Management of Hyperphosphatemia in End-Stage Renal Disease: A New Paradigm

Bone and mineral metabolism becomes dysregulated with progression of chronic kidney disease (CKD), increasing levels parathyroid hormone serve as an adaptive response to maintain normal phosphorus calcium levels. In end-stage renal disease, this maladaptive high may occur. We summarize strategies control hyperphosphatemia based on a systematic literature review clinical trial real-world observational data in hemodialysis patients CKD-mineral bone disorder (CKD-MBD). These studies suggest that current management options (diet lifestyle changes; regular dialysis treatment; use phosphate binders, vitamin D, calcimimetics) have their own benefits limitations variable outcomes. A more integrated approach be necessary, incorporating measurement multiple biomarkers CKD-MBD pathophysiology (calcium, phosphorus, hormone) correlation between diet adjustments drugs, which facilitate improved patient management. Homeostasis is maintained through interactions the kidney, gut, mediated by hormones, including active/analog (PTH), fibroblast growth factor 23 (FGF-23). As function progressively declines severe stages (CKD) leading (ESRD) requiring dialysis, balance increasingly dysregulated,1Kidney Disease: Improving Global Outcomes (KDIGO) Update Work GroupKDIGO 2017 Clinical Practice Guideline for Diagnosis, Evaluation, Prevention, Treatment Chronic Kidney Disease-Mineral Disorder (CKD-MBD).Kidney Int Suppl (2011). 2017; 7: 1-59Abstract Full Text PDF PubMed Scopus (667) Google Scholar (CKD-MBD) secondary hyperparathyroidism (SHPT) develop. addition biochemical imbalances, associated gland hyperplasia, vascular calcification, uremic disorders increased risk fractures, pain, cardiovascular (CV) events, has been linked poor health outcomes diminished quality length life.2Zhou C. Wang F. J.W. Zhang L.X. Zhao M.H. 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Accordingly, receiving achieved involving medical intervention when necessary. Indeed, viewed complexity inter-relationships/compensatory mechanisms involved progression, particularly unique roles contributing focuses SHPT, particular attention given how progressive disturbances mitigated these patients. trial, real-world, specifically focused SHPT was conducted. Relevant published 2013 2019 were identified using MEDLINE Embase databases. following search terms applied: “phosphorus” AND “phosphate” “phosphate binders” “secondary hyperparathyroidism’ “SHPT” “chronic disorder” “CKD-MBD.” Common included following: (CKD); (CKD-MBD); (ESRD); (SHPT); dialysis; hemodialysis; parathyroidectomy; guidelines; Disease Quality Initiative (KDOQI) calcimimetic; Sensipar®; Parsabiv®; etelcalcetide; cinacalcet; D; D sterols; analogues; analogs; calcitriol; 1,25(OH)2D; dialysate; diet; nutrition; malnutrition; dietitian; dietician; gastrointestinal; calcium; sensing receptor (CASR, CAR); (PTH, iPTH); additives; paricalcitol; (in CKD); binder; sevelamer; calcium-based binders; non-calcium-based aluminum-based iron-based lanthanum. cross-referenced separately common lack differentiation contents (see Box 1).12Iheagwara O.S. Ing T.S. Kjellstrand C.M. Lew S.Q. Phosphorus, phosphorous, phosphate.Hemodial 2013; 479-482PubMed Scholar,13Hansen Marckmann P. Importance phosphorous phosphate.J 27 ([abstract]): 447Abstract (1) ScholarBox 1Phosphorus or phosphate?Phosphorus used interchangeably literature; however, there differences meanings terms. required every cell body function.•Physiological functions formation repair bones teeth, muscle contraction, nerve signaling, function, maintaining heartbeat, generation Adenosine Triphosphate other high-energy bonds, signal transduction cellular effectors.Due highly reactive nature, bound oxygen biological systems.•Organic phosphates form structural components cells distributed skeleton (85%), teeth (0.4%), soft tissue (14%), blood (0.3%), extravascular fluid (0.3%). Inorganic exist ions protein (10%) complexed magnesium, sodium (5%).12Iheagwara Scholar•It amount measured phosphorus/phosphate test.•Because mass (H2PO4) times greater than recommended daily intake 1,000 mg equivalent ?3,000 phosphate.13Hansen Case reports, reviews, preclinical reports describing peritoneal post-transplant excluded. 132 articles selected (Fig. 1) approaches dialysis. Serum dependent contribution absorption intestine, glomerular filtration, tubular excretion reabsorption resorption. part physiological process, work tandem tight (3.0-4.5 mg/dL adults). adaptation changes rapid, thus net During early failure, decreased (with increases levels) coupled reductions synthesis active D3 decreases D-mediated uptake intestine) lowered calcium. Hypocalcemia main trigger release, turn release excretion.3Beto FGF-23, secreted rising acts increase but inhibitory effect synthesis, exacerbating metabolism. Together, compensatory actions physiology homeostasis With handling dysregulated, maladaptive. severe, become clinically deficient impaired, exacerbation imbalances elevations levels, eventually SHPT.4Goodman Elevated turnover resorption, releases reduces reservoir capacity skeleton, contributes fracture pain CKD-MBD.1Kidney Scholar,5Moe Eventually, regardless no longer excrete homeostasis, resulting 2).14Levin A. Bakris G.L. Molitch al.Prevalence abnormal PTH, study evaluate disease.Kidney 71: 31-38Abstract (1082) Excessive retention cause wide conditions, such impaired mineralization, signaling death.15Razzaque M.S. Phosphate toxicity: new insights into old problem.Clin Sci (Lond). 2011; 120: 91-97Crossref (146) less 5% those 1 2 exhibit hyperphosphatemia, prevalence stage 3b (estimated filtration rate [eGFR] ? 44 mL/minute/1.73 m2) incrementally higher (eGFR 15-29 (?20%) < 15 (?40%).14Levin By time receives they likely hyperphosphatemic. Several demonstrated associations adverse CV patients, cases levels.16Covic Kothawala Bernal Robbins Chalian Goldsmith Systematic evidence underlying all-cause events disease.Nephrol Dial Transpl. 2009; 24: 1506-1523Crossref (173) meta-analysis (N = 25,546 non-dialysis–dependent patients), shown failure (hazard ratio 1.36) 1.20).17Da Xie Wolf mortality: studies.Am 2015; 66: 258-265Abstract (72) 47 327,644 patients) observed death 18% phosphorous.18Palmer S.C. Hayen Macaskill hormone, risks individuals meta-analysis.JAMA. 305: 1119-1127Crossref (505) some linking high-quality supporting ideal target lacking. ongoing pragmatic, multicenter Pragmatic Trial Higher vs Lower Targets Patients Undergoing Hemodialysis (NCT04095039) aims assess optimal compares hospitalization rates assigned experimental Hi arm (phosphorus ? 6.5 mg/dL) Lo 5.5 mg/dL).19HiLo: lower undergoing hemodialysis.https://clinicaltrials.gov/ct2/show/NCT04095039Google recent update guideline emphasizes recommends serial assessments phosphate, iPTH, considered together. states decisions pertaining phosphate-lowering phosphate—that limited—and dose binders restricted. When making recommendations, source (e.g., animal, vegetable, additives) considered. updated guidelines focus treating lowering toward range.20Ketteler Block Evenepoel al.Executive summary Update: what's changed it matters.Kidney 92: 26-36Abstract (433) Conventional involve stepwise therapies advances. traditional first; if does CKD-MBD, added followed calcimimetics final resort difficult-to-treat goal laboratory values achieved. recommendations key PTH) addressed simultaneously (goal listed below), well thinking modification, we discuss sections. cornerstone collectively and/or calcimimetics.1Kidney Scholar,3Beto Scholar,21Cunningham Locatelli Rodriguez Secondary hyperparathyroidism: pathogenesis, therapeutic options.Clin 6: 913-921Crossref (338) referred 3Ds management: diet, (Box 2).Box 2Novel Paradigm Hyperphosphatemia Management sections three 3D detail. and, therefore, singularly isolation holistic improve markers Dietary awareness control, limiting central because limit available gut. foods plentiful meats fish, nuts, whole grains, legumes, cheese) contain many nutrients. Thus, avoiding phosphorus-rich difficult CKD, malnutrition concern already nutritionally compromised population. Moreover, healthier diets inconvenient expensive compared inexpensive fast food very additive phosphorus. burden what eat depends upon factors (animal- vs. plant-derived), presence additives, method preparation,22St-Jules D.E. Woolf K. Pompeii M.L. Kalantar-Zadeh Sevick M.A. Reexamining phosphorus-protein dilemma: restriction compromise status?.J 26: 136-140Abstract impact This complicated hidden sources medications 3).23Murphy-Gutekunst Hidden popular beverages.Nephrol Nurs 32: 443-445PubMed 24León J.B. Sehgal A.R. phosphorus-containing additives top-selling grocery stores.J 23: 265-270.e2Abstract (87) 25Lou-Arnal Arnaudas-Casanova Caverni-Muñoz al.Hidden phosphorus: processed foods.Nefrologia. 2014; 34: 498-506PubMed 26Cupisti Moriconi D'Alessandro al.The extra-phosphate intestinal load medications: real concern?.J 857-862Crossref (8) 27Nelson S.M. Sarabia S.R. Christilaw E. al.Phosphate-containing prescription contribute third 27: 91-96Abstract (19) 3Hidden phosphorusThere surprisingly traditionally medications, due additives. difficult-to-measure forms ingested termed “hidden” sources.•Food pH regulators, stabilizers, flavor/color enhancers, up one-third roughly doubled 1990 2005, approximately 50% supermarkets additives.23Murphy-Gutekunst Scholar,24León Scholar•Poor labeling content. Food labels little information content, present, discrepancy value level sample.25Lou-Arnal Scholar•Phosphorus medications. More 10% formulations significantly taking simultaneously.26Cupisti Scholar,27Nelson include:1.Paroxetine (antidepressant)2.Amlodipine (calcium channel blocker)3.Lisinopril (antihypertensive)4.Sitagliptin (antidiabetic) There medication