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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
Notas do Editor
Receptor-mediated uptakeacross the basolateral tubular cell membraneTubular brush border peptidases in certain small peptides(angiotensin I and II, bradykinin, glucagon)Fragments either excreated or reabsorbed as single amino acids
Proinsulin , which is not converted appropriately to insulin or C-peptide in patients with end-stage renal diseasePro IGF 1Aprecur-sor of insulin-like growth factor 1 (IGF1) which is notdetectable in normal serum
Low T3 before kidney transplantation associated with decreased graft survival
Defect in JAK/STAT phosphorylation with concurrent inflammation