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Assessment of calcium and phosphate homeostasis in chronic kidney disease
/content/chapter/10.22233/9781910443354.chap11
Assessment of calcium and phosphate homeostasis in chronic kidney disease
- Authors: Rebecca Geddes and Jonathan Elliott
- From: BSAVA Manual of Canine and Feline Nephrology and Urology
- Item: Chapter 11, pp 143 - 150
- DOI: 10.22233/9781910443354.11
- Copyright: © 2017 British Small Animal Veterinary Association
- Publication Date: January 2017
Abstract
The reduction in the number of functioning nephrons associated with chronic kidney disease affects the homeostasis of a number of solutes excreted in the urine, including phosphate and calcium. This chapter will review the physiology of phosphate homeostasis, the pathophysiology of chronic kidney disease-mineral and bone disorder at different stages of chronic kidney disease and discuss the potential utility of the hormones involved as prognostic markers and indicators of response to treatment.
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11.1
The main stimulus of parathyroid hormone (PTH) secretion by the parathyroid glands is a decrease in extracellular fluid (ECF) ionized calcium (Ca2+). PTH acts to increase ionized calcium concentration, but also has effects on phosphate (P) concentration. PTH decreases excretion of calcium and increases excretion of phosphate by the kidney. It also increases production of calcitriol by the kidney, and both calcitriol and PTH stimulate release of calcium and phosphate from bone. Calcitriol also increases absorption of calcium and phosphate in the intestines. Overall, therefore, ECF calcium concentrations are increased and phosphate concentrations are kept approximately stable. Once ECF calcium is normalized, secretion of PTH is inhibited, forming a homeostatic feedback loop. Drawn by S.J. Elmhurst BA Hons (www.livingart.org.uk) and reproduced with her permission. © 2017 British Small Animal Veterinary Association
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11.1
The main stimulus of parathyroid hormone (PTH) secretion by the parathyroid glands is a decrease in extracellular fluid (ECF) ionized calcium (Ca2+). PTH acts to increase ionized calcium concentration, but also has effects on phosphate (P) concentration. PTH decreases excretion of calcium and increases excretion of phosphate by the kidney. It also increases production of calcitriol by the kidney, and both calcitriol and PTH stimulate release of calcium and phosphate from bone. Calcitriol also increases absorption of calcium and phosphate in the intestines. Overall, therefore, ECF calcium concentrations are increased and phosphate concentrations are kept approximately stable. Once ECF calcium is normalized, secretion of PTH is inhibited, forming a homeostatic feedback loop. Drawn by S.J. Elmhurst BA Hons (www.livingart.org.uk) and reproduced with her permission.
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11.2
Renal function curves for phosphate excretion. In the normal situation, phosphate ions appear in the urine once plasma phosphate exceeds the reabsorptive transport maximum for phosphate. Above the threshold, if dietary intake of phosphate increases, phosphate excretion increases. The slope of the curve is dependent on glomerular filtration rate (GFR), although its position is shifted to the left by increases in parathyroid hormone (PTH) and fibroblast growth factor (FGF)-23, both of which reduce the number of sodium–phosphate co-transporters in the proximal tubules, thereby increasing phosphate excretion. In CKD, as GFR falls the gradient of this renal excretion curve becomes less steep and the plasma phosphate concentration for a given dietary intake will increase, despite increases in plasma PTH and FGF-23. (Modified after
Geddes et al., 2013c
with permission from the Journal of Veterinary Emergency and Critical Care) © 2017 British Small Animal Veterinary Association
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11.2
Renal function curves for phosphate excretion. In the normal situation, phosphate ions appear in the urine once plasma phosphate exceeds the reabsorptive transport maximum for phosphate. Above the threshold, if dietary intake of phosphate increases, phosphate excretion increases. The slope of the curve is dependent on glomerular filtration rate (GFR), although its position is shifted to the left by increases in parathyroid hormone (PTH) and fibroblast growth factor (FGF)-23, both of which reduce the number of sodium–phosphate co-transporters in the proximal tubules, thereby increasing phosphate excretion. In CKD, as GFR falls the gradient of this renal excretion curve becomes less steep and the plasma phosphate concentration for a given dietary intake will increase, despite increases in plasma PTH and FGF-23. (Modified after
Geddes et al., 2013c
with permission from the Journal of Veterinary Emergency and Critical Care)
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11.3
Fibroblast growth factor (FGF)-23 is secreted mostly from bone in response to raised plasma phosphate or calcitriol concentrations. In the kidney, FGF-23 increases phosphate excretion using the same mechanism as parathyroid hormone (PTH), but it also inhibits calcitriol formation. FGF-23 also inhibits PTH secretion. Therefore, there is no drive to resorb calcium (Ca2+) or phosphate (P) from bone and no increase in absorption of calcium or phosphate from the intestines in response to FGF-23 (this contrasts with PTH; see
Figure 11.1
). Overall, extracellular fluid (ECF) phosphate concentrations decrease and calcium concentrations remain approximately stable in response to increased secretion of FGF-23. Once ECF phosphate is normalized, secretion of FGF-23 is inhibited, forming a homeostatic feedback loop. Drawn by S.J. Elmhurst BA Hons (www.livingart.org.uk) and reproduced with her permission. © 2017 British Small Animal Veterinary Association
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11.3
Fibroblast growth factor (FGF)-23 is secreted mostly from bone in response to raised plasma phosphate or calcitriol concentrations. In the kidney, FGF-23 increases phosphate excretion using the same mechanism as parathyroid hormone (PTH), but it also inhibits calcitriol formation. FGF-23 also inhibits PTH secretion. Therefore, there is no drive to resorb calcium (Ca2+) or phosphate (P) from bone and no increase in absorption of calcium or phosphate from the intestines in response to FGF-23 (this contrasts with PTH; see
Figure 11.1
). Overall, extracellular fluid (ECF) phosphate concentrations decrease and calcium concentrations remain approximately stable in response to increased secretion of FGF-23. Once ECF phosphate is normalized, secretion of FGF-23 is inhibited, forming a homeostatic feedback loop. Drawn by S.J. Elmhurst BA Hons (www.livingart.org.uk) and reproduced with her permission.
/content/figure/10.22233/9781910443354.chap11.ch11fig4
11.4
Cats were divided into four groups according to a modified IRIS staging system: control group: plasma creatinine concentration ≤177 μmol/l (n = 44); Stage 2: plasma creatinine concentration 177–250 μmol/l (n = 20); Stage 3: plasma creatinine concentration 250–440 μmol/l (n = 22); and Stage 4: plasma creatinine concentration >440 μmol/l (n = 14). The boxes represent the 25th and 75th percentiles and the central lines in the boxes represent the median values. The whiskers represent the range of concentrations. The scale for fibroblast growth factor (FGF)-23 is logarithmic. The dotted lines represent the upper and lower limits of the 95% reference interval for FGF-23 in geriatric cats. The Kruskal–Wallis test and Mann–Whitney U tests with Bonferroni correction found that FGF-23 concentrations were significantly different among all four groups (Kruskal–Wallis test: P <0.001, Mann–Whitney U tests all P <0.002). (Modified after
Geddes et al., 2013b
with permission from the Journal of Veterinary Internal Medicine) © 2017 British Small Animal Veterinary Association
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11.4
Cats were divided into four groups according to a modified IRIS staging system: control group: plasma creatinine concentration ≤177 μmol/l (n = 44); Stage 2: plasma creatinine concentration 177–250 μmol/l (n = 20); Stage 3: plasma creatinine concentration 250–440 μmol/l (n = 22); and Stage 4: plasma creatinine concentration >440 μmol/l (n = 14). The boxes represent the 25th and 75th percentiles and the central lines in the boxes represent the median values. The whiskers represent the range of concentrations. The scale for fibroblast growth factor (FGF)-23 is logarithmic. The dotted lines represent the upper and lower limits of the 95% reference interval for FGF-23 in geriatric cats. The Kruskal–Wallis test and Mann–Whitney U tests with Bonferroni correction found that FGF-23 concentrations were significantly different among all four groups (Kruskal–Wallis test: P <0.001, Mann–Whitney U tests all P <0.002). (Modified after
Geddes et al., 2013b
with permission from the Journal of Veterinary Internal Medicine)
/content/figure/10.22233/9781910443354.chap11.ch11fig5
11.5
The traditional versus recently updated views of the ‘trade-off’ hypothesis. Under the classical explanation of the ‘trade-off’ hypothesis, the reduction in glomerular filtration rate (GFR) leads to reduced phosphate ion clearance in the kidney and therefore to an increase in plasma phosphate concentration. Increasing plasma phosphate stimulates parathyroid hormone (PTH) secretion directly, and indirectly via inhibition of calcitriol production in the kidney and by reducing plasma ionized calcium (iCa) concentration via the law of mass action. The ‘trade-off’ for an increase in phosphate ion excretion is an increase in plasma PTH concentration, leading to a number of deleterious effects. In the updated hypothesis, the decrease in phosphate ion clearance stimulates fibroblast growth factor (FGF)-23 secretion, which increases the fractional excretion (FE) of phosphate ions and inhibits calcitriol production in the kidney in early CKD. This maintains plasma phosphate concentration within normal limits. In late stage CKD, the kidney is unable to increase the FE of phosphate ions any further owing to low nephron mass, and hyperphosphataemia develops. Increased plasma phosphate, reduced calcitriol and reduced ionized calcium all drive the increase in PTH concentration, and the clinical manifestations of chronic kidney disease mineral and bone disorders (CKD-MBD) develop. (Modified after
Geddes et al., 2013c
with permission from the Journal of Veterinary Emergency and Critical Care) © 2017 British Small Animal Veterinary Association
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11.5
The traditional versus recently updated views of the ‘trade-off’ hypothesis. Under the classical explanation of the ‘trade-off’ hypothesis, the reduction in glomerular filtration rate (GFR) leads to reduced phosphate ion clearance in the kidney and therefore to an increase in plasma phosphate concentration. Increasing plasma phosphate stimulates parathyroid hormone (PTH) secretion directly, and indirectly via inhibition of calcitriol production in the kidney and by reducing plasma ionized calcium (iCa) concentration via the law of mass action. The ‘trade-off’ for an increase in phosphate ion excretion is an increase in plasma PTH concentration, leading to a number of deleterious effects. In the updated hypothesis, the decrease in phosphate ion clearance stimulates fibroblast growth factor (FGF)-23 secretion, which increases the fractional excretion (FE) of phosphate ions and inhibits calcitriol production in the kidney in early CKD. This maintains plasma phosphate concentration within normal limits. In late stage CKD, the kidney is unable to increase the FE of phosphate ions any further owing to low nephron mass, and hyperphosphataemia develops. Increased plasma phosphate, reduced calcitriol and reduced ionized calcium all drive the increase in PTH concentration, and the clinical manifestations of chronic kidney disease mineral and bone disorders (CKD-MBD) develop. (Modified after
Geddes et al., 2013c
with permission from the Journal of Veterinary Emergency and Critical Care)
/content/figure/10.22233/9781910443354.chap11.ch11fig6
11.6
Soft tissue calcification affecting the kidneys and gastric wall, with some mestastatic calcification evident in the abdominal vasculature, due to chronic kidney disease mineral and bone disorder (CKD-MBD) in an 11-year-old male Domestic Shorthaired Cat. Radiograph taken post mortem. (Reproduced from
Barber, 1998
) © 2017 British Small Animal Veterinary Association
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11.6
Soft tissue calcification affecting the kidneys and gastric wall, with some mestastatic calcification evident in the abdominal vasculature, due to chronic kidney disease mineral and bone disorder (CKD-MBD) in an 11-year-old male Domestic Shorthaired Cat. Radiograph taken post mortem. (Reproduced from
Barber, 1998
)
/content/figure/10.22233/9781910443354.chap11.ch11fig7
11.7
Post-mortem (a) lateral radiograph of the proximal humerus and (b) cranial–caudal radiograph of the proximal tibia of a cat with severe chronic kidney disease (CKD) and marked CKD-mineral and bone disorder (CKD-MBD). Note the cystic lesions in both long bones leading to thinning of the cortices. (Reproduced from
Barber, 1998
) © 2017 British Small Animal Veterinary Association
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11.7
Post-mortem (a) lateral radiograph of the proximal humerus and (b) cranial–caudal radiograph of the proximal tibia of a cat with severe chronic kidney disease (CKD) and marked CKD-mineral and bone disorder (CKD-MBD). Note the cystic lesions in both long bones leading to thinning of the cortices. (Reproduced from
Barber, 1998
)