Submitted by: Patricia Shea, DVM
J Am Vet Med Assoc 2021;259:1325-31.
Concerns related to dietary phosphorus intake in cats (Viewpoint).
Stockman J, Villaverde C.
Phosphorus is a critically essential and ubiquitous mineral in all living organisms. Skeletal tissue contains about 85% of the body’s phosphorus, and this mineral can be stored in or released from skeletal tissue and bone as needed. The goal of phosphorus homeostasis is to keep bone mineralized and to have sufficient phosphorus available for biochemical functions such as enzyme activation and deactivation while avoiding mineralization of soft tissue.
When serum inorganic phosphorus becomes excessively high, it becomes a metabolic poison, especially in animals with chronic kidney disease (CKD). Moreover, chronically high phosphorus intake may be detrimental to healthy animals, including cats, especially when the dietary calcium:phosphorus ratio is low, and the dietary phosphorus is highly bioavailable.
Most absorption of dietary phosphorus occurs in the duodenum and jejunum. Once phosphorus is absorbed from the gastrointestinal tract, the kidneys are principally responsible for eliminating excess phosphorus from the body. In addition to intestinal absorption and renal excretion, serum phosphorus concentration is regulated by calcitriol, the activated form of Vitamin D, which increases phosphorus absorption from the intestine and from skeletal tissue, and parathyroid hormone (PTH), which promotes bone resorption and activates calcitriol. A peptide, fibroblast growth factor 23 (FGF-23), which is secreted by bone in response to hyperphosphatemia, will reduce intestinal phosphorus absorption and increase renal phosphorus excretion. In animals with high serum phosphate concentrations, levels of both PTH and FGF-23 will increase in the blood.
Phosphorus requirements are highest in growing kittens, as well as in late gestation and during lactation. Serum hypophosphatemia is uncommon in adult cats, and can lead to hemolytic anemia, reduced mobility, and metabolic acidosis, and can be induced with a diet very low in phosphorus and high calcium:phosphorus ratio of 4.
The form of phosphorus contained in the diet, as well as the presence of other dietary minerals, including calcium and magnesium, influences phosphorus absorption and bioavailability. Dietary phosphorus is present in both organic (natural) and inorganic forms. The natural/organic phosphorus comes from raw materials in the food such as bone ash, as well as any added natural phosphorus supplementation. Inorganic phosphorus comes from phosphate-containing additives such as flavor enhancers and preservatives as well as calcium-binding phosphates, which are included to reduce dental tartar formation. Phosphorus in the form of inorganic phosphates, when supplied as water-soluble phosphate salts, is more bioavailable than organic phosphorus.
In cats with chronic kidney disease (CKD), a high serum phosphorus concentration is associated with shorter survival times and a greater risk of mortality. The hyperphosphatemia will initially trigger compensatory responses, but these eventually will be overwhelmed, and dietary phosphorus intake has to be reduced to control the hyperphosphatemia. Chronic hyperphosphatemia will lead to soft tissue mineralization, including in the kidneys, which can further the progression of CKD.
Kidneys experiencing loss of functional tissue will produce less 1-alpha-hydroxylase, an enzyme important in the production of calcitriol. With less calcitriol, the intestines absorb less calcium, and this triggers increased secretion of PTH. Also in CKD, there is depletion of Klotho, the cofactor for FGF-23, as well as a decrease in the number of FGF-23 receptors in the parathyroid gland; the increased FGF-23 contributes to even more PTH secretion and less calcitriol production. A significant amount of time can lapse during which biomarkers of renal function continue to deteriorate while these phosphate-regulating feedback loops struggle to control serum phosphorus levels. In pre-azotemic geriatric cats with early CKD, an association has been found between FGF-23 concentrations, which cannot be measured in commercial reference laboratories, and symmetric dimethylarginine (SDMA) levels. Therefore, changes in phosphorus metabolism are already taking place before other signatures of decreased renal function in feline patients manifest.
High levels of inorganic phosphates are often found in highly processed human foods. It is also known that high dietary phosphorus content is a risk factor for all-cause mortality in humans and other species, and this includes renal and cardiovascular disease. With regard to cats, there is published evidence going back over two decades that high dietary levels of bioavailable phosphorus may contribute to the development of CKD. However, there are no long-term studies of the effects of high levels of organic phosphorus on renal function in cats. The authors of the present paper speculate that a high concentration of extracellular phosphorus may be toxic to cells and contribute to premature cellular aging, as well as promote renal tubular injury and interstitial renal fibrosis. Increased PTH and FGF-23 can promote metastatic calcification and have adverse effects on cardiovascular health. None of these changes may be accompanied by obvious measurable changes in serum phosphorus levels.
Although minimum feline dietary requirements for phosphorus, calcium, and magnesium have been available in published literature for many years, no maximum allowable dietary concentrations of calcium and phosphorus have been included in feline nutrition guidelines published by the National Research Council and the American Association of Feed Control Officials in the USA. In 2019, the European Pet Food Industry Federation produced guidelines stating that the calcium:phosphorus ratio in adult cats should be in the range of 1:1 to 2:1. However, no distinction was made between inorganic/bioavailable phosphorus and organic/less bioavailable phosphorus levels, as there is no standard test to distinguish these two types of phosphorus in pet foods.
A 2020 study evaluating 82 commercial cat foods available in North America demonstrated marked variability in total phosphorus content. A third of these foods had 3.6-5.8 grams of phosphorus/1,000 kcal of metabolizable energy (ME), but it is unknown how much of the phosphorus in these foods is inorganic. The calcium:phosphorus ratio in 13 of the foods (16%) ranged from 1:2 to 1:1. None of the 82 foods evaluated had a calcium:phosphorus ratio greater than 2:1.
To reduce the risk of potential diet-related renal damage in pet cats, the authors of this review recommend an interim limit of 4.0 g/1,000 kcal of ME total phosphorus in cat foods, a maximum inorganic phosphorus content of 1 g/1,000 kcal of ME, and a calcium:phosphorus ratio between 1:1 to 2:1, until such time as safe limits for inorganic and organic phosphorus in cat foods can be established. Long-term feeding trials will be required to determine safe levels of inorganic and inorganic phosphorus in feline diets, rather than just evaluating the total phosphorus content of the foods. Additionally, the impact of dietary protein, calcium, and magnesium content on phosphorus homeostasis must be considered in the feeding trials. It is also essential to learn more about the potential of high dietary phosphorus levels, high inorganic or soluble phosphorus intake, and dietary calcium:phosphorus ratio of less than 1, to promote renal dysfunction in adult cats, and if diets with lower total phosphorus and/or lower inorganic phosphorus can help reduce the risk of CKD in this population.
J Am Vet Med Assoc 2021;259:1009-24.
Relationships between congenital peritoneopericardial diaphragmatic hernia or congenital central diaphragmatic hernia and ductal plate malformations in dogs and cats.
Seibert LM, Center SA, et al.
This retrospective study from a veterinary teaching hospital of 18 dogs and 18 cats with congenital diaphragmatic herniation is the first to describe the association between ductal plate malformations and these congenital hernias. Ductal plate malformations (DPMs) are histologically identifiable congenital abnormalities that arise in the embryo secondary to dysfunction of primary cilia. These malformations disrupt embryonic tubulogenesis and result primarily in abnormalities of the biliary ducts (because primary cilia are present on cholangiocytes, but not hepatocytes), and sometimes, abnormalities in the renal tubules or pancreatic ducts. Other congenital abnormalities can occur with peritoneopericardial diaphragmatic hernias (PPDHs) or congenital central diaphragmatic hernias (CCDHs), including umbilical hernias, body wall defects, cardiac malformations, and skeletal anomalies.
Four DPM phenotypes are recognized: (1) proliferative-like DPM, which can lead to periportal fibrosis; (2) Caroli DPM, in which malformed medium- to large bile ducts with sacculated or distended silhouettes occur, and which can evolve to congenital hepatic fibrosis; (3) choledochal cyst DPM, which usually produces cystic malformations at the junction of the common bile duct and duodenal papilla; and (4) expansive cystadenoma DPMs, which start as microcystic ductal malformations that efface hepatic parenchyma. Choledochal cyst DPMs and expansive cystadenoma DPMs are more commonly found in cats than dogs. Both cats and dogs with DPMs may have gallbladder agenesis or hypoplasia, agenesis or hypoplasia of one or more liver lobes, and in rare instances, a congenital portosystemic shunt.
Pathological and healthy control cats and dogs were also utilized in this study to compare histologic and immunohistochemical staining findings in these animals with those diagnosed with PPDH or CCDH. The pathological control animals included 4 dogs and one cat with traumatic diaphragmatic hernia, 2 dogs and one cat with liver lobe torsion, and one dog with thromboembolic hepatic ischemia. Healthy control animals were 15 cats and 8 dogs.
The median age of the cats with PPDH or CCDH was 4.5 years (range 0.2 to 15 years); 10 were male and 8 were female; breeds included 8 domestic shorthairs, 4 domestic longhairs, 3 Persians, and one each of Maine Coon, Ragdoll, and Siamese. Clinical signs in this group included tachypnea or dyspnea (12/18), lethargy (11/18), vomiting or inappetence (8/18), increased liver enzymes on previous laboratory evaluations (2/14), and abdominal effusion (1/18). Of the 18 cats with congenital diaphragmatic herniation, 15 were found to have DPMs, and the median age of these animals was 4.0 years; 9 were male and 6 were female. Hepatic DPM was found in 13 cats, one of whom also had renal DPM, and 2 cats had renal DPM only. The median age and sex of cats with congenital diaphragmatic hernias were not significantly different between those with or without DPM. Hematologic and serum biochemical profiles, which were available for 12/18 cats with congenital diaphragmatic hernias did not distinguish between cats with and without DPM.
Antemortem liver tissue biopsy samples were collected from 8 of the cats with PPDH or CCDH. In the other 10 cats, liver tissue biopsy samples were collected during necropsy. Of the 15 cats in this group in which DPM was identified, 5 cats had proliferative-like DPM, and 3 had Caroli DPM. Combined proliferative-like DPM and Caroli DPM was identified in 2 cats, proliferative-like and Caroli DPM along with a large cystadenoma in one, Caroli DPM and a choledochal cyst with cholelithiasis in one, Caroli and proliferative-like DPM along with polycystic kidneys in one (a Persian), and polycystic kidneys without hepatic DPM in one (also a Persian). Given the strong relationship between congenital diaphragmatic hernias and DPM found in this study, it is likely that primary cilia also may be involved in the development of the diaphragm in the embryo.
The clinically most severe DPMs are those associated with congenital hepatic fibrosis, and this was found in two of the cats. One of these cats died at 5.2 years of age, and the other at 15 years of age, and congenital hepatic fibrosis was the cause of death in one of these animals, but which one of these animals is not specified in this paper. Congenital hepatic fibrosis differs histopathologically and pathogenetically from the fibrosis of necroinflammatory liver disease.
This study has clinical relevance in that animals with hepatic DPM, just like humans with DPM, have an increased risk for bile-borne bacterial infections. In addition, those animals with Caroli DPM have increased risk for intra-or extrahepatic cholelithiasis and choledochitis. When renal DPM is present, there is an enhanced risk for renal cyst expansion causing compressive injury to adjacent nephron segments. It is important to understand that DPM may differentially affect liver lobes in an individual, with some liver lobes being histologically normal, while others may have DPM, or be hypoplastic or atretic. Histopathologic evaluation of herniated liver lobes from animals with congenital diaphragmatic hernias and from liver lobes damaged by other conditions harvested from the pathologic control animals demonstrated that proliferative-like bile duct DPM persists in herniated liver lobes in animals with PPDH.
Whenever cats and dogs are diagnosed with congenital diaphragmatic hernias, reflex evaluation for DPM should take place, and this should involve histologic and immunohistochemical evaluation of liver tissue biopsies from both herniated and nonherniated liver lobes. Agenesis of the gallbladder, hypoplasia or atresia of nonherniated liver lobes, and polycystic kidney lesions, whether identified by imaging studies, surgery, or necropsy, should likewise trigger a histologic search for DPMs. When DPM is identified in a living animal, lifelong monitoring of this patient for bacterial cholangitis, cholecystitis, and cholelithiasis, is mandatory of the case.