Upload
others
View
5
Download
0
Embed Size (px)
Citation preview
Washington University School of MedicineDigital Commons@Becker
All Kidneycentric
2014
Pathophysiology and treatment of calcineurininhibitor nephrotoxicityJonna KemperSt. Louis Children's Hospital
Kara KniskaSt. Louis Children's Hospital
Follow this and additional works at: http://digitalcommons.wustl.edu/kidneycentric_all
This Article is brought to you for free and open access by the Kidneycentric at Digital Commons@Becker. It has been accepted for inclusion in All byan authorized administrator of Digital Commons@Becker. For more information, please contact [email protected].
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%
References:
1) Lexi-Comp OnlineTM
, Pediatric Lexi-Drugs OnlineTM
, Hudson, Ohio: Lexi-Comp, Inc.; 2013;
February 15, 2014.
2) Naesens M, Kuypers DR, Sarwal M. Calcineurin Inhibitor Nephrotoxicity. Clin J Am Soc Nephrol.
2009; 4:481-508.
3) Webster, AC, Woodroffe RC, Taylor RS, Chapman JR, Craig JC. Tacrolimus versus cyclosporine as
primary immunosuppression for kidney transplant recipients: meta- analysis and meta-
regression of randomized trial data. Cochrane Database Syst Rev. 2005; 19(4): CD003961.
4) Ojo AO, Held PJ, Port FK, Wolfe RA, Leichtman AB. Chronic renal failure after transplantation of a
nonrenal organ. N Eng J Med. 2003; 349 (10): 931-40.
5) Nankivell BJ, Borrows RJ, Fung CL, O’Connell PJ, Allen RD, et al. The natural history of chronic
allograft nephropathy. N Eng J Med. 2003; 349 (24): 2326-33.
6) Almawi WY, Melemedjian OK. Clinical and mechanistic differences between FK506 (tacrolimus)
and cyclosporine A. Nephrol Dial Transplant.2000; 14: 1916-1918.
7) Myers BD, Ross J, Newton L, Leutscher J, Perlroth M. Cyclosporine- associated chronic
nephropathy. N Engl J Med. 1984; 311 (11):669-705.
8) Issa N, Kukla A, Ibrahim HN. Calcineurin inhibitor nephrotoxicity: a review and perspective of the
evidence. Am J Nephrol. 2013; 37(6): 602-612
9) Laskow DA, Curtis JJ, Luke RG, Julian BA, Jones P, et al. Cyclosporine- induced changes in
glomerular filtration rate and urea excretion. Am J Med. 1990; 5(88): 497-502.
10) Klein IH, Abrahams A, van Ede T, Hene RJ, Koomans HA. Different effects of tacrolimus and
cyclosporine on renal hemodynamics and blood pressure in healthy subjects. Transplantation.
2002; 73 (5): 732-736.
Table 1. Calcineurin Inhibitor
6
11) Bobadilla NA, Gamba G. New insights into the pathophysiology of cyclosporine nephrotoxicity: a
role of aldosterone. Am J Physiol Renal Physil. 2007; 293 (1):F2-9.
12) Hoorn EJ, Walsh SB, McCormick JA, Furstenberg A, Yang CL, et al. The calcineurin inhibitor
tacrolimus activates the renal sodium chloride transport to cause hypertension. Nat Med. 2011;
17(10): 1304-9.
13) Nielsen FT, Jensen BL, Skott O, Bie P. Inhibition of mineral corticoid receptors with eplerenone
alleviates short- term cyclosporine A nephrotoxicity in the rat. J Am Soc Nephrol. 2006; 17:1-6.
14) Morozumi K, Thiel G, Albert FW, Banfi G, Gudat F. Studies on morphological outcome of
cyclosporine- associated arteriologpathy after discontinuation of cyclosporine in renal allografts.
Clin Nephrol. 1992; 38:1-8.
15) Remuzzi G, Cattaneo, and Perico N. The aggravating mechanisms of aldosterone on kidney
fibrosis. J Am Soc Nephrol. 2008; 19 (8):1459-62.
16) Kuypers DR, Neumayer HH, Fritsche L, Budde K, Rodicio J, et al. Lacidipine study group: calcium
channel blockade and preservation of renal graft function in cyclosporine- treated recipients: a
prospective randomized placebo- controlled 2-year study. Transplantation. 2004; 78:1204-1211.
17) Textor SC, Burnett JC, Romero C, Canzanello VJ, Taler SJ, et al. Urinary endotheliin and renal
vasoconstriction with cyclosporine or FK506 after liver transplantation. Kidney Int. 1995; 47 (5):
1426-33.
18) Srinivas TR, Meier- Kriesche HU. Minimizing immunosuppression, an alternative approach to
reducing side effects: Objective and interim result. Clin J Am Soc Nephrol. 2008; 3(2): S101-116.
19) Cross NB, Webster AC, Masson P, O’Connell PJ, Craig JC. Antihypertensive treatment for kidney
transplant recipients. Cochrane Database Syst Rev. 2009; 8(3).
20) Mourad G, Ribstein J, Mimran A. Converting- enzyme inhibitor versus calcium antagonist in
cyclosporine- treated renal transplants. Kidney Int. 1993. 43(2): 419-25.
21) Midtvedt K, Hartmann A, Foss A, Fauchald P, Nordal KP, Rootwelt K, Holdaas. Sustained
improvement of renal graft function for two years in hypertensive renal transplant recipients
treated with nifedipine as compared to lisinopril. Transplantation. 2001; 72(11): 1787-92.
22) O'Grady JG, Forbes A, Rolles K, Calne RY, Williams R. An analysis of cyclosporine efficacy and
toxicity after liver transplantation. Transplantation 1988;45:575-9.
23) Dieterle A, Gratwohl A, Nizze H, et al. Chronic cyclosporine-associated nephrotoxicity in bone
marrow transplant patients. Transplantation 1990;49:1093-100.
24) Gruessner RW, Burke GW, Stratta R, et al. A multicenter analysis of the first experience with
FK506 for induction and rescue therapy after pancreas transplantation. Transplantation
1996;61:261-73.
25) Feutren G, Mihatsch MJ. Risk factors for cyclosporine-induced nephropathy in patients with
autoimmune diseases. International Kidney Biopsy Registry of Cyclosporine in Autoimmune
Diseases. N Engl J Med 1992;326:1654-60.
26) Myers BD, Newton L. Cyclosporine-induced chronic nephropathy: an obliterative microvascular
renal injury. J Am Soc Nephrol 1991;2:S45-52.