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Home , Calcineurin, Nephrotoxicity, Tacrolimus

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2014 Pathophysiology and treatment of inhibitor Jonna Kemper St. Louis Children's Hospital

Kara Kniska St. Louis Children's Hospital

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

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 by an authorized administrator of Digital Commons@Becker. For more information, please contact [email protected]. Pathophysiology and Treatment of Calcineurin Inhibitor Nephrotoxicity Jonna Kemper, PharmD and Kara Kniska, PharmD;

Cyclosporine and are immunosuppressive agents used for prophylaxis against graft rejection in transplantation, and are often used off label due to their inhibition of 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 , , and heart transplant recipients. In addition, tacrolimus did not have the adverse effects of 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 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- 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 / dependent , 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 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. 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 channel causing which directly contributes to long-term kidney damage 13.

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 , 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 ) 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 .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 , 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

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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 , 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 . 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 or , 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

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filtration rates and thus kidney function that was sustained over a period of 2 years.21 A C ochrane Review when comparing an ACEi with a CCB found a decreased GFR in humans and increased hyperkalemia with an ACEi. The incidence of decreased graft funct ion was inconclusive . The only beneficial effect found was decreased proteinuria with ACEi use.19 Alternative agents have been studied for the treatment of chronic CNI nephrotoxicity including: misoprostol, L- arginine, anti - TGF-B , antioxidants, statins, and magnesium supplementation. These agents are lacking in human data, or have not shown a beneficial effect on chronic C NI toxicity in humans.2,8,11

Tacrolimus and cyclosporine have become a cornerstone of transplant immunosuppre ssion therapy. The agents differ in terms of molecular structure and side effects. T acrolimus has more associated , , and hypomagnesmia, while cyclosporine has the adverse effects of hirsutism, gingival hyperplasia, and higher low density lipoprotein (LDL) and triglyceride levels. However, both agents cause acute and chronic nephrotoxicity partiall y elucidated by the calcineurin inhibition. Both of these agents necessitate therapeutic drug monitoring to help limit these toxicities. Calcium ch annel blocking agents should be utilized for the treatment of hypertension and prevention of nephrotoxicity . Another important aim of therapy includes avoiding concurrent nephrotoxic medications . Fu ture therapies focus on targeting other potential mechanis tic causes of acute and chronic nephrotoxicity.

Figure 1: Calcineurin Inhibitor Nephrotoxicity

Acute Nephrotoxicity Chronic Nephrotoxicity

Glomerulus ↑ PLT Aggregation ↑ Prothrombotic Activity

Arterioles: ↓Vasodilators (Prostacycline & NO) ↑ Vasoconstrictors (Thromboxane& ↓COX-2 ↑ RAAS

Tubulo - Inters titium Tubulo - Inters titium ↑ROS Interstitial Fibrosis & Ischemia Electrolyte Disturbances ↑TGF-B

PLT: platelet, NO: nitric oxide, GFR: glomerular filtration rate; RAAS: Renin- Angiotensin- Aldosterone System ; ROS: reactive oxygen species , TGF -B: transforming growth factor beta 4

Table 1. Calcineurin Inhibitor

Calcineurin Nephrotoxicity Organ Transplant Duration of Exposure (defined as decreased kidney function/histology) Kidney -Pancreas 5 1yr 30% 5yrs 55% 10yrs 100%

Orthotopic Liver 4,22 4yrs 16% 5yrs 18% Transplant 23 8yrs 67% Pancreas 24 Induction at time of transplant 13% *Autoimmune 25 2yrs 21% Heart 4,26 5yrs 9% 10yrs 9% ESRD Lung 4 5yrs 14% Intestine 4 5yrs 21%

References:

1) Lexi-Comp Online TM , Pediatric Lexi-Drugs Online TM , 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 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 . 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.

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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 . 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- 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 . 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.

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