Geddes et al., 2013. Role of phosphorus in the pathophysiology of chronic kidney disease

State of the Art Review
Journal of Veterinary Emergency and Critical Care 23(2) 2013, pp 122–133
doi: 10.1111/vec.12032
The role of phosphorus in the
pathophysiology of chronic kidney disease
Rebecca F. Geddes, MA, VetMB, MRCVS; Natalie C. Finch, BVSc, PhD, MRCVS; Harriet M. Syme,
BSc, BVetMed, PhD, DACVIM, DECVIM-CA, MRCVS and Jonathan Elliott, MA, VetMB, PhD,
DECVPT, MRCVS
Abstract
Objective – To review the human and veterinary literature on the role of phosphorus in the pathophysiology of
chronic kidney disease (CKD) and to explore why control of plasma phosphorus concentration is an important
goal in the management of patients with this disease.
Data Sources – Human and veterinary studies, reviews, clinical reports, textbooks, and recent research findings
focused on phosphate homeostasis and CKD patient management.
Human Data Synthesis – Recent studies using rodent models and human patients with CKD have focused
on trying to elucidate the role of the phosphatonins, predominantly fibroblast growth factor-23, in phosphate
homeostasis and the pathophysiology of secondary renal hyperparathyroidism (SRHP). Fibroblast growth
factor-23 is now considered to be a key regulator of plasma phosphorus concentration in people but has only
recently been investigated in companion animal species.
Veterinary Data Synthesis – Cross-sectional studies of naturally occurring CKD in dogs and cats have shown
hyperphosphatemia and SRHP to be highly prevalent and associated with increased morbidity and mortality
in these patients. Experimental studies of surgically induced renal impairment in the dog and cat, and cases
of naturally occurring CKD have emphasized the ability of renal care diets to modify plasma phosphorus and
parathyroid hormone concentrations. Evidence from these studies indicates that maintaining plasma phosphorus concentrations to within the International Renal Interest Society targets for CKD patients improves survival
time and reduces clinical manifestations of hyperphosphatemia and SRHP.
Conclusions – The maintenance of plasma phosphorus concentrations in to within the International Renal
Interest Society targets is recommended in management of CKD patients. The discovery of the phosphatonins
has improved understanding of the mechanisms involved in phosphorus homeostasis and SRHP and may lead
to improved ability to monitor and manage these patients.
(J Vet Emerg Crit Care 2013; 23(2): 122–133) doi: 10.1111/vec.12032
Keywords: cat, diet, dog, FGF-23, hyperparathyroidism, renal
Abbreviations
From the Department of Veterinary Clinical Sciences, Royal Veterinary College, Hawkshead Lane, North Mymms, Hatfield, AL9 7TA, UK (Geddes,
Syme); and Department of Veterinary Basic Sciences, Royal Veterinary
College, Royal College Street, Camden, London, NW1 0TU, UK (Finch,
Elliott).
Dr. Natalie C. Finch’s current address is School of Veterinary Sciences, University of Bristol, Langford, Bristol, BS40 5DU, UK.
The Renal Research Clinic at the RVC acknowledges support from Royal
Canin for its research on feline hyperphosphataemia and chronic kidney
disease. R. Geddes is also in receipt of an Everts Luff Trust Research Training
Fellowship.
Address correspondence and requests for reprints to
Ms. Rebecca Geddes, Department of Veterinary Clinical Sciences, The Royal
Veterinary College, Hawkshead Lane, North Mymms, Hertfordshire, AL9
7TA, UK.
Email: [email protected]
Submitted March 2, 2012; Accepted February 2, 2013.
122
CKD
Cr
FGF-7
FGF-23
GFR
GI
IRIS
ME
MF
NPD
PTH
RF
RPD
SRHP
chronic kidney disease
creatinine
fibroblast growth factor-7
fibroblast growth factor-23
glomerular filtration rate
gastrointestinal
International Renal Interest Society
metabolizable energy
maintenance food
normal phosphorus diet
parathyroid hormone
renal food
restricted phosphorus diet
secondary renal hyperparathyroidism
C Veterinary Emergency and Critical Care Society 2013
Role of phosphorus in the pathophysiology of CKD
UPC
USG
urine protein:creatinine ratio
urine specific gravity
CKD, starting with phosphorus homeostasis, and explores the importance of control of plasma phosphorus
to within the IRIS targets in the management of these
cases.
Introduction
Feline chronic kidney disease (CKD) is a common medical condition and the prevalence increases with advancing age. Thirty-one percent of cats over 15 years of age
are reported to be affected,1 and in one study, 30.5%
of nonazotemic geriatric cats (≥9 years of age) developed azotemia within 12 months.2 In many cases, the
underlying cause of feline CKD is unknown and may
not be identified even if histopathology of renal tissue
is carried out. In one report, over 50% of cases had
a morphological diagnosis recorded as chronic tubulointerstitial nephritis of unknown cause.3 CKD is less
prevalent in dogs and the age at onset is more variable due to a number of breed-associated diseases affecting the canine kidney. In one study of dogs presenting at 24 primary care veterinary practices in the
United Kingdom, 111 cases were confirmed to have
kidney dysfunction from a total of 10,700 cases presented for vaccination (1%).4 Confirmation of kidney
dysfunction in this study was based on plasma urea and
creatinine concentrations, urinary protein, and urine
sediment evaluation. Renal histological material was
available for 76 of the 111 cases; 52% of cases were
found to have glomerular disease and 48% to have nonglomerular disease.4
Reduction in the number of functioning nephrons affects the homeostasis of a number of solutes primarily excreted in the urine, including phosphorus. Hyperphosphatemia is thought to be the initiating factor
in the development of secondary renal hyperparathyroidism (SRHP), which is considered a common complication, with parathyroid hormone (PTH) concentrations reported to be increased in 84% of cats and 76%
of dogs with CKD.5, 6 Plasma phosphorus concentration is associated with survival of cats and dogs with
CKD,5, 7–11 and is therefore an important consideration
when treating these cases. The International Renal Interest Society (IRIS) provides a staging system for use in
dogs and cats with CKD. This staging system is based
on fasting plasma creatinine concentrations in the stable
CKD patient, using creatinine as a marker for glomerular filtration rate (GFR), with substaging based on urine
protein:creatinine ratio and blood pressure. In 2006, recommendations for the control of plasma phosphorus in
cats and dogs with CKD were proposed by a group of
veterinary nephrologists, and targets for plasma phosphorus were established for each IRIS stage (Table 1).
This review discusses the current knowledge regarding the role of phosphorus in the pathophysiology of
C Veterinary Emergency and Critical Care Society 2013, doi: 10.1111/vec.12032
Phosphorus
hypothesis
homeostasis
and
the
“trade-off”
Inorganic phosphorus is an important component of living cells and is an essential structural component of
bones and teeth in mammals. Phosphorus homeostasis requires a balance between dietary intake, exchange
of phosphorus between extracellular and bone storage
pools, and renal excretion. The physiological regulation of phosphorus is incompletely understood. It is interlinked with calcium homeostasis; both minerals are
subject to control by the calcitropic hormones, PTH and
calcitriol, and an increase in plasma phosphorus concentration causes a reciprocal decrease in ionized calcium
concentration via the law of mass action. Calcitriol (1,25dihydroxycholecalciferol) increases phosphorus and calcium absorption from the gastrointestinal (GI) tract. PTH
increases phosphorus and calcium resorption from bone
and acts to increase calcium reabsorption and decrease
phosphorus reabsorption from the glomerular filtrate in
the renal tubules. Increased plasma phosphorus concentration stimulates increased PTH secretion and inhibits
formation of calcitriol in the kidney, forming homeostatic feedback loops. However, over the last 11 years
a number of phosphorus-regulating hormones, termed
the “phosphatonins” have been proposed, and research
is just beginning to be published on the role of these hormones in veterinary species. A more detailed discussion
of phosphatonins can be found elsewhere in this issue.12
In the healthy kidney, phosphate ions are freely filtered
at the glomerulus and their excretion is controlled by
an overflow mechanism; in people, if plasma inorganic
phosphorus concentrations fall below approximately
1 mmol/L (3.1 mg/dL), all of the phosphate ions in
the glomerular filtrate are reabsorbed,13 whereas above
this threshold, the rate of phosphate loss is directly proportional to the plasma inorganic phosphorus concentration, with GFR determining the steepness of this relationship. PTH reduces proximal tubular capacity to
reabsorb phosphate ions (mediated by type II sodiumdependent phosphate transporters, NaPi-IIa), reducing
the threshold plasma concentration at which phosphate
ions appear in the urine and thereby rapidly increasing
phosphate ion loss in urine (see Figure 1). The phosphatonin fibroblast growth factor-23 (FGF-23) has the same
action on NaPi-IIa, as discussed below.
In CKD, GFR decreases as the number of functioning nephrons declines and this reduces the excretion
123
R. F. Geddes et al.
Table 1: The International Renal Interest Society (IRIS) targets for plasma phosphorus
Plasma creatinine
Target plasma phosphorus
Dogs
Cats
Dogs and cats
IRIS stage
mg/dL
␮mol/L
mg/dL
␮mol/L
mg/dL
mmol/L
1
2
3
4
<1.4
1.4–2.0
2.1–5.0
>5.0
<125
125–179
180–439
>440
<1.6
1.6–2.8
2.9–5.0
>5.0
<140
140–249
250–439
>440
N/A
2.5–4.5
2.5–5.0
2.5–6.0
N/A
0.81–1.45
0.81–1.61
0.81–1.94
of phosphate ions by decreasing the slope of the relationship between plasma phosphate concentration and
urinary phosphate ion excretion (see Figure 1). An increase in plasma inorganic phosphorus concentration
stimulates PTH secretion directly and indirectly (see Figure 2), and PTH subsequently inhibits phosphate ion
reabsorption in the proximal tubules, acting to increase
fractional excretion of phosphate by the kidney. However, PTH is principally a hormone regulating plasma
ionized calcium concentration, and as such, it also acts to
increase calcium and phosphate ion efflux from bone and
stimulates calcitriol production by the kidney (which
increases calcium and phosphorus absorption from the
small intestine). This serves overall to increase ionized
calcium concentrations and decrease phosphorus concentrations, but the limitation in the mechanism is that
phosphorus can only be excreted via the kidney. In CKD,
if GFR continues to decline and dietary phosphorus
intake remains stable, phosphorus retention will ultimately occur, leading to whole body overload with phosphorus, hyperphosphatemia, and increased plasma PTH
concentrations. Chronic elevation of PTH leads to demineralization of bone. Additionally, phosphorus deposition occurs in soft tissues and mineralization ensues, a
phenomenon which is thought to contribute to progressive kidney injury (ie, when the kidneys become mineralized) and to the extra-renal (particularly cardiovascular)
effects of SRHP.
Originally described in the early 1970s, this description of the pathophysiology of SRHP is known as the
“trade-off hypothesis,”14 where the “trade-off” for the
increased fractional excretion of phosphorus by each remaining nephron, is the chronic elevation in PTH (see
Figure 2). Over the past 40 years this hypothesis has been
greatly expanded, although many aspects of phosphorus
sensing and homeostasis still remain unclear.
Current Published Human Research Information
and Data
Phosphatonins
The presence of hormones primarily involved in
phosphorus regulation was first proposed in the 1990s
124
Figure 1: Renal function curves for phosphorus excretion. In the
normal situation, phosphate ions appear in the urine once plasma
phosphate exceeds 3.1 mg/dL (1 mmol/L) as this exceeds the
reabsorptive transport maximum for phosphorus. The slope of
the curve is dependent on GFR although its position is shifted
to the left by increases in PTH and FGF-23, both of which reduce the transport maximum for phosphate ion absorption in the
proximal tubule and increase phosphate ion excretion at a given
plasma phosphorus concentration. At stable GFR, for a given dietary phosphorus intake, the daily excretion of phosphorus in
the urine will match phosphorus intake (dietary intake minus
fecal losses) and the plasma phosphorus concentration at which
this occurs will be influenced by the prevailing PTH and FGF-23
concentrations. In CKD, as GFR falls the gradient of this renal excretion curve becomes less steep and plasma phosphate concentration for a given dietary intake will increase despite increases
in plasma PTH and FGF-23. GFR, glomerular filtration rate; PTH,
parathyroid hormone; FGF-23, fibroblast growth factor-23; CKD,
chronic kidney disease.
following investigations of human patients and animal
models with conditions characterized by severe derangements in phosphorus homeostasis. A number of phosphatonins have now been identified: FGF-23, secreted
frizzled-related protein 4, matrix extracellular phosphoglycoprotein, and FGF-7;15, 16 however, FGF-23 remains
the most thoroughly studied of these hormones.
FGF-23 is secreted primarily by osteocytes17 and
osteoblasts18 in response to increased plasma phosphorus or calcitriol concentrations.19 To bind to its receptor, FGFR1c, FGF-23 requires a co-factor, Klotho, which
exists in both membrane bound and circulating forms.
This heterodimeric receptor, Klotho-FGFR1c, appears to
C Veterinary Emergency and Critical Care Society 2013, doi: 10.1111/vec.12032
Role of phosphorus in the pathophysiology of CKD
Figure 2: Schematic presenting the traditional and recently updated views of the “trade-off” hypothesis. In the traditional hypothesis,
the reduction in GFR leads to reduced phosphate ion clearance in the kidney and therefore to an increase in plasma phosphorus
concentration. Increasing plasma phosphorus stimulates PTH secretion directly, and indirectly via inhibition of calcitriol production
in the kidney and by reducing plasma ionized calcium 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 FGF-23 secretion, which increases the FE of phosphate ions and inhibits
calcitriol production in the kidney in early CKD. This maintains plasma phosphorus concentration within normal limits. In late-stage
CKD, the kidney is unable to increase the FE of phosphate ions any further due to low nephron mass, and hyperphosphatemia develops.
The increased plasma phosphorus, reduced calcitriol, and reduced ionized calcium all drive the increase in PTH concentration and the
clinical manifestations of SRHP develop. GFR, glomerular filtration rate; PTH, parathyroid hormone; CKD, chronic kidney disease; FE,
fractional excretion; SRHP, secondary renal hyperparathyroidism; FGF-23, fibroblast growth factor-23.
be predominantly expressed in the kidney, parathyroid,
and pituitary glands,20 however, Klotho gene expression has also been detected in the choroid plexus21 and
sinoatrial node.22 In the kidney, FGF-23 acts to regulate
phosphorus and calcitriol homeostasis through regulation of the sodium-phosphorus type II co-transporters
(NaPi-IIa and NaPi-IIc)15 and the vitamin D synthesis
enzyme (25-hydroxyvitamin D-1␣-hydroxylase).20 In the
parathyroid gland, it acts to decrease PTH production
and secretion.23
FGF-23 is a low molecular weight protein that has
been hypothesized to be excreted by the kidney and
is therefore likely to accumulate in CKD due to reduced renal clearance.24 FGF-23 in serum from CKD
patients is predominantly that of the full-length molecular weight, termed intact FGF-23, rather than FGF-23
fragments24 and it has been well documented that circulating intact FGF-23 increases with declining renal
C Veterinary Emergency and Critical Care Society 2013, doi: 10.1111/vec.12032
function in people.24–27 The correlation of serum FGF23 concentration and GFR suggests that reduced GFR in
CKD is an important determinant of circulating FGF-23
concentration,28 but serum FGF-23 is also affected by additional factors. In a number of studies involving people
and rodents, FGF-23 concentrations increased during dietary phosphorus loading and decreased with dietary
phosphorus restriction.29–31
Although the role of FGF-23 has yet to be thoroughly
explored in companion animals, it is appropriate to update the working hypothesis for the pathophysiology of
hyperphosphatemia in CKD based on the observations
in the human literature.
An updated “trade-off” hypothesis still begins with
phosphorus retention developing as GFR starts to decline in the failing kidney, but it is necessary to consider the mechanisms involved in early CKD and latestage CKD separately. In early CKD, the increase in
125
R. F. Geddes et al.
phosphorus will drive an increase in FGF-23 concentration (via a currently unknown sensor), which has a
number of effects. First, there will be inhibition of the
sodium-phosphorus co-transporters in the kidney which
will act to increase fractional excretion of phosphorus
in the remaining nephrons. Second, inhibition of 1␣hydroxlyase, by increased phosphorus and FGF-23, will
result in lower concentrations of calcitriol, thereby decreasing phosphorus absorption from the GI tract. Third,
FGF-23 will cause direct inhibition of PTH secretion via
activation of Klotho-FGFR1c in the parathyroid gland
cells. The inhibition of PTH will prevent the drive to
increase ionized calcium concentration that also results
in a concurrent increase in phosphorus concentration
when calcium and phosphorus are released from bone
in response to PTH. In patients with early CKD this increase in FGF-23, and consequent increase in urinary
phosphate ion excretion, will therefore be enough to restore phosphorus homeostasis and prevent the development of SRHP (see Figure 2). In support of this theory, it has been observed that in human patients with
CKD, a rise in FGF-23 concentrations and fall in calcitriol concentrations precedes the development of overt
hyperphosphatemia.26
In more severe CKD, there will be 3 main reasons that
FGF-23 will continue to increase. First, as GFR decreases,
intact FGF-23 will also increase because it is freely filtered
at the glomerulus. Second, once GFR drops to below a
critical rate (which has shown to be 30 mL/min/1.73 m2
in human patients), plasma phosphate concentrations
start to increase28, 32 and will stimulate FGF-23 secretion. Third, end organ resistance to FGF-23 will develop
as a result of reduced expression of FGFR1 and Klotho
mRNA, leading to downregulation of the Klotho-FGFR1
receptors and resulting in FGF-23 losing its direct inhibition of PTH.23, 33 At this point FGF-23 might be considered a uremic toxin, because it will continue to decrease
calcitriol concentrations without hypophosphatemic action. Reduced calcitriol will both reduce inhibition of
PTH secretion in the parathyroid gland and indirectly
increase PTH secretion via reduced GI uptake of ionized
calcium leading to reduced plasma ionized calcium. Low
plasma ionized calcium concentration then becomes a
major driving force for a rise in PTH, and additionally, hyperphosphatemia will stimulate PTH secretion
directly.34, 35
The development of overt hyperphosphatemia will
only occur late in the progression of SRHP in this model
because PTH and FGF-23 are both phosphaturic, and the
fractional excretion of phosphorus is at its highest in patients with both high FGF-23 and high PTH.36 Therefore,
the increases in both of these hormones will compensate for the reduction in nephron mass until GFR falls
below 30 mL/min/1.73 m2 , at which stage plasma phos126
phate concentrations have been shown to increase.28, 32
In end-stage CKD there is loss of all feedback on PTH
through downregulation of not only FGFR1-Klotho, but
also the vitamin D receptor and the calcium sensing receptor in the parathyroid glands,23 resulting in hyperphosphatemia and calcitriol deficiency despite vastly increased plasma concentrations of FGF-23 and PTH (see
Figure 2).
FGF-23 has been shown to predict the progression of
CKD in human patients.27 This is potentially a very important finding, since increased plasma FGF-23 concentration (defined as FGF-23 > 50 pg/mL) in human CKD
patients is up to 6 times more prevalent in the mild stages
of CKD than increased plasma PTH concentrations (defined as PTH > 40 ng/L).36 FGF-23 concentrations are
also independently and directly associated with mortality rate in patients starting hemodialysis for CKD,
with a strong concentration-dependent relationship.37 At
present, it is unclear whether FGF-23 is a uremic toxin, or
whether it could be a surrogate marker for other causes of
uremic toxicity in these patients. Answering this question may clarify whether increased FGF-23 concentrations should be a target of treatment or just used as a
marker of disease severity.
Current Published Veterinary Information
The prevalence of hyperphosphatemia and SRHP in
CKD
Hyperphosphatemia and SRHP are highly prevalent in
both feline and canine CKD patients. Barber and Elliott
identified an overall prevalence of hyperparathyroidism
of 84% in cats with CKD.5 The 80 cats with naturally
occurring CKD (plasma creatinine [Cr] >177 ␮mol/L
[>2.0 mg/dL]) included in this study were categorized
subjectively into 3 groups; “compensated” for cats with
no clinical signs (mean Cr 229 ␮mol/L [2.6 mg/dL]),
“uremic” for cats with historical and physical examination findings compatible with the uremic syndrome
(mean Cr 316 ␮mol/L [3.6 mg/dL]), and “end-stage”
(mean Cr 909 ␮mol/L [10.3 mg/dL]). Hyperparathyroidism was the most common abnormality of calciumphosphorus (Ca-P) homeostasis, with plasma PTH concentrations increased in 47% of the compensated cases,
87% of the uremic cases, and 100% of the end-stage cases.
Hyperphosphatemiaa was present in 20% of the compensated cases, 49% of the uremic cases, and 100% of the
end-stage cases. SRHP was present in 13% of cases which
had normal ionized calcium and plasma phosphorus
concentrations. Calcitriol concentrations were assayed
in 31 cases and 11 of these (including 8/10 [80%] in the
end-stage group) were below the reference interval.
Similar findings have been published for cases of
canine CKD. Cortedellas and colleagues published a
C Veterinary Emergency and Critical Care Society 2013, doi: 10.1111/vec.12032
Role of phosphorus in the pathophysiology of CKD
study of 54 dogs with CKD, diagnosed based on persistent proteinuria (urine protein:creatinine ratio ≥0.5)
or azotemia (Cr ≥ 125 ␮mol/L [1.4 mg/dL]) with a
concurrent urine specific gravity <1.025, and classified
the cases according to the IRIS staging system.6 Again,
hyperparathyroidism was the most common abnormality of Ca-P homeostasis, occurring in 75.9% of cases
overall and increasing in prevalence with IRIS stage:
36.4% of stage 1, 50% of stage 2, 96% of stage 3, and
100% of stage 4 cases. Hyperphosphatemiab was documented in 68.5% of dogs, again increasing in prevalence with increasing IRIS stage: 18% of stage 1, 40%
of stage 2, 92% of stage 3, and 100% of stage 4. Calcitriol concentrations were below the reference range
in 10 cases, 5/25 (20%) in stage 3 and 5/8 (62.5%) in
stage 4.
For both species therefore, SRHP and hyperphosphatemia are common and occur with increasing prevalence as kidney function declines. It has been demonstrated that in all but IRIS stage 4 in dogs6 and end-stage
CKD in cats,5 SRHP is more prevalent than hyperphosphatemia in both species. This suggests that the increase
in PTH concentration precedes the development of hyperphosphatemia, as would be expected from the updated trade-off hypothesis in which overt hyperphosphatemia is the last derangement of Ca-P homeostasis to
occur. In support of this, a prospective longitudinal study
of nonazotemic cats by Finch et al38 demonstrated that
plasma PTH concentrations are significantly increased
in cats that develop azotemia within 12 months, when
compared to cats which remain nonazotemic over the
same time period. In that study, cats were classified into
3 groups based on their kidney function at the study
end point (12 months): group 1: Cr ≤ 140 ␮mol/L (≤1.6
mg/dL), group 2: Cr > 140 ␮mol/L (>1.6 mg/dL) but
did not meet the criteria for group 3, and group 3: persistent Cr ≥ 177 ␮mol/L (≥2.0 mg/dL) with concurrent
urine specific gravity <1.035 when available. In group 3,
32% had increased plasma PTH concentrations at entry
to the study (ie, before they became azotemic), despite
none of the cats being hyperphosphatemic. Ca-P product also increased significantly over the 12-month study
period in these cats. In agreement with previous studies,
at the 12-month time point, a greater proportion of the
azotaemic cats (30 cats in IRIS stage 2 and 1 cat in IRIS
stage 4) had SRHP (48%) than were hyperphosphatemic
(16%).38
Data presented in abstract form from studies involving
cats with naturally occurring CKD and appropriately
age-matched controls has shown plasma concentrations
of FGF-23 in cats with CKD increases with IRIS stage,
inversely correlating with GFR. In addition to plasma
creatinine, plasma phosphate has been shown to be an
C Veterinary Emergency and Critical Care Society 2013, doi: 10.1111/vec.12032
independent predictor of plasma FGF-23 concentration
in cats with CKD.
Clinical consequences of hyperphosphatemia and
SRHP in cats and dogs
Hyperphosphatemia in CKD is associated with decreased survival and significant morbidity. In dogs with
experimentally induced CKD, hyperphosphatemia has
been associated with a more rapid progression of CKD
and with decreased survival.10, 11 Hyperphosphatemia is
also associated with shorter survival times in cats with
naturally occurring CKD.7, 39 Additionally, plasma phosphorus has recently been documented to be an independent predictor for progression of feline CKD; an increase
of 0.32 mmol/L (1 mg/dL) in plasma inorganic phosphorus was independently associated with a 41% increase in
the risk of progression (where progression was defined
as an increase in plasma Cr of ≥25%).40
Clinical manifestations of SRHP include soft tissue
mineralization (see Figure 3) and renal osteodystrophy.
Cats with CKD can develop pathological fractures, loose
teeth, and “rubber jaw” syndrome as a consequence
of bone demineralization.41 It has been suggested that
soft tissue calcification may be a more common manifestation of feline SRHP than bone demineralization,42
although in one study of 74 cats with CKD, 9.8% had generalized osteoporosis, 7.3% had nephrocalcinosis, and
9.5% had soft tissue mineralization.3 Soft tissue structures that have shown mineralization in feline CKD cases
include the kidneys, thoracic and abdominal aorta, the
gastric wall, and pulmonary arteries and capillaries (see
Figure 3).43, 44 Metastatic calcifications have been documented in cases of feline and canine CKD in the paws,
which can cause lameness,43–46 and have been suggested
to occur when the serum Ca-P product is >70 mg2 /dL2
and PTH is concurrently increased.45
Evidence in support of the IRIS targets for plasma
phosphorus
A group of veterinary nephrologists established guidelines for plasma phosphorus concentrations in 2006,
to fit in with the IRIS classification of canine and feline CKD. Extrapolating from the Kidney Disease Outcomes Quality Initiative recommendations for human
CKD patients and their own clinical experience, control of plasma phosphorus concentration to well within
the laboratory reference interval was considered to be
an important goal in the management of CKD cases. It
was recommended that diets with phosphorus restriction ± intestinal phosphorus-binding agents should be
used to achieve the targets as shown in Table 1. There is a
substantial evidence basis from experimental model and
127
R. F. Geddes et al.
Figure 3: Soft tissue calcification affecting the kidneys and gastric wall, with some mestastatic calcification evident in the abdominal vasculature, due to SRHP in a cat. Radiograph taken
postmortem. SRHP, secondary renal hyperparathyroidism.
veterinary patient studies to support these guidelines, as
discussed below.
The use of phosphorus restriction in the control of
SRHP was initially investigated in the early 1970s. Using
canine remnant kidney models, with a staged approach
to reduce GFR 4 times throughout the course of the experiments, Slatopolsky et al clearly demonstrated that
PTH concentrations increased with every reduction in
GFR when the dogs were fed a normal diet, but PTH
did not increase at all when the dogs were fed a severely
phosphorus-restricted diet.47 In a follow-on study they
demonstrated that a “proportional reduction” of dietary
phosphorus in parallel with the reduction in GFR also
prevented any increase in plasma PTH concentrations.48
It was concluded from these studies that phosphorus
restriction should be the mainstay in control of SRHP.49
Only one experimental study has been published in
cats where the effect of phosphorus intake on progressive renal injury in a renal mass reduction model has
been studied.50 It compared the effect of feeding a normal
phosphorus diet (NPD; 1.56% phosphorus on a dry matter [DM] basis) and a restricted phosphorus diet (RPD;
0.42% phosphorus DM) to cats following a 4/6 nephrectomy and concluded that neither diet caused a significant
change in renal function over 343 days. After 8 weeks on
the diets, the restricted phosphorus group had a mean
plasma phosphorus concentration of approximately 1.6
mmol/L (approximately 5 mg/dL) compared to approximately 2.2 mmol/L (approximately 6.8 mg/dL) in the
normal phosphorus group.e After 28 weeks, the mean
plasma phosphorus concentrations were approximately
1.3 mmol/L (approximately 4.0 mg/dL) and approximately 2.3 mmol/L (approximately 7.0 mg/dL) for the
128
restricted phosphorus and normal phosphorus groups,
respectively. Additionally, they reported that the NPD
induced marked mineralization, fibrosis, and mononuclear cell infiltration in the remnant kidneys, whereas the
cats fed the phosphorus-restricted diet had much milder
histological changes. This study refers to the NPD as being equivalent to the phosphorus content of a commercial canned cat food; however, it should be noted that
the current recommendation by the American Association of Food Control Officials for phosphorus intake in
an adult cat at maintenance is 1.25 g/1000 kcal metabolizable energy (ME), equivalent to 0.5% phosphorus on a
DM basis (assuming a dietary energy density of 4000 kcal
ME/kg).51 Additionally, the authors of this study stated
the recommended dietary phosphorus intake for adult
cats at the time of publication to be 0.8% dry weight.
Therefore, the NPD in this study greatly exceeded recommended phosphorus food content. Overall, this study
suggests that reducing phosphorus intake and maintaining a plasma phosphorus concentration of between 1.29
and 1.61 mmol/L (4.0 and 5.0 mg/dL) is protective of
remaining functioning renal tissue in this surgical reduction model of renal failure, which is close to the IRIS
targets (<1.45 or 1.61 mmol/L [<4.5 or 5.0 mg/dL]) for
stages 2 and 3 CKD.
The effect of dietary phosphorus restriction and protein content on progressive deterioration of renal function has also been studied in a remnant kidney (15/16
surgical nephrectomy) model in dogs,10 by using 4 diets
(group 1: low phosphorus (Pi), low protein (Pr); group
2: high Pi, low Pr; group 3: low Pi, high Pr; group 4: high
Pi, high Pr). This study demonstrated that the amount of
phosphorus fed influenced survival, with 15/24 dogs fed
the low phosphorus diet (groups 1 and 3) surviving the
24 months of the study and only 8/24 dogs fed the high
phosphorus diet (groups 2 and 4) surviving. The level
of protein fed did not affect survival. GFR remained stable for longer in the dogs fed the low phosphorus diets
(groups 1 and 3; 12.7 ± 2.0 mo) when compared with
those animals receiving high phosphorus diets (groups
2 and 4; 7.5 ± 2.0 mo). There was no significant effect
of diet on renal morphology or mineral content in the
remnant kidney as assessed at the end of the 24-month
study or earlier if the dogs died or were euthanized due
to uremia.
The authors of that study concluded that dietary phosphorus content was more important than dietary protein content for preventing adverse responses to reduction in renal mass and that the survival benefit from
phosphorus restriction may be due to extra-renal effects,
since the low phosphorus diets (0.4% Pi on a DM basis)
were inadequately phosphorus restricted to prevent renal mineralization. At the 4-month time point, the mean
plasma phosphorus concentrations were 1.62 mmol/L
C Veterinary Emergency and Critical Care Society 2013, doi: 10.1111/vec.12032
Role of phosphorus in the pathophysiology of CKD
(5.03 mg/dL) for group 1, 2.61 mmol/L (8.08 mg/dL)
for group 2, 2.10 mmol/L (6.51 mg/dL) for group 3, and
2.62 mmol/L (8.11 mg/dL) for group 4. The results could
be interpreted to mean that the 4-month plasma phosphorus concentration of between 1.62 mmol/L and 2.1
mmol/L (5.03 and 6.51 mg/dL) is not optimal to protect
against soft tissue mineralization. Thus, these data are
compatible with the IRIS recommendations to maintain
plasma phosphorus at <1.45 mmol/L (<4.5 mg/dL) for
stage 2 and <1.61 mmol/L (<5.0 mg/dL) for stage 3.
Studies of feeding protein- and phosphorus-restricted
diets to cats with naturally occurring CKD have shown
that these diets can reduce plasma urea and phosphorus
concentrations, which is associated with a reduction in
the risk of a uremic crisis developing and death due to
renal causes.52 One study demonstrated a significant reduction in plasma PTH concentrations by 105–147 days
in cats with CKD eating a commercially produced renal
diet (see Figure 4).53 No significant change was demonstrated in PTH concentrations in a control group (fed
the maintenance diet preferred by their owners) over
the same time period (see Figure 4). Plasma phosphorus concentrations decreased significantly in the renal
diet group at the earlier time point of 28–49 days, and
remained significantly reduced at 105–147 days when
compared to baseline (see Figure 5). The reduction in
plasma PTH concentrations in this study was associated with a decrease in plasma phosphorus concentrations but no change in plasma total calcium or calcitriol
concentrations. In dogs with experimentally induced renal failure it has also been shown that a reduction in
dietary phosphorus decreases plasma PTH concentrations without changes in plasma ionized calcium or calcitriol concentrations.54 Additionally, in a case report by
Jackson and Barber in 1998,45 feeding a protein- and
phosphorus-restricted diet exclusively resulted in resolution of metastatic calcification in the paws of a cat
with stage 3 CKD by day 105. This was accompanied by
a reduction in the Ca-P product to <70 mg2 /dL2 , and a
reduction in plasma phosphorus concentration from 2.2
mmol/L (6.8 mg/dL) to 1.5 mmol/L (4.7 mg/dL), which
is within the target plasma phosphorus concentration for
IRIS stage 3.
Survival time of dogs was examined by Jacob et al
in 2002.55 This randomized, double-blinded, controlled
clinical trial was performed in 38 dogs with naturally occurring CKD in IRIS stage 3 or 4, and examined the effect
of feeding a renal food (RF) compared with a standardized maintenance food (MF). The dogs were managed in
an identical manner with respect to other treatment interventions. The median survival time for the RF dogs was
594 days, significantly longer than the median survival
time of 188 days in the MF group. The onset of a uremic
crisis was significantly delayed in the RF group; median
C Veterinary Emergency and Critical Care Society 2013, doi: 10.1111/vec.12032
Figure 4: Effect of feeding a commercially produced renal diet to
cats with naturally occurring chronic kidney disease (IRIS stages
2 and 3) on plasma PTH concentration. Data are mean values
from 14 cats (squares) that were fed a renal care diet and 8 cats
(circles) maintained on maintenance diets. Error bars represent 1
SD of the mean. Differences compared to the value on day 0 by
a paired t-test are illustrated, significance was taken to be P ≤
0.017 following Bonferroni correction (∗no significant difference
between the 2 groups at Day 0). IRIS, International Renal Interest
Society; PTH, parathyroid hormone; SD, standard deviation; NS,
not significant. Reproduced with permission from John Wiley
and Sons Ltd. From Barber PJ, et al. Effect of dietary phosphate
restriction on renal secondary hyperparathyroidism in the cat. J
Small Anim Pract 1999;40:62–70.
time to a uremic crisis was 615 days in the RF group and
252 days in the MF group. Additionally, renal function
(defined as the reciprocal of serum creatinine concentration) was documented to decline more slowly in the RF
group over 24 months. However, when the mean overall plasma phosphorus concentrations were compared
between the groups, no significant difference was detected. Overall, this study demonstrated that feeding a
renal diet significantly increases survival time and slows
renal function decline in dogs with stage 3 or 4 CKD.
Effect of renal diet on survival time has also been examined in cats, retrospectively56 and prospectively.52, 57
Ross et al, conducted a double-blinded, randomized,
controlled clinical trial of cats with naturally occurring
stage 2 or 3 CKD, to investigate the effect of feeding a
renal diet compared to a feline adult maintenance diet.52
In this study of 45 cats, the cats were managed in an
identical manner except for the diet they were randomly
assigned to. Over a 2-year period, the group fed the renal diet was found to have significantly lower urea and
phosphate concentrations but no significant difference
in creatinine or PTH concentrations when compared to
the maintenance diet group. The renal diet group had
significantly fewer uremic episodes (0%) than the maintenance diet group (26%) and had significantly fewer
129
R. F. Geddes et al.
Figure 5: Effect of feeding a commercially produced renal diet to
cats with naturally occurring chronic kidney disease (IRIS stages
2 and 3) on plasma phosphate concentration. Data are mean values from 14 cats (squares) that were fed a renal diet and 8 cats
(circles) maintained on maintenance diets. Error bars represent
1 SD of the mean. Differences compared to the value on day 0
by a paired t-test are illustrated, significance was taken to be
P ≤ 0.017 following Bonferroni correction (∗no significant difference between the 2 groups at Day 0). IRIS, International Renal
Interest Society; SD, standard deviation; NS, not significant. Reproduced with permission from John Wiley and Sons Ltd. From
Barber PJ, et al. Effect of dietary phosphate restriction on renal
secondary hyperparathyroidism in the cat. J Small Anim Pract
1999;40:62–70.
renal-related deaths (0% versus 21.7%) during the 2-year
study period.
A study by Elliott et al also investigated the effects of
feeding a protein- and phosphorus-restricted diet to cats
with stable naturally occurring CKD.57 All owners were
offered the protein-/phosphorus-restricted diet for their
cats and the control group (NPD group) was formed using cats that demonstrated poor compliance eating the
diet (cats which ate <50% of total intake as the renal
diet), or whose owners declined the diet. Although not a
double-blinded, placebo-controlled study, the 2 groups
were matched for physical, hematological, and biochemical parameters at the beginning of the study. The RPD
group was monitored closely to attempt to maintain
PTH concentrations within the normal range using the
diet ± a phosphorus binder but otherwise the 2 groups
were treated equally. The results indicated a significantly
longer median survival time in the RPD group of 633
days compared to 264 days for the NPD group. Furthermore, the RPD group had significant decreases in their
urea concentrations and had lower plasma phosphorus
concentrations than the NPD group. Plasma PTH concentrations significantly increased in the NPD group and
decreased in 69% of the RPD group by the mid-survival
time point, although the decrease in plasma PTH when
130
Figure 6: The relationship between the survival time and mean
plasma phosphorus concentration achieved in the first half of
the patients survival period. Data reanalyzed from Elliott (2000).
Reproduced with permission from Elliott J and Elliott D. Dietary
therapy for feline chronic kidney disease. In: Pascale P, Biourge V,
Elliott D. eds. Encyclopedia of feline clinical nutrition. Ainargues,
France: Aniwa SAS Ltd; 2008:411–45.
compared to baseline did not reach statistical significance. Overall, this study clearly demonstrated that cats
which ate a diet specially formulated for CKD had significantly longer survival times than cats that were not
willing to eat a renal diet.
Unpublished data from the same study showed that
55%, 90%, and 100% of cats presenting in stage 2, 3, and
4 CKD, respectively, had plasma phosphorus concentrations above 1.45 mmol/L (4.5 mg/dL) at diagnosis.
The relationship between the mean plasma phosphorus
concentrations for the first half of their survival period
and survival times for the cats in this study is shown
in Figure 6. Additionally, reanalysis of the data from this
study demonstrated that if the average plasma phosphorus concentration was maintained at below 1.45 mmol/L
(4.5 mg/dL) for the first half of their survival time (this
was achieved in 18 of the 50 cats) their median survival time was 799 (interquartile range 569–1,383) days
whereas for cats where the average plasma phosphorus concentration exceeded 1.45 mmol/L (4.5 mg/dL)
the median survival time was 283 (interquartile range
193–503) days. Although this study was not designed
to determine the effect of achieving a particular plasma
phosphate target by restricting phosphate intake, these
data are supportive of the target guidelines for plasma
phosphorus concentration in CKD.
To date, no studies have been published examining
the effect of dietary phosphorus restriction on plasma
FGF-23 concentrations in companion animal species.
However, in the recently published abstract examining
C Veterinary Emergency and Critical Care Society 2013, doi: 10.1111/vec.12032
Role of phosphorus in the pathophysiology of CKD
FGF-23 in a cross-section of nonazotemic and azotemic
IRIS stage 2–4 cats, plasma FGF-23 concentrations were
found to be significantly higher in stage 2 and 3 cats
with plasma phosphorus concentrations above the maximum IRIS targets for those stages (>1.45 mmol/L
[>4.5 mg/dL] for stage 2 and >1.61 mmol/L [>5mg/dL]
for stage 3).d
The evidence from the veterinary literature indirectly suggests that maintaining plasma phosphorus
concentrations below the IRIS targets for each stage of
CKD improves survival, can prevent or reverse SRHP
and can resolve clinical manifestations of hyperphosphatemia in companion animals. It is widely accepted
that intestinal phosphorus-binding agents are useful in
reducing plasma phosphorus concentrations for CKD
patients.58, 59 However, there have been no controlled
clinical studies examining the effect of using phosphate
binders on the progression of naturally occurring CKD
or on survival time of dogs and cats with CKD. One
study has demonstrated that for cats with a model of
CKD equivalent to IRIS stages 1 and 2, addition of a
chitosan and calcium carbonate phosphorus binder to a
feline maintenance diet can reduce serum phosphorus
concentration to below the IRIS target of 1.45 mmol/L
(4.5 mg/dL) after 6 months.60 Another preliminary
study has shown that lanthanum carbonate octahydrate
can significantly reduce apparent digestive phosphorus
availability and increase fecal excretion of phosphorus
in normophosphatemic cats with a model of CKD.f
Within the scope of this review, it is not possible to discuss the evidence for other aspects of CKD management,
but this is covered in detail elsewhere.61, 62
Application to Veterinary Emergency and Critical
Care
Progression of CKD to end-stage frequently occurs, but
the time frame is extremely variable and is difficult to
predict.39 Many cases remain relatively stable for long
periods of time and then suffer a sudden decline in kidney function, which is likely to be a result of a trigger
factor resulting in an acute-on-chronic presentation, although in many cases the trigger cannot be identified.9
Companion animals presenting with a uremic crisis must
be evaluated carefully to ensure accurate diagnosis of
acute kidney injury or an acute-on-chronic episode for a
patient with CKD. Hyperphosphatemia can be present
in both of these scenarios as any cause of decreased GFR
will cause a reduction in urinary phosphate ion excretion
leading to an increase in plasma phosphorus. The IRIS
staging system and plasma phosphorus targets should
only be applied following assessment of fasting plasma
creatinine concentrations in a stable patient.63 Therefore,
they cannot be used appropriately during evaluation of
C Veterinary Emergency and Critical Care Society 2013, doi: 10.1111/vec.12032
the emergency patient. Once a diagnosis of a primary
intrinsic renal cause of azotemia has been established
the differentiation between acute kidney injury and an
acutely decompensated case of CKD must be established.
This is important because unless a specific factor is causing acute decompensation in the CKD patient, which is
then identified and treated aggressively, the prognosis
for advanced CKD is poor.
Conclusions and Recommendations for Future
Studies
There is strong evidence from the veterinary literature for
feeding a renal diet to cats and dogs with CKD,61, 62 and
this should therefore be considered to be the mainstay of
management in these cases. The current general consensus of opinion is to start dietary modification once stable azotemia is demonstrated.63 Additionally, phosphorus binders should be used when necessary to achieve
plasma phosphorus concentrations within the IRIS recommendations for each stage of CKD, as maintaining
plasma phosphorus concentrations within these targets
has been demonstrated to improve survival and prevent or resolve the clinical manifestations of hyperphosphatemia and SRHP in companion animals. Due to the
prevalence of hyperparathyroidism being higher than
that of hyperphosphatemia at each stage of CKD in both
dogs6 and cats,5 it has been recommended that plasma
PTH should be measured when plasma phosphorus is
within the IRIS targets in order to establish if phosphorus
restriction is appropriate.59
FGF-23 is now considered to be a key regulator of
plasma phosphate concentrations and to be involved in
the development of SRHP in people. However, research
is only just beginning to be published on the role of FGF23 in companion animals with CKD. Further studies are
required to establish the role of this hormone in Ca-P
homeostasis and whether FGF-23 is a marker or mediator
of SRHP.
Footnotes
a
b
c
d
e
f
Hyperphosphatemia was defined in this study as a plasma phosphorus
concentration above the reference range (>1.87 mmol/L [>5.8 mg/dL]).
Hyperphosphatemia was defined in this study as plasma phosphorus
>1.78mmol/L (>5.5mg/dL).
Finch NC, Geddes, RF,Syme, H, Elliott, J. FGF-23—mediator of renal secondary hyperparathyroidism or a marker of glomerular filtration rate
(GFR) in cats? J Vet Intern Med 2011; 25:720 (Abstract).
Geddes RF, Finch NC, Syme, H., Elliott, J. Fibroblast growth factor 23
(FGF-23) in feline chronic kidney disease. J Vet Intern Med 2011; 25:720–
721 (Abstract).
The results are depicted in a figure in this paper, therefore the results
reported here are approximate.
Schmidt DH, Spiecker-Hauser U, Murphy M. Efficacy and safety of Lantharenol on phosphorus metabolism in cats with chronic kidney disease.
J Vet Intern Med 2008; 22:798 (Abstract).
131
R. F. Geddes et al.
References
1. Lulich JP. Feline renal failure: questions, answers, questions. Compend Contin Educ Pract Vet 1992; 14:127–152.
2. Jepson RE, Brodbelt D, Vallance C, et al. Evaluation of predictors of
the development of azotemia in cats. J Vet Intern Med 2009; 23:806–
813.
3. DiBartola SP, Rutgers HC, Zack PM, et al. Clinicopathologic findings
associated with chronic renal disease in cats: 74 cases (1973–1984). J
Am Vet Med Assoc 1987; 190:1196–1202.
4. Macdougall DF, Cook T, Steward AP, et al. Canine chronic renal
disease: prevalence and types of glomerulonephritis in the dog.
Kidney Int 1986; 29:1144–1151.
5. Barber PJ, Elliott J. Feline chronic renal failure: calcium homeostasis
in 80 cases diagnosed between 1992 and 1995. J Small Anim Pract
1998; 39:108–116.
6. Cortadellas O, del Palacio MJF, Talavera J, et al. Calcium and phosphorus homeostasis in dogs with spontaneous chronic kidney disease at different stages of severity. J Vet Intern Med 2010; 24:73–79.
7. Boyd LM, Langston C, Thompson K, et al. Survival in cats with
naturally occurring chronic kidney disease (2000–2002). J Vet Intern
Med 2008; 22:1111–1117.
8. Kuwahara Y, Ohba Y, Kitoh K, et al. Association of laboratory data
and death within one month in cats with chronic renal failure. J
Small Anim Pract 2006; 47:446–450.
9. Elliott J, Barber PJ. Feline chronic renal failure: clinical findings in 80
cases diagnosed between 1992 and 1995. J Small Anim Pract 1998;
39:78–85.
10. Finco DR, Brown SA, Crowell WA, et al. Effects of dietary phosphorus and protein in dogs with chronic renal failure. Am J Vet Res
1992; 53:2264–2271.
11. Brown SA, Crowell WA, Barsanti JA, et al. Beneficial effects of dietary mineral restriction in dogs with marked reduction of functional renal mass. J Am Soc Nephrol 1991; 1:1169–1179.
12. de Brito Galvao JF, Nagode LA, Schenck PA, et al. Calcitriol, calcidiol, parathyroid hormone and fibroblast growth factor-23 interactions in chronic kidney disease. J Vet Emerg Crit Care 2013;
23(2):134–162
13. Guyton AC, Hall JE. Textbook of Medical Physiology, 10th ed.
Philadelphia: W. B. Saunders; 2000.
14. Bricker NS. On the pathogenesis of the uremic state. An exposition
of the “trade-off hypothesis.” N Engl J Med 1972; 286:1093–1099.
15. Marks J, Debnam ES, Unwin RJ. Phosphate homeostasis and
the renal-gastrointestinal axis. Am J Physiol Renal Physiol 2010;
299:F285–F296.
16. Kumar R. Phosphate sensing. Curr Opin Nephrol Hypertens 2009;
18:281–284.
17. Pereira RC, Juppner H, Azucena-Serrano CE, et al. Patterns of FGF23, DMP1, and MEPE expression in patients with chronic kidney
disease. Bone 2009; 45:1161–1168.
18. Riminucci M, Collins MT, Fedarko NS, et al. FGF-23 in fibrous dysplasia of bone and its relationship to renal phosphate wasting. J Clin
Invest 2003; 112:683–692.
19. Saito H, Maeda A, Ohtomo S, et al. Circulating FGF-23 is regulated
by 1 alpha,25-dihydroxyvitamin D-3 and phosphorus in vivo. J Biol
Chem 2005; 280:2543–2549.
20. Urakawa I, Yamazaki Y, Shimada T, et al. Klotho converts canonical FGF receptor into a specific receptor for FGF23. Nature 2006;
444:770–774.
21. Tsujikawa H, Kurotaki Y, Fujimori T, et al. A gene related to a syndrome resembling human premature aging, functions in a negative
regulatory circuit of vitamin D endocrine system. Mol Endocrinol
2003; 17:2393–2403.
22. Takeshita K, Fujimori T, Kurotaki Y, et al. Sinoatrial node dysfunction and early unexpected death of mice with a defect of klotho gene
expression. Circulation 2004; 109:1776–1782.
23. Galitzer H, Ben-Dov IZ, Silver J, et al. Parathyroid cell resistance
to fibroblast growth factor 23 in secondary hyperparathyroidism of
chronic kidney disease. Kidney Int 2010; 77:211–218.
24. Larsson T, Nisbeth U, Ljunggren O, et al. Circulating concentration of FGF-23 increases as renal function declines in patients with
132
25.
26.
27.
28.
29.
30.
31.
32.
33.
34.
35.
36.
37.
38.
39.
40.
41.
42.
43.
44.
45.
chronic kidney disease, but does not change in response to variation in phosphate intake in healthy volunteers. Kidney Int 2003;
64:2272–2279.
Shigematsu T, Kazama JJ, Yamashita T, et al. Possible involvement
of circulating fibroblast growth factor 23 in the development of
secondary hyperparathyroidism associated with renal insufficiency.
Am J Kidney Dis 2004; 44:250–256.
Gutierrez O, Isakova T, Rhee E, et al. Fibroblast growth factor23 mitigates hyperphosphatemia but accentuates calcitriol deficiency in chronic kidney disease. J Am Soc Nephrol 2005; 16:
2205–2215.
Fliser D, Kollerits B, Neyer U, et al. Fibroblast growth factor 23
(FGF23) predicts progression of chronic kidney disease: the Mild to
Moderate Kidney Disease (MMKD) Study. J Am Soc Nephrol 2007;
18:2600–2608.
Filler G, Liu D, Huang SH, et al. Impaired GFR is the most important
determinant for FGF-23 increase in chronic kidney disease. Clin
Biochem 2011; 44:435–437.
Perwad F, Azam N, Zhang MY, et al. Dietary and serum phosphorus
regulate fibroblast growth factor 23 expression and 1,25-dihydroxy
vitamin D metabolism in mice. Endocrinology 2005; 146:5358–5364.
Ferrari SL, Bonjour JP, Rizzoli R. Fibroblast growth factor-23 relationship to dietary phosphate and renal phosphate handling in
healthy young men. J Clin Endocrinol Metab 2005; 90:1519–1524.
Burnett SM, Gunawardene SC, Bringhurst FR, et al. Regulation of
C-terminal and intact FGF-23 by dietary phosphate in men and
women. J Bone Miner Res 2006; 21:1187–1196.
Westerberg PA, Linde T, Wikstrom B, et al. Regulation of fibroblast
growth factor-23 in chronic kidney disease. Nephrol Dial Transplant
2007; 22:3202–3207.
Canalejo R, Canalejo A, Martinez-Moreno JM, et al. FGF23 fails to
inhibit uremic parathyroid glands. J Am Soc Nephrol 2010; 21:1125–
1135.
Nielsen PK, Feldt-Rasmussen U, Olgaard K. A direct effect in vitro
of phosphate on PTH release from bovine parathyroid tissue slices
but not from dispersed parathyroid cells. Nephrol Dial Transplant
1996; 11:1762–1768.
Almaden Y, Hernandez A, Torregrosa V, et al. High phosphate level
directly stimulates parathyroid hormone secretion and synthesis by
human parathyroid tissue in vitro. J Am Soc Nephrol 1998; 9:1845–
1852.
Evenepoel P, Meijers B, Viaene L, et al. Fibroblast growth factor23 in early chronic kidney disease: additional support in favor
of a phosphate-centric paradigm for the pathogenesis of secondary hyperparathyroidism. Clin J Am Soc Nephrol 2010; 5:
1268–1276.
Gutierrez OM, Mannstadt M, Isakova T, et al. Fibroblast growth
factor 23 and mortality among patients undergoing hemodialysis.
N Engl J Med 2008; 359:584–592.
Finch NC, Syme H, Elliott J. Parathyroid hormone (PTH) concentrations in cats prior to the development of azotemia compared to cats
remaining non-azotemic. J Am Vet Med Assoc; 2012; 241:1326–1335.
King JN, Tasker S, Gunn-Moore DA, et al. Prognostic factors in cats
with chronic kidney disease. J Vet Intern Med 2007; 21:906–916.
Chakrabarti S, Syme HM, Elliott J. Clinicopathological variables predicting progression of azotemia in cats with chronic kidney disease.
J Vet Intern Med 2012; 26:275–281.
Yaphe W, Forrester SD. Renal secondary hyperparathyroidism—
pathophysiology, diagnosis, and treatment. Compend Contin Educ
Pract Vet 1994; 16:173–181.
Barber P. Diagnosis and management of chronic renal failure in the
cat. In Practice 2003; 25:306–313.
Bertazzolo W, Toscani L, Calcaterra S, et al. Clinicopathological findings in five cats with paw calcification. J Feline Med Surg 2003;
5:11–17.
Barber PJ. Parathyroid Gland Function in the Ageing Cat. London:
University of London; 1998.
Jackson HA. Resolution of metastatic calcification in the paws of
a cat with successful dietary management of renal hyperparathyroidism. J Small Anim Pract 1998; 39:495–497.
C Veterinary Emergency and Critical Care Society 2013, doi: 10.1111/vec.12032
Role of phosphorus in the pathophysiology of CKD
46. Kowalewich NJ, Hawkins EC. Calcinosis circumscripta involving
the metatarsal region in a dog with chronic renal failure. Can Vet J
1992; 33:465–466.
47. Slatopolsky E, Caglar S, Pennell JP, et al. On the pathogenesis of
hyperparathyroidism in chronic experimental renal insufficiency in
the dog. J Clin Invest 1971; 50:492–499.
48. Slatopolsky E, Caglar S, Gradowska L, et al. On the prevention of
secondary hyperparathyroidism in experimental chronic renal disease using “proportional reduction” of dietary phosphorus intake.
Kidney Int 1972; 2:147–151.
49. Slatopolsky E, Bricker NS. The role of phosphorus restriction in
the prevention of secondary hyperparathyroidism in chronic renal
disease. Kidney Int 1973; 4:141–145.
50. Ross LA. Effect of dietary phosphorus restriction on the kidneys of
cats with reduced renal mass. Am J Vet Res 1982; 43:1023–1026.
51. AAFCO. 2011, Official Publication. Atlanta: AAFCO Inc; 2011.
52. Ross SJ, Osborne CA, Kirk CA, et al. Clinical evaluation of dietary
modification for treatment of spontaneous chronic kidney disease
in cats. J Am Vet Med Assoc 2006; 229:949–957.
53. Barber PJ, Rawlings JM, Markwell PJ, et al. Effect of dietary phosphate restriction on renal secondary hyperparathyroidism in the cat.
J Small Anim Pract 1999; 40:62–70.
54. Lopez-Hilker S, Dusso AS, Rapp NS, et al. Phosphorus restriction
reverses hyperparathyroidism in uremia independent of changes in
calcium and calcitriol. Am J Physiol 1990; 259:F432–F437.
55. Jacob F, Polzin DJ, Osborne CA, et al. Clinical evaluation of dietary
modification for treatment of spontaneous chronic renal failure in
dogs. J Am Vet Med Assoc 2002; 220:1163–1170.
C Veterinary Emergency and Critical Care Society 2013, doi: 10.1111/vec.12032
56. Plantinga EA, Everts H, Kastelein AM, et al. Retrospective
study of the survival of cats with acquired chronic renal insufficiency offered different commercial diets. Vet Rec 2005; 157:
185–187.
57. Elliott J, Rawlings JM, Markwell PJ, et al. Survival of cats with naturally occurring chronic renal failure: effect of dietary management.
J Small Anim Pract 2000; 41:235–242.
58. Nagode LA. Nephrocalcinosis caused by hyperparathyroidism in
progression of renal failure: treatment with calcitriol. Semin Vet
Med Surg (Small Anim) 1992; 7:202–220.
59. Vétoquinol. Phosphatemia management in the treatment of chronic
kidney disease, a Roundtable Discussion. Vétoquinol Academia,
2006. Available at: http://www.vetoquinol.ca/documents/
Quoi%20de%20neuf/Articles/Round%20table%20discussion.pdf.
Accessed February 2013.
60. Brown SA, Rickertsen M, Sheldon S. Effects of an intestinal phosphorus binder on serum phosphorus and parathyroid hormone concentration in cats with reduced renal function. Int J Appl Res Vet M
2008; 6:155–160.
61. Roudebush P. Therapies for feline chronic kidney disease. What is
the evidence? J Fel Med Surg 2009; 11:195–210.
62. Roudebush P, Polzin DJ, Adams LG, et al. An evidence-based review
of therapies for canine chronic kidney disease. J Small Anim Pract
2010; 51:244–252.
63. Elliott J, Elliott D. Dietary therapy for feline chronic kidney disease. In: Pibot P, Biourge V, Elliott D. eds. Encyclopedia of Feline Clnical Nutrition. Ainargues, France: Aniwa SAS Ltd; 2008,
pp. 411–445.
133