Introduction
Calcineurin inhibitors are medications that are used in liver, kidney, and heart transplant patients. These drugs are given to prevent rejection in organ transplantation patients. Calcineurin inhibitors are nephrotoxic medications. They cause acute and chronic adverse effects like infections, tumor development, metabolic disturbances, and renal failure. It causes interstitial fibrosis and tubular atrophy and may result in irreversible ischemic damage.
What Are Calcineurin Inhibitors?
Calcineurin inhibitors are immunosuppressive drugs that are given to manage autoimmune conditions like lupus nephritis, idiopathic inflammatory myositis, atopic dermatitis, and interstitial lung disease. It is the mainstay immunosuppressant agent that prevents organ rejection in transplant patients. Cyclosporine, Tacrolimus, Pimecrolimus, and Voclosporin are calcineurin inhibitor drugs. Cyclosporine and Tacrolimus are commonly used to prevent organ rejection.
How Do Calcineurin Inhibitors Cause Nephrotoxicity?
Calcineurin inhibitors cause reversible and irreversible damage to the arterioles, glomeruli, and tubulointerstitium of the kidneys. Calcineurin inhibitors target the endothelial and tubular cells and cause vasoconstriction. A reversible vasoconstriction is induced by Calcineurin inhibitors through vas afferent arterioles. Vasoconstriction results in hypoxia, progressive atherohyalinosis, arteriolohyalinosis, tubular atrophy, and interstitial fibrosis. This tubular injury progresses to a reversible dose-dependent renal failure. The vasoconstriction of afferent arterioles caused by calcineurin inhibitors leads to a decrease in glomerular blood flow and glomerular filtration rate. This decrease results in renal ischemia and hypertension. Calcineurin inhibitors also cause irreversible damage that is associated with tubular atrophy, interstitial fibrosis, arteriolar hyalinosis, and glomerulosclerosis.
What Is Acute Calcineurin Inhibitor Induced Nephrotoxicity?
Acute calcineurin inhibitor-induced nephrotoxicity is reversible and dose-dependent. It is characterized by acute kidney injury that affects the arterioles, glomeruli, and tubulointerstitium of the kidneys. Calcineurin inhibitors induce vasoconstriction and lead to hypoxia, interstitial fibrosis, and tubular atrophy, resulting in a reversible dose-dependent tubular injury. Microscopic changes like vacuoles in proximal tubules, microcalcifications, endothelial cell enlargement, arteriolar smooth muscle cell degeneration, intimal thickening, and hyaline or mucoid deposits are seen.
What Is the Difference Between Acute and Chronic Calcineurin Inhibitor Induced Nephrotoxicity?
Acute calcineurin inhibitor-induced nephrotoxicity is reversible and dose-dependent, and it is characterized by the presence of acute kidney injury that affects the arterioles, glomeruli, and tubulointerstitium. Calcineurin inhibitors induce vasoconstriction and lead to hypoxia, interstitial fibrosis, and tubular atrophy, resulting in an acute tubular injury that is reversible and dose-dependent.
Chronic calcineurin inhibitor-induced nephrotoxicity causes irreversible damage to the renal architecture. It is characterized by reversible changes in renal vascular resistance. However, the vessels, tubulointerstitium, and glomeruli are irreversibly affected. Cyclosporine and Tacrolimus cause irreversible arteriolar hyalinosis, tubular atrophy, and interstitial fibrosis; thickening and fibrosis of Bowman’s capsule; and focal segmental or global glomerulosclerosis.
How Does Acute Calcineurin Inhibitor Induced Nephrotoxicity Occur?
Calcineurin inhibitor-induced toxicity causes various acute changes in the kidneys. It can affect the native kidney and the transplanted kidney or other transplanted organs. However, the transplanted kidney lacks sympathetic innervation, so the toxic effects caused by calcineurin inhibitors by sympathetic upregulation are not seen in the transplanted kidney.
1. Vascular Effects: Calcineurin inhibitors induce vasoconstriction of the afferent arterioles and cause acute arteriolopathy. Calcineurin inhibitors cause profound changes in the vascular flow of the afferent and efferent arterioles and also reduce the diameter of the afferent arterioles. It increases the vasoconstrictor factors such as endothelin and thromboxane. Endothelin is a vasoconstrictor that is present in the kidneys. Cyclosporine stimulates the release of endothelin from the renal epithelial cells. It also activates the renin-angiotensin system and reduces the vasodilator factors like prostacyclin, prostaglandin E2, and nitric oxide. Cyclosporine also causes an imbalance in the vasodilator/vasoconstrictor ratio and promotes vasoconstriction. It increases the free radical formation and superoxide formation and induces hypoxia. It activates the kidneys' sympathetic nervous system, increases renal vascular resistance, and decreases the glomerular filtration rate. All these factors contribute to acute nephrotoxicity.
2. Tubular Effects: Calcineurin inhibitors cause toxic tubulopathy due to their direct toxic effects on tubular function. Histological examination shows the presence of isometric vacuolization of the cytoplasm of the tubules due to the enlargement of the endoplasmic reticulum and increased lysosomes. Isometric tubular vacuolization is the result of ischemia that is caused by afferent arteriolar vasoconstriction.
3. Thrombotic Microangiopathy: Thrombotic microangiopathy can be caused by renal infections, ischemia-reperfusion endothelial injury, transplant rejection, malignancies, and drugs like calcineurin inhibitors. Calcineurin inhibitors cause endothelial injury secondary to vasoconstriction-associated ischemia. Cyclosporine and Tacrolimus also increase platelet aggregation and activate the prothrombotic factors.
What Are the Other Effects of Acute Calcineurin Inhibitor Toxicity on Kidneys?
Calcineurin inhibitors cause electrolyte disturbances like hypomagnesemia and magnesium wasting, hyperkalemia, hyperchloremic metabolic acidosis, and hyperuricemia. It also causes polyuria, nephrocalcinosis, hyperreninemic hyperaldosteronism, and juxtaglomerular hyperplasia.
How Is Acute Calcineurin Inhibitor Nephrotoxicity Diagnosed?
Despite intensive research, reliable tests for diagnosing calcineurin inhibitor nephrotoxicity are Unavailable. Recent advancements in toxicogenomic studies have identified epithelial-to-mesenchymal transition and endoplasmic reticulum stress as potential markers of tubular dysfunction by calcineurin inhibitors. This could help in the early diagnosis of calcineurin inhibitor-induced nephrotoxicity.
A renal biopsy helps identify the microscopic changes associated with calcineurin inhibitor-induced nephrotoxicity. Acute toxicity shows the presence of vacuoles in proximal tubules due to the dilation of the endoplasmic reticulum with giant mitochondria and lysosomes. It also shows microcalcifications, endothelial cell swelling, intimal thickening, and hyaline or mucoid deposits in acute toxicity.
How Is Acute Calcineurin Inhibitor Nephrotoxicity Treated?
Calcineurin inhibitor-mediated toxicity can be overcome by avoiding the drug, decreasing the dose, or switching between calcineurin inhibitors and other immunosuppressant drugs. Other approaches include the following:
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Calcium Antagonists - Calcium antagonists prevent the reduction in renal plasma flow and also improve the glomerular filtration rate. However, different calcium antagonists cause different effects on renal vascular resistance.
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RAS Inhibition - RAS (renin-angiotensin system) inhibits calcineurin inhibitor-induced nephrotoxicity.
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Vasodilatory Prostanoids - Prostaglandin E2 reduces the nephrotoxicity mediated by cyclosporine.
Conclusion
Calcineurin inhibitors have led to major advancements in the field of transplantation. However, it causes irreversible damage to all compartments of the kidneys. Acute toxicity is reversible, but if it is left untreated, it may progress to cause irreversible damage. Proper knowledge about the mechanism of calcineurin inhibitor-induced nephrotoxicity may pave the way for targeted therapy and the prevention of calcineurin inhibitor-induced nephrotoxicity.
