8. Llach F. Secondary hyperparathyroidism in renal failure: the trade-off hypothesis revisited. Am J Kidney Dis 1995; 25:663. 9. Fournier A, Morinière P, Ben Hamida F, et al. Use of alkaline calcium salts as phosphate binder in uremic patients. Kidney Int Suppl 1992; 38:S50. 10. Delmez JA, Slatopolsky E. Hyperphosphatemia: its consequences and treatment in patients with chronic renal disease. Am J Kidney Dis 1992; 19:303. 11. Mucsi I, Hercz G. Control of serum phosphate in patients with renal failure--new approaches. Nephrol Dial Transplant 1998; 13:2457. 12. Billa V, Zhong A, Bargman J, et al. High prevalence of hyperparathyroidism among peritoneal dialysis patients: a review of 176 patients. Perit Dial Int 2000; 20:315. 13. Foley RN, Parfrey PS, Sarnak MJ. Clinical epidemiology of cardiovascular disease in chronic renal disease. AmJ Kidney Dis 1998; 32:S112. 14. Isakova T, Xie H, Yang W, et al. Fibroblast growth factor 23 and risks of mortality and end-stage renal disease in patients with chronic kidney disease. JAMA 2011; 305:2432. 15. Levin A, Bakris GL, Molitch M, et al. Prevalence of abnormal serum vitamin D, PTH, calcium, and phosphorus in patients with chronic kidney disease: results of the study to evaluate early kidney disease. Kidney Int 2007;71:31. 16. Stevens LA, Djurdjev O, Cardew S, et al. Calcium, phosphate, and parathyroid hormone levels in combination and as a function of dialysis duration predict mortality: evidence for the complexity of the association between mineral metabolism and outcomes. J Am Soc Nephrol 2004; 15:770. 17. Young EW, Akiba T, Albert JM, et al. Magnitude and impact of abnormal mineral metabolism in hemodialysis patients in the Dialysis Outcomes and Practice Patterns Study (DOPPS). Am J Kidney Dis 2004; 44:34.
  • 11. Rehab Aly Rayan & Doaa Ali Hegy 23-May-14 10 HYPERPHOSPHATEMIA | In Chronic Kidney Disease 18. Kestenbaum B, Sampson JN, Rudser KD, et al. Serum phosphate levels and mortality risk among people with chronic kidney disease. J Am Soc Nephrol 2005; 16:520. 19. Kovesdy CP, Anderson JE, Kalantar-Zadeh K. Outcomes associated with serum phosphorus level in males with non-dialysis dependent chronic kidney disease. Clin Nephrol 2010; 73:268. 20. Voormolen N, Noordzij M, Grootendorst DC, et al. High plasma phosphate as a risk factor for decline in renal function and mortality in pre-dialysis patients. Nephrol Dial Transplant 2007; 22:2909. 21. Mehrotra R, Peralta CA, Chen SC, et al. No independent association of serum phosphorus with risk for death or progression to end-stage renal disease in a large screen for chronic kidney disease. Kidney Int 2013; 84:989. 22. Menon V, Greene T, Pereira AA, et al. Relationship of phosphorus and calcium-phosphorus product with mortality in CKD. Am J Kidney Dis 2005; 46:455.