HC Flashcards
Cyclosporine MOA
- In the cytoplasm CsA binds to it’s immunophilin, cyclophilin (CpN).
- The forms a complex between CsA and CpN.
- This complex then binds and blocks the function of the enzyme Calcineurin (CaN)
- Resultantly, CaN fails to dephosphorylate the cytoplasmic component of the nuclear factor of activated t-cells (NF-ATc).
- Therefore, NF-AFc doesn’t translocate to the nucleus and theres no NF-ATn complex to bind the IL-2 gene to initiate production.
Cyclosporine Tox
- The mechanism of CsA-induced nephrotoxicity are multifactorial, with inflammatory events dominating the pathogenesis.
- Acute is a functional and reversible abnormality related to a renal imbalance of vasoconstrictor and vasodilator mediators.
- Chronic nephrotoxicity is characterised by irreversible tubulointerstitial fibrosis, accompanied by renal dysfunction. Glomerulosclerosis and arteriolopathy bodadilla and gamba 2007
- Activation of RAAS
o Promotes fibrotic processes and the release of aldosterone in a mouse model (Pichler et al., 1995).
o Ang II promotes fibrosis by releasing TGFB and other profibrotic factors.
o TGFB induces fibroblast to myofibroblast formation, leading to fibrosis via deposition of ECM proteins.
o Aldosterone release acts on the distal tubules of the kidneys causing increased sodium reabsorption and potassium excretion – contributing to volume expansion, hypertension and ultimately renal injury. - Upregulation of TGFB.
o CsA can also directly stimulate TGFB production in renal cells, having similar effects (Vieira et al., 1999).
o Similarly, it has been reported to inhibit TGFB degradation. - Renal hypoxia
o Leads to the formation of ROS – causes cellular injury and apoptosis (Zhong et al., 1999).
o CsA increased ROS by increasing renal nerve activity, resulting in vasoconstriction and hypoxia-reoxygenation.
o Activation of the renal nerve can lead to vasoconstriction of the blood vessels, reducing blood flow and oxygen delivery to the kidneys.
o When blood flow is being restored through reoxygenation – it can trigger ox stress due to ROS generation during the reperfusion phase. - An exaggerated immune response has been reported during the progression of kidney injury. - TNFa mRNA, dendritic cell count and MHC class II antigen expression were all increased after CsA treatment.
- Interestingly, in a recent nature paper by Abd-Eldayem et al., (2024), the nephrotoxic effects of the drug were shown to be halted by hesperidin and sitagliptin, owing to their antioxidant, anti-inflammatory and tissue protective properties.
Biomarkers
The tubulointerstitial injury is typically diagnosed with invasive renal biopsy and hence is normally only diagnosed once the disease has progressed.
- Current diagnostics are inadequate – GFP (variable between patients).
o Serum creatinine and blood urea nitrogen (insensitive).
o Albumin in urine – more sensitive but later stage.
- Novel biomarkers of CsA nephrotoxicity would therefore be advantageous.
- The complex and multi-factorial nature of CsA-induced nephrotoxicity makes early detection challenging.
- In the current study, significantly elevated proteinuria and serum creatinine levels were evident by 4 weeks CsA treatment.
- Histopathological analysis revealed significant tubular atrophy and interstitial collagen accumulation in CsA treated mice by week 4.
- Fibroblast accumulation is also a feature of TIF (Qi et al., 2006) and this was reflected by increased levels of FSP-1 and α-SMA protein in whole kidney lysates
- Signif. changes in urinary podocin after short CsA period, prior to structural changes.
- Podocyte damage and loss, can contribute to the initiation and progression of renal disease (Wang et al., 2009).
- Podocytes are specialized epithelial cells covering the basement membrane of the glomerulus and form the final barrier to serum protein loss.
- Measurement of urinary podocin along with other podocyte proteins has been proposed as a useful tool for detecting glomerular damage and renal disease development in other settings (Sakairi et al., 2010), but this study is the first report associating podocin loss with CsA nephrotoxicity.
Rapamycin
Rapamycin, also known of sirolimus, is a medication with diverse clinical applications, primarily in immunosuppression following organ transplantation, but also in the treatment of certain cancers.
- The drug binds the cytoplasmic receptor FK506-binding protein-12 (FKBP12) to form an immunosuppressive complex.
- FKBP-12-rapamycin complex binds and inhibits the activation of the mammalian target of rapamycin (mTOR), which is a serine/threonine-specific protein kinase that regulates cell growth, proliferation, survival, mobility and angiogenesis.
- Inhibition of mTOR leads to the suppression of cytokine drive t-cell proliferation.
- T-cells are key players in the immune response, thereby dampening the immune systems activity.
- Inhibition of calcineurin by the FKBP12 complex also contributes to Il-2 and t cell dampening.
- The drug also inhibits antibody production.
- These properties make the drug valuable in preventing rejection.
- Interestingly, the drug has also been shown to block proliferation in a number of non-lymphoid tissues – including hepatocytes, vascular smooth muscle cells, endothelial cells and renal tubular epithelial cells (Lieberthal et al., 2001)
- Side effects include ulceration of the mucous membranes of the mouth and digestive tract, anxiousness, blurry vision.
Rapamycin Nephrotox
- The mechanisms through which the drug induces nephrotoxicity is a complex nexus of physiological alterations – though aspects of this nexus remain poorly understood.
- Antiproliferation
o The rapamycin-FKBP12 complex inhibits mTOR, which in turn presents P70S6K signalling. Endothelial cell proliferation is reliant on this signalling.
o Thus, the drug inhibits endothelial cell proliferation
o In a transplant setting, endothelial cells may be damaged for various reasons – direct drug toxicity, infection, immune processes.
o The antiproliferative effects may prevent repopulation, thereby promoting local clotting cascade activation leading to consumption of platelets and RBC destruction (Crew et al., 2005). - Glomerular Proteinuria
o Proteinuria is induced by rapamycin treatment, in some cases.
o Proteinuria is an important marker for kidney damage, and a risk factor for renal disease progression.
o The mechanism underlying this effect is still an open matter.
o Proteinuria involves changes in glomerular permeability/proximal tubule reabsorption.
o Chronic use of rapamycin is known to also inhibit mTORC2 – in some cases.
o The mTOR pathway is involved in the regulation of both processes.
o This pathway relies on a scavenger receptor termed megalin.
o Megalin is crucial for protein endocytosis in proximal tubule epithelial cells.
o Impairing this results in proteinuria.
o Expression of PTEC is also modulated by the mTOR pathway (Peres et al., 2023). - Despite this, incidence of renal side effects is far lower than that of other immunosuppressants, such as Calcineurin Inhibitors.
