Disorders of Degradation of hormones by kidney

1. DISORDERS IN DEGRADATION OF
HORMONES BY KIDNEY
Dr SIVARAJ S
DEPT OF PHYSIOLOGY
ALL INDIA INSTITUTE OF MEDICAL SCIENCES
NEW DELHI
23/04/2013

2. • Uremia interferes with metabolism and
regulation of hormones by various mechanism
• Endocrine defects occurs due to
– Inappropriate circulating hormone concentration
– Altered hormone action at target tissue level

3. Metabolism of peptide hormones
Most polypeptide hormones almost freely
filtered in the glomerulus
 Intratubular (brush border peptidases)
 Intracellular (cytosolic or lysosomal) degradation
in tubular cell
In certain hormones
 Receptor-mediated uptake
Emmanouel DS et al.,1980

4. Metabolism of peptide hormones
Intratubular&
Intracellular
degradation
Uptake from
peritubular
blood
Emmanouel DS et al.,1980

5. Increased Plasma Hormone
Concentrations
• Reduction of renal mass result in decrease in
the metabolic clearance
• If catabolic mechanisms differ, alteration in
the relation between biologically active and
inactive hormone fragments occur
• Concentrations of certain prohormones are
elevated e.g., pro-insulin, pro-IGF1A
Avner Paediatric Nephrology 6th Ed

6. • Extrarenal hormone elimination may also be
reduced
e.g., degradation of insulin in skeletal muscle tissue
is diminished
• Hypersecretion of various hormones or
hormone binding proteins
Appropriate response to secretory stimuli
e.g., PTH
Without an apparent homeostatic signal
e.g., prolactin

7. Decreased Plasma Hormone
Concentrations
• The reduction in functional renal mass main
cause for decreased levels of hormones
produced by thekidney
e.g., Erythropoietin, 1,25-(OH)2 vit D3
• Uremic milieu may suppress the production of
hormones
e.g.,Intracellular phosphate accumulation
may inhibit 1α hydroxylase

8. • Extra renal hormones decreased when the
hormone-producing gland is the final effector
organ of complex hormonal axis
e.g., Testis-testosterone, Ovary-estradiol
Direct toxic damage
Insufficient stimulatory input from superior part of
the hormonal axis
Hypo responsiveness of the gland

9. Disorders of Hormone Action
Hormone Binding to Plasma Proteins
– Excessive concentrations of several insulin-like
growth factor (IGF) binding proteins
– Binding proteins can compete for the hormone
with target organ receptors
e.g., Reduced somatomedin bioactivity in the
presence of normal total serum IGF

10. Disturbed Activation of Prohormones
– Peripheral conversion of T4 to tissue active T3 is
impaired
• Low T3 syndrome
– Chronic Met acidosis and IL-6 downregulates
peripheral conversion of T4 to T3
– Uremia blunt bioavailability and cell uptake of
Thyroid hormone leads to thyroid resistance state
Wiederkehr MR et al., 2004; Torpy DJ et al., 1998

11. Alterations of Target Tissue Sensitivity
• Reduced cellular receptor activation due to
the diminished receptor abundance
• Presence of inhibitory substances
• Accumulation of molecules inhibiting
hormone-receptor interaction
• Defects of hormone receptor complex
dependent intracellular signalling
e.g., Insulin and GH resistance in uraemia
Smith D, Defronzo RA et al., 1982; Schaefer F et al 2001