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2014

Pathophysiology and treatment of calcineurininhibitor nephrotoxicityJonna KemperSt. Louis Children's Hospital

Kara KniskaSt. Louis Children's Hospital

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Recommended CitationKemper, Jonna and Kniska, Kara, "Pathophysiology and treatment of calcineurin inhibitor nephrotoxicity" (2014). All. Paper 2.http://digitalcommons.wustl.edu/kidneycentric_all/2

Pathophysiology and Treatment of Calcineurin Inhibitor Nephrotoxicity Jonna Kemper, PharmD and Kara Kniska, PharmD;

Cyclosporine and tacrolimus are immunosuppressive agents used for prophylaxis against graft rejection

in transplantation, and are often used off label due to their inhibition of T cell activation in autoimmune

disorders.1 With the introduction of cyclosporine in the 1970s, transplant medicine was transformed. In

1984, tacrolimus was discovered and shown to be effective in human liver, kidney, and heart transplant

recipients. In addition, tacrolimus did not have the adverse effects of hypertrichosis and gingival

hyperplasia, and was associated with lower graft failure rates in kidney transplant patients when

compared to cyclosporine.2,3

However, both cyclosporine and tacrolimus are limited by their

nephrotoxicity. Cyclosporine has more data associated with its nephrotoxicity due to an extended time

on the market. The nephrotoxic effects of tacrolimus may be slightly less, but ultimately the effects of

both medications are thought to be due to a similar mechanism despite their structural differences .2,3

The rate of nephrotoxicity cited in the literature is variable (table 1), but is dependent on transplanted

organ and years of exposure. For instance, 7-21% of non-renal solid organ transplant recipients after

five years of exposure to calcineurin inhibitors had chronic kidney disease (defined as a GFR

<29ml/min/1.73M).4 In a study of 120 kidney-pancreas transplant recipients, after 10 years of

calcineurin inhibition nephrotoxicity was universal on biopsy with 60% of these patients having severe

allograft dysfunction. 5

While cyclosporine and tacrolimus are not structurally related, both agents work by inhibiting

calcineurin, a calcium/calmodulin dependent phosphatase, which ultimately inhibits T-Cell activation.

Cyclosporine binds to cyclophylin and tacrolimus binds with FKBP12. These complexes antagonize

calcineurin preventing downstream phosphatase activity, including a decreased actuation of the nuclear

factor of activated T- cells (NFAT). NFAT promotes transcription of IL-2 and activation of T-cells.2,6

Due to

differences in molecular structure and binding characteristics, nephrotoxicity induced by cyclosporine

and tacrolimus is thought to be related to the inhibition of calcineurin and NFAT.2,6

Initial consideration of cyclosporine-induced toxicity was thought to be a reversible side effect due to

functional changes. This was known as acute nephrotoxicity.2 Unfortunately in 1984, Myers and

colleagues suggested in heart transplant patients that long term use was associated with permanent and

progressive tubule interstitial injury and glomerulosclerosis.7 The probable pathophysiology of acute and

chronic injury due to calcineurin inhibitors (CNIs) will be reviewed (figure 1).

Acute CNI Nephrotoxicity:

Acute calcineurin inhibitor induced nephrotoxicity is primarily due to acute arteriolopathy. The original

finding of acute arteriole vasoconstriction caused by cyclosporine on the afferent arterioles was first

discovered by Murray and colleagues and later confirmed by subsequent studies.2 Additional research

has shown a change in vascular flow and a decreased diameter of the afferent arteriole with

cyclosporine treatment.8,9

Afferent arteriole vasoconstriction has been seen with tacrolimus but has a

lower potential of acute arteriolar constriction compared with cyclosporine. This finding has been

consistent in both animal and human studies .2,10

Even though tacrolimus has been found to have less

arteriole vasoconstriction, it is still clinically significant and presents a significant challenge when

managing patients.

2

The true etiology of acute arterial effects has yet to be clearly established. It is thought to be

multifactorial, resulting from a combination of an increase in vasoconstrictive factors (endothelin and

thromboxane), activation of the renin- angiotensin- aldosterone system (RAAS), reduction of vasodilator

factors (nitric oxide (NO) and prostacycline), and formation of free radicals. 2,8,11

Endothelin is released

from cultured renal epithelial cells when exposed to cyclosporine. This finding has been confirmed in

both animal and human studies with tacrolimus and cyclosporine. Additional endothelial dysfunction

occurs via the inhibition of NO synthesis resulting in a decreased production of vasodilators.2 Endothelial

dysfunction promotes platelet aggregation and prothrombotic activity in the glomeruli. Activation of

RAAS system with CNIs involves both direct and indirect mechanisms. Directly, CNIs can activate

juxtaglomerular cells to release renin. Indirectly, CNIs can cause renin release from decreased perfusion

as a result of arteriolar vasoconstriction.2,11,12

Ultimately, increased renin production increases

angiotensin II resulting in vasoconstriction. Additionally, decreased levels of cyclooxygenase (COX-2)

have been found with CNI administration. This is due to an association with NFAT, which has important

implications on the gene transcription of COX-2. By inhibiting calcinurein/NFAT, the production of COX-

2 is attenuated which would contribute to afferent arteriole vasoconstriction.2 In addition to this

arteriolar imbalance tacrolimus has been shown to activate the thiazide channel causing hypertension

which directly contributes to long-term kidney damage13

.

Chronic CNI Nephrotoxicity:

Even though CNIs have significantly contributed to the advancement in transplantation, the

disadvantage associated with CNIs is the chronic nephrotoxicity. This includes irreversible deterioration

of renal function as a result of interstitial fibrosis, tubular atrophy, arteriolar hyalinosis, as well as

glomerulosclerosis.14,15

Part of the mechanism of chronic interstitial nephritis is thought to be influenced

by the acute effects. These include afferent arteriole vasoconstriction, local hypoxia or ischemia, free

radical formation, and activation of the RAAS system, in particular angiotensin II and aldosterone.2, 11, 15

Secondary release of aldosterone is thought to play a significant role in chronic CNI nephropathy.

Aldosterone can release growth factors, release reactive oxidative species, and inhibit extracellular

matrix degradation.10,13

Aldosterone inhibitors (eplerenone and spironolactone) have been studied for

their protective effects in rodents. Rodents who received a mineralocorticoid receptor antagonist in

addition to cyclosporine, compared to those who were just given cyclosporine, had significantly less

associated arteriolopathy and tubulointersitial fibrosis, reduced renal tissue injury, hypofiltration,

hypertension, and growth impairment. The rodents also sustained creatinine clearance .13,14,15

Sustained

creatinine clearance suggests that inhibiting aldosterone may protect against acute nephropathy.

Unfortunately, this has not been studied in humans.

Up regulation of transforming growth factor beta (TGB-F), a growth factor is also thought to have

important implications in chronic CNI toxicity. TGB-F decreases the breakdown and encourages the

production of extracellular matrix proteins, which ultimately promotes interstitial fibrosis. This growth

factor has been shown to be elevated upon CNI administration. Other potential factors linked with CNI

chronic nephropathy include macrophage infiltration, ischemia, and reactive oxidative species .2,13

3

Prevention and Treatment of Nephropathy:

Managing the adverse effects associated with CNI toxicity can be challenging. Systemic hypertension is

the primary adverse effect associated with renal artery constriction and activation of RAAS. Electrolyte

disturbances can also result from CNI induced nephrotubular dysfunction resulting in hyperkalemia,

hypomagnesemia, hyperchloremic metabolic acidosis, and hyperuricemia.2

A concentration toxicity relationship has been established with CNIs thus concentration dependent

effects must be monitored. CNIs have a narrow therapeutic index in which high plasma concentrations

can result in acute nephrotoxicity (leading to chronic toxicity), and low plasma levels are associated with

graft rejection.17

Due to the high interpatient pharmacokinetic variability, particularly with absorption

and metabolism, plasma concentrations should be measured to ensure the patient is optimally

treated.1,2,10

Unfortunately even with therapeutic drug monitoring, local renal accumulation can occur.2,8

Research has been done in transplant recipients regarding avoidance, withdrawal, and minimization of

CNIs to prevent these toxicities. Current practice and research suggests minimization of CNIs after the

initial transplant period to target lower plasma concentrations appears to be safe. However, there are

no studies available to date that provide evidence supporting a reduction in CNI nephrotoxicity without

an increased rejection occurrence.18

Because vasoconstriction of the afferent arteriole plays a central role with acute nephrotoxicity,

medications that dilate the afferent arteriole have been studied to treat the acute toxicity. Treatment

with a calcium channel blocker (CCB), such as amlodipine or nifedipine, has shown to improve blood

pressure control and maintain glomerular filtration.2 In renal transplant patients, use of a calcium

channel blocker has additionally shown to have better renal allograft function independent of its effects

on blood pressure after one year of therapy.16

In a Cochrane review of renal transplant patients, when

compared to placebo, the use of a CCB resulted in a reduction of graft loss and improved glomerular

filtration.17

In heart transplant recipients, CCBs helped improve both renal function and blood pressure.

However, with long term treatment, CCBs did not influence the evolution of renal function.2,16,17

This

study did not specify which type of calcium channel blocker, dihydropyridine vs non- dihydropyridine,

was used. Different CCBs can affect renal vasculature and CNI metabolism differently.18

The central role of RAAS activation could suggest a role for an ACE inhibitor (ACEi) or angiotensin II

receptor blocker (ARB). In rodents, it has been demonstrated that these agents can prevent cyclosporine

induced interstitial fibrosis and improve renal function. In humans, ACEi have decreased CNI induced

nephrotoxicity and improved alterations in blood pressure. ARBs have shown to decrease the plasma

levels of TGF-B and endothelin. However, creatinine clearance tends to lack improvement due to

decrease filtration as a result of dilation of the efferent arteriole.2,8,11

As mentioned previously,

spironolactone has shown in rodents to decrease aldosterone mediated effects, but no human studies

are available.11

There have been two randomized studies comparing lisinopril (an ACEi) versus nifedipine (a CCB) in renal

transplant patients. Mourad and colleagues found no change in renal function and a similar change in

mean arterial pressure.20

Midtvedt and colleagues found that both lisinopril and nifedipine were

effective in treating hypertension.21

However, patients receiving nifedipine had improved kidney

Acute Nephrotoxicity

filtration rates and thus kidney function that was sustained over a

Review when comparing an ACEi with a CCB

hyperkalemia with an ACEi. The incidence of decreased

beneficial effect found was decreased proteinuria

for the treatment of chronic CNI nephrotoxicity

antibodies, antioxidants, statins, and magnesium supplementation.

data, or have not shown a beneficial effect on chronic C

Tacrolimus and cyclosporine have become a cornerstone of transplant

agents differ in terms of molecular structure and side effects. T

tremor, and hypomagnesmia, while

hyperplasia, and higher low density

cause acute and chronic nephrotoxicity partiall

agents necessitate therapeutic drug monitoring

agents should be utilized for the treatment of hypertension

important aim of therapy includes avoiding concurrent nephrotoxic medications

on targeting other potential mechanis

PLT: platelet, NO: nitric oxide, GFR: glomerular filtration rate;

oxygen species, TGF-B: transforming growth factor beta

Tubulo- Interstitium

Electrolyte Disturbances

Figure 1: Calcineurin Inhibitor Nephrotoxicity

Acute NephrotoxicityChronic Nephrotoxicity

and thus kidney function that was sustained over a period of 2 years.21

A C

when comparing an ACEi with a CCB found a decreased GFR in humans and increased

The incidence of decreased graft function was inconclusive

decreased proteinuria with ACEi use.19

Alternative agents have been studied

for the treatment of chronic CNI nephrotoxicity including: misoprostol, L- arginine, anti

, antioxidants, statins, and magnesium supplementation. These agents are lacking in human

beneficial effect on chronic CNI toxicity in humans.2,8,11

become a cornerstone of transplant immunosuppression

agents differ in terms of molecular structure and side effects. Tacrolimus has more associated

while cyclosporine has the adverse effects of hirsutism, gingival

low density lipoprotein (LDL) and triglyceride levels. However,

acute and chronic nephrotoxicity partially elucidated by the calcineurin inhibition. Both of these

therapeutic drug monitoring to help limit these toxicities. Calcium ch

for the treatment of hypertension and prevention of nephrotoxicity

avoiding concurrent nephrotoxic medications. Future therapies focus

other potential mechanistic causes of acute and chronic nephrotoxicity.

GFR: glomerular filtration rate; RAAS: Renin- Angiotensin- Aldosterone System

B: transforming growth factor beta

Interstitial Fibrosis & IschemiaElectrolyte Disturbances

Tubulo- Interstitium

↑ROS

↑TGF-B

Figure 1: Calcineurin Inhibitor Nephrotoxicity

4

Chronic Nephrotoxicity

A Cochrane

and increased

ion was inconclusive. The only

have been studied

arginine, anti- TGF-B

These agents are lacking in human

ssion therapy. The

more associated diabetes,

of hirsutism, gingival

levels. However, both agents

inhibition. Both of these

to help limit these toxicities. Calcium channel blocking

and prevention of nephrotoxicity. Another

ture therapies focus

Aldosterone System; ROS: reactive

Interstitial Fibrosis & Ischemia

Glomerulus

↑ PLT Aggregation

↑ Prothrombotic Activity

Arterioles:

↓Vasodilators

(Prostacycline & NO)

↑ Vasoconstrictors

(Thromboxane&

↓COX-2

↑ RAAS

5

Organ Transplant Duration of Exposure Calcineurin Nephrotoxicity (defined as decreased kidney

function/histology)

Kidney-Pancreas5

1yr

5yrs

10yrs

30%

55%

100%

Orthotopic Liver4,22

4yrs

5yrs

16%

18%

Bone Marrow Transplant23

8yrs 67%

Pancreas24

Induction at time of transplant 13%

*Autoimmune Uveitis25

2yrs 21%

Heart4,26

5yrs

10yrs

9%

9% ESRD

Lung4

5yrs 14%

Intestine4

5yrs 21%

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