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

• 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

2 Drug Nephrotoxicity

Glomerulopathy Tubulopathy Thrombotic Acute Tubular Necrosis Microangiopathy Rhabdomyolysis Vasoactive effects

Arteriolosclerosis

Interstitial Nephritis Crystal Nephropathy Obstructive Uropathy http://www.old-ib.bioninja.com.au/_Media/nephron2_med.jpeg 3 Type of Immunosuppressive Drugs

Immunosuppression Common Examples Nephrotoxicity Category Adrenocorticoids Prednisolone No Immunophilin binding drugs Cyclosporine Yes Tacrolimus Sirolimus Everolimus Antimetabolites Azathioprine No except Leflunomide methotrexate Methorexate Mycophenolate Alkylating agents Cyclophosphamide No Biologics Monoclonal antibodies No e.g. Rituximab Poyclonlal antibodies e.g. Thymoglobulin

4 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 5 Mechanism of Action of CNI

Also other proteins e.g. nitric oxide synthase TGF-beta, collagen I / IV Endothelin bcl-2

6 CNI Nephrotoxicity

Thrombotic Microangiopathy Glomerular capsular fibrosis Tubulopathy Global glomerulosclerosis Tubular vaculolization Acute Tubular Necrosis Acute Arteriolopathy

Medial arteriolar hyalinosis

Interstitial Fibrosis (Striped) Tubular Atrophy http://www.old-ib.bioninja.com.au/_Media/nephron2_med.jpeg 7 Incidence of CNI Nephrotoxicity

Indication Duration of Exposure Nephrotoxicity Kidney pancreas transplant 1 yr 30% 5 yrs 55% 10 yrs 100% Liver transplant 4 yrs 16% 5 yrs 18% Bone Marrow transplant 8 yrs 67% Heart transplant 5 yrs 9% 10 yrs 9% ESRF Lung transplant 5 yrs 14% Intestine transplant 5 yrs 21% Autoimmune uveitis 2 yrs 21%

Kemper, Jonna and Kniska, Kara, “ Pathophysiology and treatment of calcineurin inhibitor nephrotoxicity http://digitalcommons.wustl.edu/kidneycentric_all/2 8 Cyclosporine Nephrotoxicity

Calne RY, et al. Lancet 1978; 2: 1323-1327 Klintmalm GB, et al. Lancet 1981;1: 470-471 9 Clinical Features of Acute CNI Nephrotoxicity

• 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

10 Mechanisms of Acute CNI Nephrotoxicity

Hemodynamically mediated Multifactorial pathogenesis

Naesens M, et al. Clin J Am Soc Nephrol 2009; 4: 481-508 11 Pathology of Acute CNI Nephrotoxicity

Toxic Tubulopathy Acute Arteriolopathy (Isometric tubular vacuolization, Focal tubular calcification)

Acute Tubular Necrosis Thrombotic Microangiopathy

12 Metabolic Acidosis of CNI

Collecting Ducts

Type 4 Renal Tubular Acidosis

Lee CH, et al. Electrolyte and Blood Pressure 2007; 5: 126-130 13 Hyperkalemia of CNI

(-)

(-) (-)

Lee CH, et al. Electrolyte and Blood Pressure 2007; 5: 126-130 14 CNI induced Ca2+ and Mg2+ Wasting

FK506 = Tacrolimus

Nijenhuis T, et al. J Am Soc Nephrol 2003; 15: 549-557. 15 Hyperuricemia

CNI reduces uric acid clearance via reduced glomerular filtration and tubular secretion of uric acid

Clive D. J Am Soc Nephrol 2000;11: 974-979 16 Chronic Cyclosporine Nephrotoxicity

Myers BD, et al. N Eng J Med 1984; 311: 699-705 17 Mechanisms of Chronic CNI Nephrotoxicity

Nankivell BJ, et al. Transplantation 2016; 100: 1723-1731 18 Clinical Features of Chronic CNI Nephrotoxicity

• 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

19 Mechanisms of Chronic CNI Nephrotoxicity

Naesens M, et al. Clin J Am Soc Nephrol 2009; 4: 481-508 20 Pathology of Chronic CNI Nephrotoxicity

Hyaline Arteriolopathy

Interstitial Fibrosis (Stripped Pattern) Tubular Atrophy 21 Risk Factors for CNI Nephrotoxicity

• 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 22 Prevention and Management of CNI Nephrotoxicity

• 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 23 Summary

• 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

24 Thank You [email protected]