nephrotoxicity of immunosuppressive drugs...nephrotoxicity of immunosuppressive drugs terence kee...
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Nephrotoxicity of Immunosuppressive Drugs
Terence Kee MBBS, MRCP, FAMS, FRCP, FASN, GDipHML Senior Consultant, Department of Renal Medicine Medical Director, Renal Transplant Program
Scope of Lecture
2
• Mechanism of drug nephrotoxicity using calcineurin inhibitors as an
example of immunosuppressive drugs which are nephrotoxic
• Clinical features and pathophysiology of nephrotoxicity of calcineurin
inhibitors
• Prevention and management of calcineurin inhibitor nephrotoxicity
Drug Nephrotoxicity
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Vasoactive effects
Glomerulopathy
Thrombotic
Microangiopathy
Tubulopathy
Acute Tubular Necrosis
Rhabdomyolysis
Interstitial
Nephritis Crystal Nephropathy
Obstructive Uropathy
Arteriolosclerosis
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Immunosuppression
Category
Common Examples Nephrotoxicity
Adrenocorticoids Prednisolone No
Immunophilin binding drugs Cyclosporine
Tacrolimus
Sirolimus
Everolimus
Yes
Antimetabolites Azathioprine
Leflunomide
Methorexate
Mycophenolate
No except
methotrexate
Alkylating agents Cyclophosphamide No
Biologics Monoclonal antibodies
e.g. Rituximab
Poyclonlal antibodies
e.g. Thymoglobulin
No
Type of Immunosuppressive Drugs
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Calcineurin Inhibitors
• First line prevention of allograft rejection and treatment of immune-
mediated disorders e.g. glomerulonephritis, rheumatoid arthritis,
psoriasis, inflammatory bowel diseases, etc
• Cyclosporine was first isolated in 1971 from the fungus Tolypocladium
inflatum while Tacrolimus was isolated in 1987 from the bacterium
Streptomyces tsukubaensis
Cyclosporine Tacrolimus
Mechanism of Action of CNI
6
Also other proteins
e.g. nitric oxide synthase
TGF-beta, collagen I / IV
Endothelin
bcl-2
CNI Nephrotoxicity
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Acute Arteriolopathy
Thrombotic Microangiopathy
Glomerular capsular fibrosis
Global glomerulosclerosis
Tubulopathy
Tubular vaculolization
Acute Tubular Necrosis
Medial arteriolar
hyalinosis
Interstitial Fibrosis
(Striped)
Tubular Atrophy
Incidence of CNI Nephrotoxicity
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Kemper, Jonna and Kniska, Kara, “ Pathophysiology and treatment of calcineurin inhibitor nephrotoxicity
http://digitalcommons.wustl.edu/kidneycentric_all/2
Indication Duration of Exposure Nephrotoxicity
Kidney pancreas transplant 1 yr
5 yrs
10 yrs
30%
55%
100%
Liver transplant 4 yrs
5 yrs
16%
18%
Bone Marrow transplant 8 yrs 67%
Heart transplant 5 yrs
10 yrs
9%
9% ESRF
Lung transplant 5 yrs 14%
Intestine transplant 5 yrs 21%
Autoimmune uveitis 2 yrs 21%
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Cyclosporine Nephrotoxicity
Calne RY, et al. Lancet 1978; 2: 1323-1327
Klintmalm GB, et al. Lancet 1981;1: 470-471
• Elevation of serum creatinine / Reduced glomerular filtration rate
• Occurs early after drug exposure e.g. post-transplant operative period
• Associated with high serum CNI drug levels
• May be associated with electrolyte disturbances e.g. hyperkalemia,
metabolic acidosis, hypomagnesemia
• Reversible by lowering dose of CNI or stopping CNI
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Clinical Features of Acute CNI Nephrotoxicity
Mechanisms of Acute CNI Nephrotoxicity
11 Naesens M, et al. Clin J Am Soc Nephrol 2009; 4: 481-508
Hemodynamically mediated
Multifactorial pathogenesis
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Pathology of Acute CNI Nephrotoxicity
Acute Tubular Necrosis
Toxic Tubulopathy
(Isometric tubular vacuolization, Focal tubular calcification)
Acute Arteriolopathy
Thrombotic Microangiopathy
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Metabolic Acidosis of CNI
Type 4 Renal Tubular Acidosis
Lee CH, et al. Electrolyte and Blood Pressure 2007; 5: 126-130
Collecting Ducts
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Hyperkalemia of CNI
Lee CH, et al. Electrolyte and Blood Pressure 2007; 5: 126-130
(-) (-)
(-)
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CNI induced Ca2+ and Mg2+ Wasting
Nijenhuis T, et al. J Am Soc Nephrol 2003; 15: 549-557.
FK506 = Tacrolimus
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Hyperuricemia
Clive D. J Am Soc Nephrol 2000;11: 974-979
CNI reduces uric acid clearance via reduced glomerular filtration and tubular secretion of uric acid
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Chronic Cyclosporine Nephrotoxicity
Myers BD, et al. N Eng J Med 1984; 311: 699-705
Mechanisms of Chronic CNI Nephrotoxicity
18 Nankivell BJ, et al. Transplantation 2016; 100: 1723-1731
• Slow, insidious increase in serum creatinine
• Occurs several months after drug exposure
• Associated with hypertension and moderate to nephrotic range
proteinuria
• CNI drug levels may be high
• Not reversible – need to reduce dose or discontinue CNI and use
alternative immunosuppression
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Clinical Features of
Chronic CNI Nephrotoxicity
Mechanisms of Chronic CNI Nephrotoxicity
20 Naesens M, et al. Clin J Am Soc Nephrol 2009; 4: 481-508
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Pathology of Chronic CNI Nephrotoxicity
Hyaline Arteriolopathy
Interstitial Fibrosis (Stripped Pattern)
Tubular Atrophy
Risk Factors for CNI Nephrotoxicity
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• Systemic exposure - High drug levels
• Genetic polymorphism - Cytochrome P450 3A (CYP3A4/CYP35)
• Renal tissue exposure - multidrug efflux transporter P-glycoprotein
• TGF-beta and ACE polymorphism
• Drugs that inhibit CYP3A/5 and P-glycoprotein function
• Older kidney age
• Concurrent use of nonsteroidal anti-inflammatory drugs
• Salt-depletion and diuretic use
Naesens M, et al. Clin J Am Soc Nephrol 2009; 4: 481-508
Prevention and Management of
CNI Nephrotoxicity
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• Monitor renal function and CNI drug levels regularly
• Avoid other nephrotoxic exposures and drugs that increase drug levels
• Decrease exposure to CNI – avoid, withdraw or minimize (using lower dose)
• Decrease exposure to CNI metabolites – inhibitors of CYP3A e.g. ketoconazole
• Decrease local renal susceptibility to CNI nephrotoxicity – dihyrdopyridine
calcium channel blockers, ACE inhibitors and angiotensin II receptor blockers
• Only in animal studies – spironolactone, vasodilatory prostanoids, NO donors,
e.g. L-arginine, anti-oxidants, anti-TGF-beta antibodies, statins, magnesium
supplementation
Naesens M, et al. Clin J Am Soc Nephrol 2009; 4: 481-508
Summary
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• CNI are an important class of immunosuppressive drugs that are
effective in the prevention of transplant rejection and treatment of
autoimmune conditions
• Nephrotoxicity is the Achilles’ heel of CNI-based immunosuppression
and it is critical to monitor renal function and drug levels when CNIs are
used
• The pathophysiology of CNI-associated nephrotoxicity is complex and
prevents effective targeted therapy at addressing nephrotoxicity
• Thence, the mainstay of minimizing CNI-associated nephrotoxicity is to
minimize duration and intensity of exposure or to avoid it altogether
