A murine model of phosphate nephropathy

We established a murine model of phosphate nephropathy with secondary hyperparathyroidism. db/db mice, which develop obesity and type 2 diabetes mellitus, were uninephrectomized at the age of 6 weeks and were fed either standard chow or a phosphorus-rich diet during the next 8 weeks. Thereafter, renal cryosections showed abundant tubular casts with a strong histochemical von Kossa reaction in all db/db mice on the phosphorus-rich diet but none in the controls. X-ray diffraction and Raman spectroscopy proved that these tubular casts consist mostly of hydroxyapatite Ca₅(PO₄)₃(OH). These intraluminal precipitations were located in distal tubuli and collecting ducts and were associated with degenerative tubular changes and peritubular infiltration of T cells and macrophages. In line, kidneys of db/db mice on the phosphorus-rich diet displayed significantly increased mRNA expression of the T_H1 cytokines interferon γ, IL-6, and tumor necrosis factor α. In addition, mice developed signs of secondary hyperparathyroidism as shown by elevated serum phosphate, decreased serum calcium, and increased parathyroid hormone, osteopontin, and fibroblast growth factor 23 levels. db/db mice on the phosphorus-rich diet also presented with significantly lower body weight, lower homeostasis model assessment of insulin resistance index, and hypertrophic cardiomyopathy. Thus, we provide a murine model of phosphate nephropathy and secondary hyperparathyroidism, which can be used for future pharmacologic and pathophysiologic studies to analyze the effect of hyperphosphatemia on renal, metabolic, and cardiovascular phenotypes.Inorganic phosphorus is essential for multiple biological functions, such as intracellular signal transduction, the production and function of cell membranes, and energy exchange. Although more than 80% of total body phosphorus is stored in bone and teeth, phosphorus is also found in the intracellular compartment and in serum (primarily in the form of anions such as H₂PO₄⁻ and HPO₄²⁻, which are commonly referred to as phosphate). In the steady state, serum phosphate levels are maintained within the physiological range by regulation of dietary absorption, bone formation, bone resorption, and by renal excretion. In the presence of a normal kidney function, renal excretion of excess phosphate is primarily responsible for maintaining phosphate balance. This regulation relies on the inhibition of the tubular sodium phosphate cotransporters and on increased levels of fibroblast growth factor 23 (FGF23) and parathyroid hormone.^1–4Hyperphosphatemia occurs whenever the amount of phosphate in the extracellular space exceeds the renal capacity for excretion. Hyperphosphatemia is, thus, a nearly universal complication of advanced renal failure. Large observational studies have also shown a graded association between levels of serum phosphate and all-cause mortality in patients with chronic renal failure. The positive phosphate balance seems to cause an accelerated progression of vascular calcification.^5–8An acute phosphate load that overwhelms renal capacity for excretion can be derived from endogenous and exogenous sources. Large amounts of endogenous phosphates are released from intracellular stores in tumor lysis syndrome, rhabdomyolysis, and lactic acidosis. Acute hyperphosphatemia can also result from ingestion of excessive amounts of phosphate-containing laxatives and enemas administered for colonoscopy preparation.⁹ Both endogenous and exogenous phosphate loads can lead to phosphate nephropathy.^10–15 Acute phosphate nephropathy is a clinical pathologic entity characterized by acute and subsequent chronic renal failure due to tubular precipitation of calcium phosphate deposits forming crystals of hydroxyapatite.¹⁶ It often followed exposure to oral sodium phosphate bowel purgatives, which were withdrawn from the market in December 2008 after a respective warning from the US Food and Drug Administration. Inadequate hydration and chronic kidney disease are established risk factors for acute phosphate nephropathy.¹⁶ Most of our present information on phosphate nephropathy derives from case series and retrospective epidemiologic analyses.^{11,14,17–19} Moreover, there is no specific therapy for established phosphate nephropathy.To study hyperphosphatemia and its renal, metabolic, and cardiovascular complications in more detail, we established and present herein a new animal model for phosphate nephropathy with established secondary hyperparathyroidism.