The intact nephron hypothesis: the concept and its implications for phosphate management in CKD-related mineral and bone disorder

Abstract

Mechanistic understanding of secondary hyperparathyroidism, vascular calcification, and regulation of phosphate metabolism in chronic kidney disease (CKD) has advanced significantly in the past five decades. In 1960, Bricker developed the 'intact nephron hypothesis', opening the door for hundreds of investigations. He emphasized that 'as the number of functioning nephrons decreases, each remaining nephron must perform a greater fraction of total renal excretion'. Phosphate per se, independent of Ca²+ and calcitriol, directly affects the development of parathyroid gland hyperplasia and secondary hyperparathyroidism. Vitamin D receptor, Ca²+ sensing receptor, and Klotho-fibroblast growth factor (FGF) receptor-1 complex are all significantly decreased in the parathyroid glands of patients with CKD. Duodenal instillation of phosphate rapidly decreases parathyroid hormone release without changes in calcium or calcitriol. The same procedure also rapidly increases renal phosphate excretion independently of FGF-23, suggesting the possibility of an 'intestinal phosphatonin'. These observations suggest a possible 'phosphate sensor' in the parathyroid glands and gastrointestinal tract, although as yet there is no proof for the existence of such a sensor. Evidence shows that phosphate has a key role in parathyroid hyperplasia by activating the transforming growth factor-α-epidermal growth factor receptor complex. Thus, control of serum phosphorus early in the course of CKD will significantly ameliorate the pathological manifestations observed during progressive deterioration of renal function.

Figure 1

Hypothetical treatment of sodium excretion in chronic kidney disease (see text for details). GFR, glomerular filtration rate; FENa, fractional excretion of sodium; FLNa, filtered load of sodium. Figure newly constructed from data in Bricker et al. and Bricker.

Figure 2

Urinary sodium excretion in patients with advanced chronic kidney disease (stages 4–5). All patients with glomerular filtration rates ranging from 25 to 2.6 ml/min maintain perfect Na balance after ingestion of 60 or 120 mEq of Na/day. Reproduced by permission from Slatopolsky et al. Copyright 1968 by the American Society for Clinical Investigation. Reproduced with permission from the American Society for Clinical Investigation in the format Journal via Copyright Clearance Center.

Figure 3

Comparison of tubular reabsorption of phosphate (TRP) and glomerular filtration rate (GFR) in a group of normal subjects and 24 patients with different degrees of chronic kidney disease. The lower the GFR, the lower the TRP or the greater the excretion of phosphate per nephron. Reproduced by permission from Slatopolsky et al. Copyright 1968 by the American Society for Clinical Investigation. Reproduced with permission from the American Society for Clinical Investigation in the format Journal via Copyright Clearance Center.

Figure 4

Effects of a low-phosphate, low-calcium diet on serum calcium, calcitriol, phosphorus, and parathyroid hormone (PTH) in dogs with chronic kidney disease and established secondary hyperparathyroidism. ^*p<0.05. Figure newly constructed from data in Lopez-Hilker et al.

Figure 5

The effects of phosphorus in the culture media on the secretion of parathyroid hormone (PTH) in a normal rat parathyroid gland in vitro. In the two experimental conditions, the concentrations of ionized calcium and 1,25(OH)₂D₃ were identical. Error bars denote standard error. Adapted with permission from Slatopolsky et al.

Figure 6

Summary of the factors involved in the pathogenesis of secondary hyperparathyroidism. A decrease in ionizing calcium (ICa) is crucial in the development of secondary hyperparathyroidism. This change in ICa is secondary to phosphate retention and to low levels of 1,25(OH)₂D₃. Phosphate retention increases fibroblast growth factor (FGF)-23, which, in conjunction with its cofactor, the Klotho protein, decreases the activity of the 1α-hydroxylase and increases the 24α-hydroxylase, thus decreasing the levels of circulating 1,25(OH)₂D₃. In addition, phosphate retention, independent of change in ICa, posttranscriptionally increases the synthesis of parathyroid hormone (PTH). The 1,25(OH)₂D₃, independent of calcium, suppresses the transcription of the PTH gene. Decreases in the vitamin D receptor, calcium sensor receptor, and Klotho–FGFR1 receptor complex in the parathyroid gland also aggravate the development of secondary hyperparathyroidism.