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

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• 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

3 http://www.old-ib.bioninja.com.au/_Media/nephron2_med.jpeg

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

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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

8

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

Thank You

terence.kee.y.s@singhealth.com.sg