Less than 1% of the total body phosphorus is in the plasma with 1/3 of this as inorganic phosphate ions, most of which are
unbound. Laboratory analysis of serum phosphorus measures all forms of H3PO4 (H3PO4, H2PO4, HPO4) referred to as inorganic
phosphate. Serum phosphate levels are higher in serum than plasma due to the clotting process that releases phosphorus from
cells and platelets.
Serum phosphate is maintained within a narrow range in health. Levels of serum phosphate are often higher in young growing
animals than in adults possibly owing to the effects of higher levels of growth hormone that increases renal tubular reabsorption
of phosphorus; higher levels of calcitriol during growth may also contribute. The normal range for many laboratories unfortunately
includes that of adult and growing animals, making it difficult or impossible to detect early rises in serum phosphorus above
normal. Serum phosphate concentration is less than 5.5 mg/dl in most healthy adults.
Serum phosphorus concentration depends on the dietary phosphorus intake, the degree of GI absorption across the duodenum and
jejunum, translocation into intracellular sites, and how much is excreted into the urine. The kidney is the major organ for
regulation of serum phosphate concentration. Renal excretion depends on how much phosphorus undergoes glomerular filtration
and how much is subsequently reabsorbed by the tubules. Most of the reabsorption of phosphorus occurs in the proximal tubules,
an effect that is largely controlled by the expression of Na-phosphate co-transporters on the brush border. PTH, increasing
concentrations of circulating phosphate, and metabolic acidosis are known for their ability to reduce the expression of this
transport system, which results in more phosphorus excreted into urine (phosphaturia). Na-phosphate transporters under the
control of calcitriol exist in the intestine. Increased levels of PTH can keep serum phosphorus within the normal range by
this adaptive renal mechanism despite continued loss of renal mass and function in patients with CKD until more than 85% nephron
mass has been lost, at which point the serum phosphate concentration progressively increases.
Pathophysiology of Phosphorus in Renal Disease, and Renal Failure
Total phosphorus burden/retention during chronic renal failure adversely affects renal function, renal histopathology, and
soft tissue mineralization in the kidneys and other organs. It is not possible to evaluate the damaging effects of phosphate
retention as a separate entity since circulating phosphate has a complex relationship that affects and is affected by PTH,
ionized calcium, and calcitriol. Deleterious effects of phosphate accumulation in the body (eventually leading to hyperphsophatemia)
can be a direct consequence of phosphate, from calcium phosphate precipitates into the tissues (increased calcium x phosphate
product), decreased ionized calcium, and increased PTH (from insufficient calcitriol, low ionized calcium, and or a direct
effect of phosphate to stabilize mRNA for PTH synthesis in the parathyroid gland).
It has been known since the early 1980's that dietary phosphorus restriction provided dramatic benefits to the histologic
renal architecture of cats with the remnant model of chronic renal failure. Though renal function was not different over time
in cats of this study, cats fed the normal maintenance diet had obvious mineralization, fibrosis, and mononuclear cell infiltration
whereas the kidneys of cats fed the phosphate-restricted diet had minimal or no changes. Serum phosphorus and PTH concentrations
were considerably increased in cats fed the normal phosphate diet compared to those fed the restricted phosphate diet (Ross
In a study of 50 CKD cats (mean serum creatinine near 3.0 mg/dL), twenty-four of 50 cats were hyperphosphatemic at the start
of the study. Plasma phosphate concentration at the mid-survival time point increased over baseline in 62% of those eating
a normal diet (n = 21) and decreased in 76% of cats eating the renal veterinary diet (n = 29). Forty-six of 50 cats had increased
PTH at the start of the study. PTH declined in 69% of cats that were eating the veterinary renal diet at the mid-survival
time point, whereas PTH increased in 62% of those eating a maintenance diet. Intestinal phosphate binders were added as treatment
when serum phosphorus remained increased within 4 months of feeding the renal diet in 4 cats; an additional 6 cats required
the addition of an intestinal phosphate binder throughout the study for a total of 34% (10/29). Survival time for CKD cats
eating the renal diet was considerably longer for cats eating the renal diet (633 median and 616 mean days) compared to those
eating a maintenance diet (264 median and 383 mean days) [Elliott JSAP 2000].
Increased levels of serum phosphorus have been associated with increased all-cause mortality, cardiovascular mortality, vascular
calcification and valvular calcification in humans with CKD. One human study showed that end-stage renal failure patients
with a serum phosphorus level >6.5 mg/dl (>2.10 mmol/l) had a 27% higher mortality risk than patients with a phosphorus level
of 2.4–6.5 mg/dl (0.78–2.10 mmol/l); and that patients with a calcium x phosphate (Ca x P) product >72 mg2/dl2 had a 34% higher risk of death compared with those with a Ca x P product between 42 and 52 mg2/dl2 (Block Am J Kidney Ds
1998). Vascular mineralization and death due to cardiac effects is a major cause of death in people with CKD. Death related
to cardiovascular system abnormalities was reported to be second to renal related causes of death in one study of cats with
CKD, though detailed micropathology of vascular structures was not provided (Elliott JSAP 2000). In one retrospective study
in cats, the only clinicopathologic variable that was associated with survival in animals with naturally occurring CKD was
serum phosphorus. For each 1 unit increase in phosphorus there was an 11.8% increase in the risk of death (Boyd JVIM 2008).
In another study, increased plasma phosphate concentration was found to be highly significantly associated with shorter renal
survival times (King JVIM 2007).