Recent Advances in Mineral and Bone Disorders in CKD (2018)

Adapted from the IRIS education article by Henk van den Broek and Jonathan Elliott, London, UK (2018).

Introduction

High blood phosphate (hyperphosphatemia) is a well-known risk factor for disease progression and reduced survival in cats and dogs with chronic kidney disease (CKD), and multiple studies have shown the benefits of lowering serum phosphate by feeding phosphate-restricted clinical kidney diets (Elliott et al., 2000; Jacob et al., 2002; Plantinga et al., 2005; Ross et al., 2006; Boyd et al., 2008; Chakrabarti et al., 2012). The reduced ability of diseased kidneys to excrete enough phosphate each day is thought to underlie the abnormalities of calcium-phosphate balance, bone disease, and soft tissue calcification grouped together as chronic kidney disease–mineral and bone disorder (CKD-MBD) (Moe et al., 2006; Slatopolsky, 2011).

For decades, the disturbances of calcium-phosphate balance in patients with CKD, and their consequences, were explained by hyperphosphatemia and increases in parathyroid hormone (PTH), that is, secondary renal hyperparathyroidism. More recently, understanding of phosphate balance has advanced with the discovery of the phosphate-excreting hormone fibroblast growth factor 23 (FGF23) and its co-receptor, α-Klotho. Recognition of the role of magnesium in CKD-MBD is another recent breakthrough in nephrology.

Fibroblast Growth Factor 23

FGF23 is released by osteocytes in bone (Pereira et al., 2009). It lowers serum phosphate in two ways: by reducing the number of sodium-dependent phosphate transporters (NaPi2a) in the proximal tubules, which limits the reabsorption of phosphate from the tubular fluid, and by inhibiting the enzyme 1α-hydroxylase, which activates vitamin D, so reducing serum calcitriol and therefore the absorption of phosphate from the intestine (Shimada et al., 2004a; Shimada et al., 2004b). To bind to its receptor and act, FGF23 needs a co-factor, the α-Klotho protein (Urakawa et al., 2006; Nakatani et al., 2009). Kidney expression of α-Klotho is thought to decrease in CKD, limiting the effect of FGF23 on phosphate excretion (Sakan et al., 2014). No studies had yet been published on α-Klotho expression in veterinary patients with CKD, but several studies have investigated FGF23 in cats and dogs with CKD.

FGF23 and IRIS CKD Stage

In cats, plasma FGF23 increases in the early stages of CKD, before overt azotemia develops (Finch et al., 2013), and it rises considerably with IRIS CKD stage, from a median of 354 pg/mL in Stage 2 to 1,282 pg/mL in Stage 3 and 33,478 pg/mL in Stage 4 (Geddes et al., 2013a).

Dogs with CKD also have significantly higher plasma FGF23 concentrations than healthy dogs (Dittmer et al., 2017), but mainly in IRIS Stages 3 and 4 (Harjes et al., 2017). In dogs with CKD, plasma FGF23 increased from a median of 336 pg/mL in IRIS Stage 2 to 2,302 pg/mL in Stage 3 and 7,733 pg/mL in Stage 4 (Harjes et al., 2017).

FGF23 and Hyperphosphatemia

Cats that are hyperphosphatemic for their IRIS stage have significantly higher plasma FGF23 than normophosphatemic cats with the same severity of CKD (Geddes et al., 2013a). This could not be clearly established in dogs with CKD, probably because of the small number of dogs in each group of that study (Harjes et al., 2017). However, in both cats and dogs with CKD, plasma FGF23 correlates significantly with phosphate concentration (Geddes et al., 2013a; Dittmer et al., 2017). Moreover, feeding a phosphate-restricted kidney diet was associated with a decrease in plasma FGF23 in both hyperphosphatemic and normophosphatemic cats with stable azotemic CKD (Geddes et al., 2013b), so plasma FGF23 might be used to monitor the effect of treatment in cats with CKD. The effect of dietary phosphate restriction on plasma FGF23 in dogs with CKD has not yet been examined.

FGF23 and Survival

In cats, higher plasma FGF23 at the diagnosis of CKD has been associated with an increased risk of death (Geddes et al., 2015; van den Broek et al., 2018). In a retrospective study of 214 cats with CKD, cats with plasma FGF23 above 3,000 pg/mL at the diagnosis of azotemic CKD had significantly shorter survival than cats with plasma FGF23 below the upper limit of its proposed reference interval (700 pg/mL), independent of IRIS stage or age (Geddes et al., 2015). Cats with plasma FGF23 below 700 pg/mL had a median survival time of 577 days from the diagnosis of azotemic CKD, while cats with FGF23 between 3,000 and 10,000 pg/mL had a median survival of 277 days (Geddes et al., 2015). Median survival fell further, to 38 days, in cats with plasma FGF23 above 10,000 pg/mL at diagnosis.

A prospective survival study of 27 dogs with various stages of CKD found a significantly increased risk of death in dogs with plasma FGF23 above 450 pg/mL compared with dogs below 450 pg/mL (Rudinsky et al., 2018). Dogs with FGF23 below 450 pg/mL had a median survival of 26 months, while dogs above 450 pg/mL had a median survival of 10 months. However, multivariable analysis was not performed because of the small number of dogs in the study (Rudinsky et al., 2018).

The mechanisms linking FGF23 to shorter survival have not been investigated in cats and dogs, but in people, FGF23 excess has been associated with left ventricular hypertrophy, anemia, and inflammation (Faul et al., 2011; Scialla et al., 2014; Singh et al., 2016; Mehta et al., 2017).

FGF23 and Progression of CKD

In cats, a higher plasma FGF23 has been identified as an independent predictor of disease progression in the first 12 months after the diagnosis of azotemic CKD (Geddes et al., 2015; van den Broek et al., 2018). In the study by Geddes et al. (2015), cats whose plasma creatinine increased by more than 25% within a year of diagnosis had a median baseline FGF23 of 1,243 pg/mL, while cats with stable disease had a median of 504 pg/mL.

Plasma FGF23 is increased before overt renal azotemia develops in cats. Finch et al. (2013) showed that plasma FGF23 was significantly higher in non-azotemic cats that progressed to azotemic CKD within a 12-month follow-up period than in cats that remained non-azotemic. Such observations have not been reported in dogs.

Measuring FGF23

Intact FGF23 can be measured by a sandwich ELISA (Kainos, Tokyo, Japan) in a small volume (0.1 mL) of heparinized plasma, although at the time of writing this test was not available clinically. In geriatric cats, the reference interval for plasma FGF23 appears much higher than in people: 56 to 700 pg/mL, compared with 8.2 to 54.3 pg/mL (Geddes et al., 2013a). In the study by Finch et al. (2013), cats that remained non-azotemic over 12 months generally had plasma FGF23 below 200 pg/mL, which suggests that an upper reference limit of 700 pg/mL for cats is too high. In dogs, no reference interval has been established, but the highest plasma FGF23 found in healthy dogs (449 pg/mL) has been used as the cut-off to define FGF23 excess in this species (Harjes et al., 2017).

For more on this hormone, see our article reviewing the role of FGF-23.

Magnesium

Magnesium is an important mineral for many physiological processes, such as energy (ATP) production and bone formation, and it inhibits soft tissue calcification (Jahnen-Dechent and Ketteler, 2012; Louvet et al., 2013). It is stored mainly in bone and muscle, and only 1% of the body's total magnesium is in serum, where it exists in three forms: ionized, protein-bound, and complexed with anions (Elin, 2010; Jahnen-Dechent and Ketteler, 2012; Humphrey et al., 2015).

Magnesium and IRIS CKD Stage

Plasma total magnesium is relatively stable in cats with IRIS Stage 2 and 3 CKD, and it becomes increased when kidney excretory function is severely impaired in Stage 4 (Barber and Elliott, 1998; van den Broek et al., 2018). In a study of 174 cats with azotemic CKD, hypomagnesemia, defined as a serum total magnesium below 0.71 mmol/L, was found in 9%, 18%, and 10% of cats with IRIS Stage 2, 3, and 4 CKD, respectively (van den Broek et al., 2018). Hypermagnesemia was found in only 3% of cats with Stage 2 CKD and 6% with Stage 3 CKD, but in 50% of cats with Stage 4 CKD. Information on ionized magnesium was not available (van den Broek et al., 2018).

Magnesium and FGF23

In human hemodialysis patients, an inverse relationship has been observed between serum magnesium and FGF23 (Iguchi et al., 2014). The findings in cats with azotemic CKD were very similar: plasma total magnesium was inversely associated with plasma FGF23 at each IRIS CKD stage (van den Broek et al., 2018). Studies in rodents suggest that dietary magnesium intake influences plasma FGF23 (Matsuzaki et al., 2013). Dietary magnesium supplementation could therefore be an additional way to lower plasma FGF23, just as dietary phosphate restriction effectively reduces it (Geddes et al., 2013b).

Magnesium and Survival

Several observational studies have identified hypomagnesemia, based on serum total magnesium, as a risk factor for death in people with CKD, both those on dialysis and those not on dialysis (Ishimura et al., 2007; Kanbay et al., 2012; Van Laecke et al., 2013; Sakaguchi et al., 2014a). Moreover, a higher serum magnesium appears to reduce the mortality risk associated with hyperphosphatemia in people with CKD (Sakaguchi et al., 2014b). In cats, hypomagnesemia at the diagnosis of azotemic CKD was also significantly associated with an increased risk of death, independent of age, packed cell volume, plasma FGF23, and the severity of CKD and proteinuria (van den Broek et al., 2018). The results also suggested that, as in people, higher plasma magnesium reduces the risk of death associated with hyperphosphatemia in cats, but this needs further investigation.

Hypermagnesemia was also associated with an increased risk of death, but not after correcting for IRIS CKD stage, so this association was probably due to the higher prevalence of hypermagnesemia in cats with end-stage CKD (van den Broek et al., 2018).

In unadjusted analysis, hypomagnesemia was associated not only with shorter survival but also with an increased risk of progression of azotemia (van den Broek et al., 2018). This association was lost after correcting for other variables, however, and further studies are needed to assess it.

Measuring Magnesium

Most laboratories can measure total magnesium in serum or heparinized plasma, but EDTA plasma must be avoided because it gives falsely low results (Sharratt et al., 2009). Ionized magnesium is the biologically active form and so might reflect magnesium status better than total magnesium (Bateman, 2012; Humphrey et al., 2015). However, there is no consensus on whether total or ionized magnesium best reflects the body's magnesium status, and current knowledge from the studies in people and cats described above is based on total magnesium. A reference interval for plasma total magnesium of 1.73 to 2.57 mg/dL (0.71 to 1.06 mmol/L) was derived from 120 apparently healthy senior cats (van den Broek et al., 2018).

Bone Disease and Soft Tissue Calcification

The clinical focus in veterinary medicine has been mainly on the biochemical abnormalities associated with CKD in cats and dogs. Less attention has been paid to bone disease (renal osteodystrophy) and soft tissue calcification, which do occur in cats and dogs with CKD, although in the more advanced stages of disease. Osteitis fibrosa cystica and bone resorption most likely result from the high bone turnover caused by secondary renal hyperparathyroidism, and they were reported in early radiographic and necropsy studies of cats with CKD (Lucke, 1968; DiBartola et al., 1987). In dogs, osteodystrophy affects the bones of the face and jaw and can ultimately cause "rubber jaw" (Davis, 2015). Two studies using micro-CT compared the bone structure of cats and dogs with CKD with that of healthy controls. The bones of cats with IRIS Stage 3 and 4 CKD had reduced mineral density and increased cortical porosity (Shipov et al., 2014). A similar study in dogs found relatively mild changes in bone quality, probably because the disease lasts a shorter time in dogs than in cats and people (Shipov et al., 2018).

Vascular calcification, the deposition of calcium phosphate salts in the middle layer of the blood vessel wall, is an important predictor of death from cardiovascular disease in people with CKD (London et al., 2003; Górriz et al., 2015). Increases in serum phosphate and calcium stimulate calcification of the vessel walls, which leads to stiffer blood vessels, increased pulse pressure, and left ventricular hypertrophy (London et al., 2003; Lomashvili et al., 2006; Shanahan et al., 2011). In cats, there is radiographic evidence of calcification of the thoracic and abdominal aorta and of other soft tissues, such as the stomach wall, the kidneys, and the spaces between the toes (DiBartola et al., 1987; Jackson and Barber, 1998; Bertazzolo et al., 2003; Chakrabarti et al., 2013; McLeland et al., 2014).

CKD upsets the balance in serum between promoters of calcification, such as phosphate and calcium, and inhibitors, such as magnesium and fetuin-A. The effect of this imbalance on the tendency of an individual patient's serum to calcify can be measured by an assay called the T50 test (Pasch et al., 2012). An increased serum calcification propensity has been associated with an increased risk of death and with mineral imbalances in people with CKD (Smith et al., 2014; Bielesz et al., 2017). The authors have presented data showing that more severe CKD-MBD appears to be associated with a greater tendency of a cat's serum to calcify (van den Broek et al., 2018, abstract presented at the ACVIM Forum 2018, Seattle, USA). Whether vascular calcification is clinically significant in dogs and cats with CKD, and how it relates to systemic hypertension, is unknown.

Conclusion

The importance of restricting dietary phosphate in patients with CKD has been recognized for many years, and it is a key part of managing CKD in both veterinary and human medicine. Recent advances in understanding the role of the FGF23–α-Klotho axis in the bone and mineral disorders associated with CKD, and recognition of how serum magnesium affects this hormonal system and influences the tendency toward vascular calcification, are important. Routine measurement of serum FGF23 and magnesium could identify the veterinary patients that will benefit most from effective management of these bone and mineral disturbances.

References

  • Barber PJ, Elliott J. Feline chronic renal failure: calcium homeostasis in 80 cases diagnosed between 1992 and 1995. Journal of Small Animal Practice 1998;39:108–116.
  • Bateman S. Disorders of magnesium: magnesium deficit and excess. In: DiBartola SP, ed. Fluid, Electrolyte, and Acid-Base Disorders in Small Animal Practice. St. Louis, MO: Elsevier Saunders, 2012:212–229.
  • Bertazzolo W, Toscani L, Calcaterra S, et al. Clinicopathological findings in five cats with paw calcification. Journal of Feline Medicine and Surgery 2003;5:11–17.
  • Bielesz B, Reiter T, Marculescu R, et al. Calcification propensity of serum is independent of excretory renal function. Scientific Reports 2017;7:17941.
  • Boyd LM, Langston C, Thompson K, Zivin K, Imanishi M. Survival in cats with naturally occurring chronic kidney disease (2000–2002). Journal of Veterinary Internal Medicine 2008;22:1111–1117.
  • Chakrabarti S, Syme HM, Elliott J. Clinicopathological variables predicting progression of azotemia in cats with chronic kidney disease. Journal of Veterinary Internal Medicine 2012;26:275–281.
  • Chakrabarti S, Syme HM, Brown CA, et al. Histomorphometry of feline chronic kidney disease and correlation with markers of renal dysfunction. Veterinary Pathology 2013;50:147–155.
  • Davis EM. Oral manifestations of chronic kidney disease and renal secondary hyperparathyroidism: a comparative review. Journal of Veterinary Dentistry 2015;32:87–98.
  • DiBartola SP, Rutgers HC, Zack PM, et al. Clinicopathologic findings associated with chronic renal disease in cats: 74 cases (1973–1984). Journal of the American Veterinary Medical Association 1987;190:1196–1202.
  • Dittmer KE, Perera KC, Elder PA. Serum fibroblast growth factor 23 concentrations in dogs with chronic kidney disease. Research in Veterinary Science 2017;114:348–350.
  • Elin RJ. Assessment of magnesium status for diagnosis and therapy. Magnesium Research 2010;23:S194–S198.
  • Elliott J, Rawlings JM, Markwell PJ, et al. Survival of cats with naturally occurring chronic renal failure: effect of dietary management. Journal of Small Animal Practice 2000;41:235–242.
  • Faul C, Amaral AP, Oskouei B, et al. FGF23 induces left ventricular hypertrophy. Journal of Clinical Investigation 2011;121:4393–4408.
  • Finch NC, Geddes RF, Syme HM, et al. Fibroblast growth factor 23 (FGF-23) concentrations in cats with early nonazotemic chronic kidney disease (CKD) and in healthy geriatric cats. Journal of Veterinary Internal Medicine 2013;27:227–233.
  • Geddes RF, Finch NC, Elliott J, et al. Fibroblast growth factor 23 in feline chronic kidney disease. Journal of Veterinary Internal Medicine 2013a;27:234–241.
  • Geddes R, Elliott J, Syme H. The effect of feeding a renal diet on plasma fibroblast growth factor 23 concentrations in cats with stable azotemic chronic kidney disease. Journal of Veterinary Internal Medicine 2013b;27:1354–1361.
  • Geddes R, Elliott J, Syme H. Relationship between plasma fibroblast growth factor-23 concentration and survival time in cats with chronic kidney disease. Journal of Veterinary Internal Medicine 2015;29:1494–1501.
  • Górriz JL, Molina P, Cerverón MJ, et al. Vascular calcification in patients with nondialysis CKD over 3 years. Clinical Journal of the American Society of Nephrology 2015.
  • Harjes L, Parker V, Dembek K, Young G, Giovaninni L, Kogika M, Chew D, Toribio R. Fibroblast growth factor-23 concentration in dogs with chronic kidney disease. Journal of Veterinary Internal Medicine 2017;31:784–790.
  • Humphrey S, Kirby R, Rudloff E. Magnesium physiology and clinical therapy in veterinary critical care. Journal of Veterinary Emergency and Critical Care 2015;25:210–225.
  • Iguchi A, Watanabe Y, Iino N, et al. Serum magnesium concentration is inversely associated with fibroblast growth factor 23 in haemodialysis patients. Nephrology 2014;19:667–671.
  • Ishimura E, Okuno S, Yamakawa T, Inaba M, Nishizawa Y. Serum magnesium concentration is a significant predictor of mortality in maintenance hemodialysis patients. Magnesium Research 2007;20:237–244.
  • Jackson HA, Barber PJ. Resolution of metastatic calcification in the paws of a cat with successful dietary management of renal hyperparathyroidism. Journal of Small Animal Practice 1998;39:495–497.
  • Jacob F, Polzin DJ, Osborne CA, et al. Clinical evaluation of dietary modification for treatment of spontaneous chronic renal failure in dogs. Journal of the American Veterinary Medical Association 2002;220:1163–1170.
  • Jahnen-Dechent W, Ketteler M. Magnesium basics. Clinical Kidney Journal 2012;5:i3–i14.
  • Kanbay M, Yilmaz MI, Apetrii M, et al. Relationship between serum magnesium levels and cardiovascular events in chronic kidney disease patients. American Journal of Nephrology 2012;36:228–237.
  • Lomashvili K, Garg P, O'Neill WC. Chemical and hormonal determinants of vascular calcification in vitro. Kidney International 2006;69:1464–1470.
  • London GM, Guérin AP, Marchais SJ, et al. Arterial media calcification in end-stage renal disease: impact on all-cause and cardiovascular mortality. Nephrology Dialysis Transplantation 2003;18:1731–1740.
  • Louvet L, Buchel J, Steppan S, et al. Magnesium prevents phosphate-induced calcification in human aortic vascular smooth muscle cells. Nephrology Dialysis Transplantation 2013;28:869–878.
  • Lucke VM. Renal disease in the domestic cat. Journal of Pathology and Bacteriology 1968;95:67–91.
  • Matsuzaki H, Kajita Y, Miwa M. Magnesium deficiency increases serum fibroblast growth factor-23 levels in rats. Magnesium Research 2013;26:18–23.
  • McLeland SM, Lunn KF, Duncan CG, et al. Relationship among serum creatinine, serum gastrin, calcium-phosphorus product, and uremic gastropathy in cats with chronic kidney disease. Journal of Veterinary Internal Medicine 2014;28:827–837.
  • Mehta R, Cai X, Hodakowski A, et al. Fibroblast growth factor 23 and anemia in the Chronic Renal Insufficiency Cohort Study. Clinical Journal of the American Society of Nephrology 2017;12:1795–1803.
  • Moe S, Drüeke T, Cunningham J, et al. Definition, evaluation, and classification of renal osteodystrophy: a position statement from Kidney Disease: Improving Global Outcomes (KDIGO). Kidney International 2006;69:1945–1953.
  • Nakatani T, Ohnishi M, Razzaque MS. Inactivation of klotho function induces hyperphosphatemia even in presence of high serum fibroblast growth factor 23 levels in a genetically engineered hypophosphatemic (Hyp) mouse model. FASEB Journal 2009;23:3702–3711.
  • Pasch A, Farese S, Graber S, et al. Nanoparticle-based test measures overall propensity for calcification in serum. Journal of the American Society of Nephrology 2012;23:1744–1752.
  • Pereira RC, Jüppner H, Azucena-Serrano CE, et al. Patterns of FGF-23, DMP1, and MEPE expression in patients with chronic kidney disease. Bone 2009;45:1161–1168.
  • Plantinga EA, Everts H, Kastelein AM, et al. Retrospective study of the survival of cats with acquired chronic renal insufficiency offered different commercial diets. Veterinary Record 2005;157:185–187.
  • Ross SJ, Osborne CA, Kirk CA, et al. Clinical evaluation of dietary modification for treatment of spontaneous chronic kidney disease in cats. Journal of the American Veterinary Medical Association 2006;229:949–957.
  • Rudinsky AJ, Harjes LM, Byron J, et al. Factors associated with survival in dogs with chronic kidney disease. Journal of Veterinary Internal Medicine 2018;32:1864–1873.
  • Sakaguchi Y, Fujii N, Shoji T, et al. Hypomagnesemia is a significant predictor of cardiovascular and non-cardiovascular mortality in patients undergoing hemodialysis. Kidney International 2014a;85:174–181.
  • Sakaguchi Y, Fujii N, Shoji T, et al. Magnesium modifies the cardiovascular mortality risk associated with hyperphosphatemia in patients undergoing hemodialysis: a cohort study. PLoS One 2014b;9:e116273.
  • Sakan H, Nakatani K, Asai O, Imura A, Tanaka T, et al. Reduced renal α-Klotho expression in CKD patients and its effect on renal phosphate handling and vitamin D metabolism. PLoS One 2014;9:e86301.
  • Scialla JJ, Xie H, Rahman M, et al. Fibroblast growth factor-23 and cardiovascular events in CKD. Journal of the American Society of Nephrology 2014;25:349–360.
  • Shanahan CM, Crouthamel MH, Kapustin A, et al. Arterial calcification in chronic kidney disease: key roles for calcium and phosphate. Circulation Research 2011;109:697–711.
  • Sharratt CL, Gilbert CJ, Cornes MC, et al. EDTA sample contamination is common and often undetected, putting patients at unnecessary risk of harm. International Journal of Clinical Practice 2009;63:1259–1262.
  • Shimada T, Hasegawa H, Yamazaki Y, et al. FGF-23 is a potent regulator of vitamin D metabolism and phosphate homeostasis. Journal of Bone and Mineral Research 2004a;19:429–435.
  • Shimada T, Kakitani M, Yamazaki Y, et al. Targeted ablation of Fgf23 demonstrates an essential physiological role of FGF23 in phosphate and vitamin D metabolism. Journal of Clinical Investigation 2004b;113:561–568.
  • Shipov A, Segev G, Meltzer H, et al. The effect of naturally occurring chronic kidney disease on the micro-structural and mechanical properties of bone. PLoS One 2014;9:e110057.
  • Shipov A, Shahar R, Sugar N, Segev G. The influence of chronic kidney disease on the structural and mechanical properties of canine bone. Journal of Veterinary Internal Medicine 2018;32:280–287.
  • Singh S, Grabner A, Yanucil C, et al. Fibroblast growth factor 23 directly targets hepatocytes to promote inflammation in chronic kidney disease. Kidney International 2016;90:985–996.
  • Slatopolsky E. The intact nephron hypothesis: the concept and its implications for phosphate management in CKD-related mineral and bone disorder. Kidney International Supplement 2011:S3–S8.
  • Smith ER, Ford ML, Tomlinson LA, et al. Serum calcification propensity predicts all-cause mortality in predialysis CKD. Journal of the American Society of Nephrology 2014;25:339–348.
  • Urakawa I, Yamazaki Y, Shimada T, et al. Klotho converts canonical FGF receptor into a specific receptor for FGF23. Nature 2006;444:770–774.
  • van den Broek DHN, Chang YM, Elliott J, Jepson RE. Prognostic importance of plasma total magnesium in a cohort of cats with azotemic chronic kidney disease. Journal of Veterinary Internal Medicine 2018;32:1359–1371.
  • Van Laecke S, Nagler EV, Verbeke F, et al. Hypomagnesemia and the risk of death and GFR decline in chronic kidney disease. American Journal of Medicine 2013;126:825–831.