Does Parathyroid Hormone (PTH) affect the kidneys?

Effect of Parathyroid Hormone (PTH) on the Kidneys

Yes, parathyroid hormone (PTH) significantly affects kidney function through multiple direct mechanisms, including regulation of calcium reabsorption, phosphate excretion, and vitamin D activation. 1, 2

Key Renal Effects of PTH

PTH exerts several important effects on the kidneys:

1. Calcium and Phosphate Regulation

   • PTH binding to PTH1R in the distal and proximal renal tubules increases calcium reabsorption while simultaneously decreasing phosphate reabsorption 1, 2
   • This dual action helps maintain normal serum calcium levels without causing hyperphosphatemia 2

2. Vitamin D Activation

   • PTH stimulates the enzyme 1-α-hydroxylase (CYP27B1) in the kidneys to convert 25-hydroxyvitamin D into the active form 1,25-dihydroxyvitamin D (calcitriol) 1, 2
   • This activated vitamin D then increases intestinal calcium absorption, completing a key regulatory pathway

3. Interaction with FGF23

   • In the kidneys, FGF23 (released in response to PTH) binds to the FGF23 receptor/Klotho complex, which:
     • Increases phosphate excretion
     • Inhibits CYP27B1, decreasing 1,25-dihydroxyvitamin D production
     • Suppresses PTH secretion by the parathyroid gland 1, 2

PTH Metabolism and Kidney Disease

• PTH circulates as both the full-length 84-amino acid peptide and multiple C-terminal fragments 1

• The kidney is the primary site for clearance of PTH fragments:

  • Full-length PTH has a short half-life (2-4 minutes)
  • C-terminal fragments have a 5-10 times longer half-life with normal kidney function 1
  • In kidney disease, these fragments accumulate due to reduced clearance 1, 2

• In chronic kidney disease (CKD):

  • C-terminal PTH fragments accumulate at higher proportions than in healthy individuals 1
  • This accumulation affects PTH measurement and calcium regulation 2
  • Secondary hyperparathyroidism develops as a compensatory mechanism 2, 3

Clinical Implications

• In CKD, the kidney's reduced ability to respond to PTH contributes to:

  • Decreased calcium reabsorption
  • Impaired vitamin D activation
  • Hyperphosphatemia 3, 4

• PTH fragments that accumulate in kidney disease may have antagonistic effects:

  • The 7-84 PTH fragment can decrease the phosphaturic response to full-length PTH by approximately 50% 5
  • This contributes to skeletal resistance to PTH in uremia 5

• A feedback loop exists between PTH and FGF23:

  • PTH increases FGF23 expression in bone
  • FGF23 normally suppresses PTH secretion
  • In CKD, this loop becomes dysregulated, contributing to both high PTH and FGF23 levels 6

Monitoring and Management Considerations

• In CKD patients, monitoring of calcium, phosphate, and PTH levels is essential:

  • Target calcium levels: 8.4-9.5 mg/dL
  • Measurement frequency: at least every 3 months 2

• Accurate PTH measurement is complicated by:

  • Different assay generations detecting different fragments
  • Posttranslational modifications affecting bioactivity 1, 7

• Understanding PTH's renal effects is crucial for managing disorders like:

  • Primary hyperparathyroidism (with risk of nephrolithiasis and nephrocalcinosis) 4
  • Secondary hyperparathyroidism in CKD 2, 3

In conclusion, PTH has profound effects on kidney function that are essential for normal calcium and phosphate homeostasis, and disruption of these pathways contributes significantly to the complications of kidney disease.