Version May 2024
INTRODUCTION — Patients treated with the calcineurin inhibitors (CNIs) cyclosporine and tacrolimus are at high risk of developing kidney injury [1]. CNI nephrotoxicity is manifested either as acute kidney injury (AKI), which is largely reversible after reducing the dose, or as chronic progressive kidney disease, which is usually irreversible [2-5]. Other kidney effects of the CNIs include tubular dysfunction and, rarely, a thrombotic microangiopathy (TMA) that can lead to acute kidney allograft loss [2]. Most data on CNI nephrotoxicity pertain to cyclosporine since it has been used for a much longer time. However, a similar pattern of kidney injury from cyclosporine is seen with the use of tacrolimus, thereby suggesting a drug class effect. CNI toxicity is seen most frequently in kidney transplant recipients, but it has been reported in other populations including hematopoietic cell transplant [6] and non-kidney solid organ transplant [7-10] recipients.
This topic will review the acute and chronic nephrotoxicity of cyclosporine and tacrolimus as well as strategies to prevent chronic CNI nephrotoxicity. The pharmacology of CNIs, including a discussion of the nonrenal side effects of cyclosporine and tacrolimus, is presented elsewhere. (See "Pharmacology of cyclosporine and tacrolimus".)
INCIDENCE — In the earliest clinical kidney transplant trials using cyclosporine, a high incidence of oliguric acute kidney injury (AKI) and primary nonfunction (ie, acute calcineurin inhibitor [CNI] nephrotoxicity) was observed; the risk was greatest with prolonged ischemia time of the donated kidney prior to transplantation [11]. Subsequent trials using lower doses of cyclosporine showed that these problems were dose related, although there was considerable variability in the incidence of AKI in various centers.
Support for the hypothesis of chronic CNI nephrotoxicity comes most directly from non-kidney transplant patients and patients with autoimmune diseases in whom the nephrotoxic potential of CNIs can be evaluated in the absence of coexisting acute or chronic rejection of a kidney allograft. These patients have a 35 to 45 percent reduction in glomerular filtration rate (GFR) compared with patients not treated with cyclosporine. This is discussed in detail separately. (See "Kidney function and non-kidney solid organ transplantation".)
The best data on the overall incidence of chronic kidney disease (CKD) with CNIs come from a cohort study of non-kidney transplant recipients (mostly liver, heart, and lung) in the United States [12]. Cyclosporine was given to 60 percent and tacrolimus to 28 percent. At a median follow-up of 36 months, 17 percent developed CKD (defined as an estimated GFR [eGFR] ≤29 mL/min/1.73 m2). The risk continued to increase over time with all kinds of transplants and, at 5 years, ranged from 7 to 21 percent (figure 1). These patients had a 4.6-fold increase in the risk of death compared with those without CKD. Risk factors for CKD included calcineurin therapy, older age, lower pretransplant GFR, female sex, postoperative AKI, baseline diabetes and hypertension, and hepatitis C virus infection. (See "Kidney function and non-kidney solid organ transplantation".)
Some patients with CKD, 29 percent in the above report, eventually progress to end-stage kidney disease (ESKD) and require kidney replacement therapy [12-14].
Cyclosporine versus tacrolimus — Acute and chronic nephrotoxicity are generally similar with both cyclosporine and tacrolimus [15]. However, tacrolimus has less nephrotoxicity with lower doses without compromising overall outcomes [16-18]. This was best shown in the Efficacy Limiting Toxicity Elimination-Symphony (ELITE-Symphony) study [16]. In this trial, 1645 kidney transplant recipients were randomly assigned to one of four immunosuppressive arms: conventional-dose cyclosporine, glucocorticoids, and mycophenolate mofetil or daclizumab induction therapy, mycophenolate mofetil, and glucocorticoids with either low-dose cyclosporine (target trough level of 50 to 100 ng/mL), low-dose sirolimus (target trough level of 4 to 8 ng/mL), or low-dose tacrolimus (target trough level of 3 to 7 ng/mL). At one year, the low-dose tacrolimus group had the highest mean calculated GFR compared with the other three groups (65 versus 57 to 60 mL/min). The tacrolimus-based regimen was also associated with the lowest allograft rejection and highest allograft survival rates. At three years, the low-dose tacrolimus group continued to have the highest mean calculated GFR (69 mL/min versus 64 to 66 mL/min) [19]. Further discussion of this study is presented separately. (See "Kidney transplantation in adults: Maintenance immunosuppressive therapy".)
Long-term trials comparing cyclosporine and tacrolimus in liver transplant recipients found a similar incidence of early AKI and late hypertension, while late kidney function impairment was more prevalent with tacrolimus [20-22]. By contrast, the registry data from almost 70,000 non-kidney solid organ transplant recipients found that tacrolimus was associated with less nephrotoxicity in liver transplants and similar nephrotoxicity in other transplants [12]. Another retrospective study of liver transplant recipients also found that tacrolimus was associated with relatively better kidney function [23].
However, these data are confounded by evidence that CKD in non-kidney transplant patients is not necessarily due to CNI therapy alone. In one kidney biopsy study of 26 liver transplant recipients, for example, CKD was due to four different pathogenic processes: chronic CNI therapy, diabetic nephropathy, thrombotic microangiopathy (TMA) due to cyclosporine/tacrolimus and/or alfa-interferon, and tubular disease due to hydroxyethyl starch [7].
RISK FACTORS — Several factors may contribute to the risk of calcineurin inhibitor (CNI) nephrotoxicity [5]:
●High doses of cyclosporine [24,25] or tacrolimus [26]
●Older age of donated kidney [27]
●Concomitant use of nephrotoxic drugs, particularly nonsteroidal antiinflammatory drugs (NSAIDs) [28,29]
●Salt depletion and diuretic use
●Drugs that inhibit cytochrome P-450 3A4/5 (CYP3A4/5), thereby increasing exposure to CNI metabolites (table 1)
●Drugs that inhibit P-glycoprotein-mediated efflux of CNIs from tubular epithelial cells, thereby increasing local renal exposure to CNIs (table 2)
●Genetic polymorphisms in the genes encoding CYP3A4/5 (CYP3A4/5) and P-glycoprotein (ABCB1) [30-35]
●Recipient arteriosclerosis in a zero-time allograft biopsy [36]
PATHOGENESIS AND PATHOLOGY
Acute calcineurin inhibitor nephrotoxicity — Most data in this field pertain to cyclosporine, although the effects of tacrolimus are thought to be similar. Studies have demonstrated that cyclosporine causes vasoconstriction of the afferent and efferent glomerular arterioles [37] and reductions in renal blood flow and glomerular filtration rate (GFR). The exact mechanism of vasoconstriction is unclear, but there appears to be substantial impairment of endothelial cell function, leading to reduced production of vasodilators (prostaglandins and nitric oxide) and enhanced release of vasoconstrictors (endothelin and thromboxane) [37-40]. Increased sympathetic tone also may be present [41], although renal vasoconstriction occurs even in denervated kidneys. In addition, transforming growth factor (TGF)-beta-1, endothelin-1, and the production of reactive oxygen and nitrogen species have also been implicated [40].
Kidney biopsy typically reveals an acute arteriolopathy and tubular vacuolization. Rarely, vascular lesions similar to those in the hemolytic uremic syndrome (HUS) are seen.
There may also be an intrinsic kidney susceptibility to cyclosporine-induced renal vasoconstriction. Experimental support for this hypothesis is derived from a study examining the effect of raising the cyclosporine dose in eight pairs of stable, unrelated kidney transplant recipients who had received a deceased-donor kidney from the same donor [42]. Seven of the eight pairs showed a parallel response to increasing the cyclosporine dose (four pairs showed an elevation in the plasma creatinine concentration, while three pairs showed no change).
The increase in renal vascular tone induced by cyclosporine may not attenuate with time. Maintenance cyclosporine therapy is associated with transient reductions in renal plasma flow and GFR, which correlate both with dose and with peak cyclosporine levels reached two to four hours after the oral dose [39]. These functional abnormalities are also associated with increased urinary excretion of endothelin, which decreases when trough drug levels are reached. Studies with an endothelin receptor antagonist suggest that endothelin mediates cyclosporine-induced afferent arteriolar constriction, an effect that will lower the intraglomerular pressure and the GFR [37].
Administration of a calcium channel blocker can prevent the renal vasoconstriction, although not the rise in endothelin excretion [39]. This observation constitutes part of the rationale for the use of calcium channel blockers to treat hypertension in cyclosporine- and tacrolimus-treated transplant recipients. The role of cyclosporine in the elevation of blood pressure is discussed elsewhere. (See "Hypertension after kidney transplantation".)
The increase in vascular resistance may therefore be reflected clinically by an elevated plasma creatinine concentration and hypertension [2,41,43]. Cyclosporine-induced renal vasoconstriction can cause delayed recovery from early AKI and, in severe cases, primary nonfunction. These complications are most likely to occur with prolonged ischemia time and high cyclosporine doses [11]; however, even patients with therapeutic trough levels may show signs of nephrotoxicity. (See 'Acute reversible kidney injury' below.)
It is also possible that repeated episodes of kidney ischemia contribute to the development of chronic cyclosporine nephrotoxicity described below (see 'Chronic calcineurin inhibitor nephrotoxicity' below). The continued release of endothelin after administration of a calcium channel blocker suggests that vascular injury may still be occurring. Thus, short-term prevention of renal vasoconstriction, possibly due to limiting endothelin-induced calcium entry into vascular smooth muscle cells, may not necessarily be associated with long-term protection against vascular disease [39].
Chronic calcineurin inhibitor nephrotoxicity — Chronic calcineurin inhibitor (CNI) nephrotoxicity is manifested by kidney function impairment due to glomerular and vascular disease, abnormalities in tubular function, and an increase in blood pressure [2,15].
●(See 'Chronic kidney disease' below.)
●(See 'Electrolyte and acid-base disturbances' below.)
●(See 'Hyperuricemia and gout' below.)
●(See "Hypertension after kidney transplantation".)
Kidney biopsy reveals an obliterative arteriolopathy (suggesting primary endothelial damage), ischemic collapse or scarring of the glomeruli, vacuolization of the tubules, global and focal segmental glomerulosclerosis, and focal areas of tubular atrophy and interstitial fibrosis (producing a picture of "striped" fibrosis) (picture 1A-C) [1,3,5,44-47]. These changes are seen with both low-dose and higher-dose cyclosporine therapy, although they seem to occur earlier with higher doses [44,48,49].
One histologic study reported the association of these changes with cyclosporine dose and over time [50]. Mild arteriolar hyalinosis at six months appeared to be associated with high doses and was reversible. By comparison, at three years, irreversible severe arteriolar hyalinosis and glomerulosclerosis were observed, despite decreased doses and trough levels.
The factors responsible for chronic CNI nephrotoxicity are not well understood. The development of interstitial fibrosis is associated with increased expression of osteopontin (a potent macrophage chemoattractant secreted by the tubular epithelial cells [51]), chemokines (a class of cytokines that are strong chemoattractants for a variety of hematopoietic cells [52]), and transforming growth factor (TGF)-beta (a powerful stimulator of extracellular matrix production [53,54]).
Support for a central role for TGF-beta has been provided by findings in mice in which cyclosporine nephropathy was significantly diminished with anti-TGF-beta therapy [55,56]. TGF-beta appears to be induced in part by decreased secretion of nitric oxide [57] as well as increased local concentrations of angiotensin II, possibly explaining at least in part the beneficial effects observed with angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor antagonists [51,53,58].
Cyclosporine is a substrate for the transmembrane pump P-glycoprotein. There is some evidence in animals and in vitro that decreased expression of this pump may contribute to increased cyclosporine levels, leading to nephrotoxicity [59,60]. Altered protein pump expression has also been observed in association with several polymorphisms in its gene. As an example, the TT genotype is associated with decreased P-glycoprotein expression in the kidney. In a case-control study of donor and recipient pairs, the TT genotype in the donor directly correlated with chronic cyclosporine nephrotoxicity in the allograft recipient (odds ratio [OR] 13.4, 95% CI 1.2-148) [61]. This suggests that underlying genetic factors that increase cyclosporine concentrations in the kidney may contribute to chronic nephrotoxicity.
It has been proposed that the arterial lesions are the primary abnormality, with secondary ischemia being responsible for the tubular and interstitial lesions. Some animal studies, for example, have shown that the vascular and interstitial findings can be dissociated:
●A report found that inhibiting angiotensin II with an ACE inhibitor or an angiotensin II receptor antagonist (losartan) minimized the interstitial fibrosis without affecting the glomerular or tubular injury; this beneficial effect was not observed with the combination of hydralazine and furosemide [58].
●Another study had somewhat different results [51]. Both losartan and the combination of hydralazine and furosemide minimized interstitial fibrosis, while only losartan protected against the arteriolopathy.
Increased apoptosis (ie, programmed cell death) occurs in kidneys exposed to cyclosporine [62]. This finding may help explain the interstitial abnormalities associated with cyclosporine toxicity: the loss of cells and renal tubules accompanied by fibrosis. The expression of specific apoptotic genes, such as p53 and Fas ligand, is enhanced in rats administered cyclosporine, thereby favoring the induction of apoptosis [63].
CLINICAL PRESENTATIONS — Calcineurin inhibitor (CNI) nephrotoxicity encompasses several different clinical manifestations that reflect functional and/or morphologic changes in the kidney allograft (in kidney transplant recipients) or the native kidney (in non-kidney solid organ transplant recipients or nontransplant patients). Acute CNI nephrotoxicity commonly presents as an acute but typically reversible functional kidney impairment and rarely as a thrombotic microangiopathy (TMA). Chronic CNI nephrotoxicity manifests as a chronic progressive deterioration in kidney function. In addition, CNIs have also been associated with a number of electrolyte and acid-base abnormalities that are a result of CNI-induced tubular dysfunction.
Acute reversible kidney injury — Acute cyclosporine and tacrolimus nephrotoxicity typically presents as an acute increase in plasma creatinine concentration, which is dose related and largely reversible after dose reduction or cessation of therapy [40]. This reversible functional kidney impairment is primarily due to acute vasoconstriction of the afferent arterioles and resembles the clinical picture of prerenal disease (see 'Acute calcineurin inhibitor nephrotoxicity' above). The onset of acute CNI nephrotoxicity can occur anytime within hours to days to even years after CNI initiation. In kidney transplant recipients, acute CNI nephrotoxicity can also manifest as delayed recovery of function of a newly transplanted but malfunctioning allograft.
Early studies of cyclosporine in kidney transplantation demonstrated a relationship between whole blood or plasma cyclosporine concentrations and acute CNI nephrotoxicity that was reversible with dose reduction [25,64]. A similar dose relationship exists between tacrolimus concentrations and nephrotoxicity [26,65].
In kidney transplant recipients, acute CNI nephrotoxicity may be difficult to differentiate from acute rejection. The only definitive diagnostic test is biopsy of the kidney allograft. Although there are no specific pathologic changes induced acutely by cyclosporine or tacrolimus [3,66], the absence of acute T cell-mediated or antibody-mediated rejection as well as reversibility of kidney dysfunction with drug cessation (over days to a week) strongly suggest CNI nephrotoxicity. It is also important to appreciate that the presence of rejection does not exclude concomitant CNI toxicity. (See "Kidney transplantation in adults: Evaluation and diagnosis of acute kidney allograft dysfunction", section on 'Evaluation of acute allograft dysfunction' and "Kidney transplantation in adults: Clinical features and diagnosis of acute kidney allograft rejection".)
Chronic kidney disease — Chronic CNI nephrotoxicity commonly presents as a chronic and progressive kidney function impairment due to glomerular and vascular disease, abnormalities in tubular function, and an increase in blood pressure [2,15]. It is usually irreversible. Chronic CNI nephrotoxicity is thought to be caused by a combination of CNI-induced hemodynamic changes and toxic effects of CNIs on renal tubular epithelial cells. (See 'Chronic calcineurin inhibitor nephrotoxicity' above and "Hypertension after kidney transplantation", section on 'Immunosuppressive agents'.)
In kidney transplant recipients, chronic CNI nephrotoxicity may be difficult if not impossible to distinguish from chronic allograft nephropathy. (See "Kidney transplantation in adults: Chronic allograft nephropathy", section on 'Similar histologic findings'.)
Thrombotic microangiopathy — The use of CNIs has been associated with the development of de novo TMA after kidney transplantation. Patients typically present with a microangiopathic hemolytic anemia with schistocytes on the blood smear, thrombocytopenia, and acute kidney injury (AKI). The TMA associated with CNIs is presumably initiated by CNI-induced injury to the vascular endothelial cells. Concurrent use of cyclosporine with mammalian (mechanistic) target of rapamycin (mTOR) inhibitors has been shown to increase the risk of TMA [67].
A more detailed discussion of TMA after kidney transplantation is presented elsewhere. (See "Thrombotic microangiopathy after kidney transplantation", section on 'Clinical presentation' and "Drug-induced thrombotic microangiopathy (DITMA)", section on 'Immunosuppressive agents'.)
Electrolyte and acid-base disturbances — CNIs have been associated with the development of several electrolyte and metabolic abnormalities, including hyperkalemia, hyperuricemia and gout, metabolic acidosis, hypophosphatemia, hypomagnesemia, and hypercalciuria [20,21,68,69].
Hyperkalemia — An elevation in the plasma potassium concentration due to reduced efficiency of urinary potassium excretion is common in CNI-treated patients; it may be severe and potentially life-threatening with concurrent administration of an angiotensin-converting enzyme (ACE) inhibitor, which diminishes aldosterone release. CNIs may reduce potassium excretion both by decreasing the activity of the renin-angiotensin-aldosterone system and by impairing tubular responsiveness to aldosterone [70,71].
Urinary potassium excretion is primarily derived from potassium secretion in the collecting tubules via potassium channels in the luminal membrane (figure 2). This process is stimulated by sodium reabsorption (which, unless chloride follows the sodium, creates a lumen-negative electrical gradient that promotes potassium secretion), aldosterone (which increases the number of open sodium channels in the luminal membrane), and the basolateral Na-K-ATPase pump (which removes reabsorbed sodium from the cell in exchange for potassium, thereby increasing the size of the potassium secretory pool). (See "Causes of hypokalemia in adults", section on 'Increased urinary losses'.)
In vitro studies suggest that cyclosporine may directly impair the function of the potassium-secreting cells in the cortical collecting tubule by affecting each of these steps: reduced activity of the Na-K-ATPase pump [72], inhibition of the luminal potassium channel [73], and increased chloride reabsorption, which prevents generation of lumen-negative potential, which drives potassium secretion [71]. Tacrolimus has been shown to have inhibitory effects on the Na-K-ATPase pump [74].
Cyclosporine may also have a second effect on potassium homeostasis in patients concurrently treated with a beta blocker. In this setting, there is often a modest (<1 mEq/L) and transient elevation in the plasma potassium concentration due to the movement of potassium out of the cells, into the extracellular fluid [75]. Why this occurs is not known.
Issues surrounding the management of hyperkalemia are discussed separately. (See "Treatment and prevention of hyperkalemia in adults".)
Metabolic acidosis — Tubular injury induced by cyclosporine can also impair acid excretion. This may be manifested as a normal anion gap (hyperchloremic) metabolic acidosis that may also reflect decreased aldosterone activity and suppression of ammonium excretion by hyperkalemia [2]. (See "Etiology, diagnosis, and treatment of hypoaldosteronism (type 4 RTA)".)
Hypophosphatemia — Some patients treated with cyclosporine develop hypophosphatemia due to urinary phosphate wasting [2,76].
Hypomagnesemia — Renal magnesium wasting is common in cyclosporine- and tacrolimus-treated recipients, presumably due to drug effects on magnesium reabsorption [77-79]. Hypomagnesemia has been implicated as a contributor to the nephrotoxicity associated with cyclosporine [80]. (See "Hypomagnesemia: Causes of hypomagnesemia".)
Hypercalciuria — Both cyclosporine and tacrolimus are associated with hypercalciuria [79,81].
Hyperuricemia and gout — Cyclosporine and tacrolimus, via glomerular and tubular effects, can decrease urinary uric acid excretion, leading to hyperuricemia in most patients and occasionally symptomatic gout. (See "Kidney transplantation in adults: Hyperuricemia and gout in kidney transplant recipients".)
PREVENTION OF CHRONIC CALCINEURIN INHIBITOR NEPHROTOXICITY
Reduced exposure to calcineurin inhibitors — The replacement of calcineurin inhibitors (CNIs) with non-nephrotoxic immunosuppressive agents may ameliorate kidney dysfunction among patients with CNI nephrotoxicity. Benefits have been observed among kidney and non-kidney organ transplant recipients with decreased kidney function due to CNI therapy. Some studies, however, question whether CNI withdrawal is safe in those with adequate kidney function [82]. A detailed discussion related to CNI withdrawal in kidney allograft recipients is discussed in detail separately. (See "Kidney transplantation in adults: Chronic allograft nephropathy", section on 'Reducing calcineurin inhibitor exposure'.)
Whether there is a "safe" chronic dose of a CNI that is effective immunologically, but does not cause progressive kidney dysfunction, is difficult to answer because of the lack of well-controlled prospective trials. (See "Kidney transplantation in adults: Maintenance immunosuppressive therapy".)
Short-term studies suggest that low doses of cyclosporine may not lead to kidney dysfunction [11,82,83]. As an example, the Cyclosporine Avoidance Eliminates Serious Adverse Renal-toxicity (CAESAR) study found similar kidney function at one year among a group of 536 first-time kidney transplant recipients randomly assigned to low-dose cyclosporine (target trough level of 50 to 100 ng/mL), low-dose cyclosporine and cyclosporine withdrawal at six months, and standard-dose cyclosporine therapy (first four months at 150 to 300 ng/mL target trough level and 100 to 200 ng/mL thereafter) [82]. In addition, although acute rejection was similar at six months, at approximately 25 percent, it was significantly higher at one year in the cyclosporine withdrawal group, with a one-year rejection rate of 38 percent.
Overall, however, there is a strong association between chronic kidney allograft dysfunction and long-term continuous exposure to maintenance doses of cyclosporine or tacrolimus [4,50,84,85]. Perhaps the best insight into the time dependence of chronic CNI nephrotoxicity was provided by a study of 120 kidney-pancreas recipients who underwent sequential kidney protocol biopsies over a 10-year posttransplantation period [84]. Triple-agent immunosuppressive therapy consisting of cyclosporine/tacrolimus, prednisone, and azathioprine/mycophenolate mofetil was administered.
Early damage, which was observed within one year posttransplantation, resulted primarily from immunologic factors such as severe acute rejection and persistent early subclinical rejection, as well as from ischemic injury. By comparison, after one year posttransplant, damage was characterized by progressive high-grade arteriolar hyalinosis, with vessel narrowing, glomerulosclerosis, and additional tubulointerstitial injury. This was thought to principally be the result of CNI injury. By comparison, chronic immune rejection was uncommon with prolonged follow-up. At 10 years, severe allograft nephropathy was present in 60 percent of patients, with glomerulosclerosis being observed in almost 40 percent of glomeruli. (See "Kidney transplantation in adults: Chronic allograft nephropathy".)
Other approaches — In view of the utility of CNIs in transplantation and autoimmune diseases, there has been a great deal of interest in developing therapeutic strategies to minimize their nephrotoxic effects. Although multiple agents have been evaluated, including cold water fish oil, calcium channel blockers, thromboxane synthesis inhibitors, and pentoxifylline, none is clearly effective.
Therapies with unclear benefit
Fish oil — The fish oils, which contain omega-3 fatty acids, may act by competitively reducing thromboxane synthesis, thereby diminishing cyclosporine-induced vasoconstriction and hypertension, and by direct immunosuppressive actions, such as decreasing the generation of cytokines [86]. Swallowing problems, a fishy aftertaste, and impaired hemostasis are potential complications.
To assess the efficacy of fish oil in kidney transplantation, a systematic review and meta-analysis published in 2005 were performed of 16 studies enrolling a total of 812 patients [87]. Cyclosporine was used in combination with prednisone and/or azathioprine in all but one study, which evaluated cyclosporine alone. Among the 11 trials reporting effects on glomerular filtration rate (GFR), there was no consistent benefit of fish oil on kidney function, with only a modest benefit being reported in a few studies [86,88-90]. Meta-analyses also found no survival benefit or decreased incidence of rejection with fish oil. Similar findings were noted in two subsequent meta-analyses that largely analyzed the same studies [91,92]. These data suggest that fish oil is not associated with a consistent clinical benefit.
The long-term administration of arginine and canola oil, which contain both omega-3 and -9 fatty acids, was associated with a decreased incidence of CNI drug toxicity in a randomized, prospective, three-year study of 78 kidney allograft recipients (9 versus 35 percent in controls) [93]. Additional benefits with this diet, as noted in this study, included decreased incidence of first rejection episodes, posttransplant diabetes, and cardiovascular events. However, a longer-term evaluation in a larger number of patients is required to better understand the role for this diet, particularly given that a large number of patients stopped taking or were noncompliant with the agent.
Calcium channel blockers — Animal and human data suggest that concurrent administration of calcium channel blockers may be protective against cyclosporine nephrotoxicity, at least in part by minimizing renal vasoconstriction [94]. However, there is at present no proof that these agents increase graft survival [95,96]. In one report, for example, 113 cyclosporine-treated patients were randomly assigned to diltiazem or placebo after kidney transplantation [95]. At two years, there was no difference between the groups in blood pressure, plasma creatinine concentration, the number of rejection episodes, or the frequency of graft loss. The patients treated with diltiazem did have a lower incidence of primary nonfunction and fewer episodes of severe rejection, particularly vascular rejection; they also required 35 percent less cyclosporine due to the diltiazem-induced slowing of cyclosporine metabolism.
A similar lack of benefit on long-term kidney function has been noted with nifedipine in two studies of hypertensive transplant recipients receiving cyclosporine: One prospectively compared nifedipine with the angiotensin-converting enzyme (ACE) inhibitor lisinopril, and one retrospectively compared nifedipine with treatment without a calcium channel blocker [97,98]. Neither study was able to demonstrate a better outcome with nifedipine in terms of blood pressure control, the directly measured GFR, or the plasma creatinine concentration at two to five years.
However, it is possible that some calcium channel blockers may have a small protective effect on the kidney [99,100]:
●A prospective study randomly assigned 109 normotensive kidney transplant recipients treated with cyclosporine to placebo or nitrendipine (5 mg two-times daily) and 146 hypertensive transplant patients to placebo or nitrendipine (10 mg two-times daily) [99]. Among all individuals at two years or at the time of study withdrawal, active therapy was associated with a slightly but significantly lower serum creatinine concentration (1.68 versus 1.80 mg/dL [149 versus 161 micromol/L]). This effect was statistically significant only among the hypertensive patients, but the small benefit was independent of any antihypertensive effect.
●In a multicenter study, 131 kidney transplant recipients being administered cyclosporine were randomly assigned to lacidipine or placebo [100]. Allograft function was significantly better with the calcium channel blocker at one and two years posttransplant (50 versus 43 mL/min/1.73 m2 and 50 versus 42 mL/min/1.72 m2 at year 1 and 2, respectively).
One possible explanation for the conflicting results demonstrating a long-term benefit with calcium channel blockers in patients treated with cyclosporine is that renal vasoconstriction may not be responsible for the chronic vascular and tubulointerstitial injury. This hypothesis is supported by observations in animals showing that administration of an endothelin A receptor antagonist minimized the fall in GFR and renal plasma flow but had no effect on the arteriolopathy or tubular damage [101]. Alternatively, the inability to demonstrate a better outcome with a calcium channel blocker versus an ACE inhibitor may result from inhibition of angiotensin II activity also protecting against kidney injury, although by a different mechanism [51,58]. (See "Kidney transplantation in adults: Chronic allograft nephropathy".)
Renin-angiotensin system inhibitors — Given the role of renin-angiotensin system (RAS) activation in the pathogenesis of CNI nephrotoxicity (see 'Chronic calcineurin inhibitor nephrotoxicity' above), RAS inhibition has been proposed as a potential strategy to prevent its development. Although studies in animals have shown that ACE inhibitors and angiotensin receptor blockers (ARBs) can prevent cyclosporine-induced interstitial fibrosis and improve kidney function [102-104], studies in humans have not demonstrated a clear benefit:
●In one small trial, 24 patients with recent-onset insulin-dependent diabetes mellitus with no prior kidney involvement were randomly assigned to receive a three-month course of cyclosporine alone or cyclosporine plus enalapril [105]. At three months, GFR remained unchanged in those treated with cyclosporine and enalapril but decreased by 17 percent in patients treated with cyclosporine alone.
●Another small trial compared the effects of lisinopril versus nifedipine in 25 kidney transplant recipients treated with cyclosporine [97]. Kidney function was similar in both groups at baseline. At approximately 1 and 2.5 years, there was no change in GFR in each group compared with baseline, suggesting that each drug provided a similar degree of kidney protection. However, in a larger randomized trial comparing nifedipine and lisinopril in kidney transplant patients treated with cyclosporine, an improvement in graft function at two years posttreatment occurred in those treated with nifedipine but not those treated with lisinopril [106].
Studies in animals suggest a possible protective benefit to treatment with an aldosterone antagonist (eg, spironolactone) [107-111] although kidney benefits have not been shown in humans [112].
Therapies with no benefit
●Pentoxifylline – Attenuation of cyclosporine-induced renal vasoconstriction and nephrotoxicity in animal studies with pentoxifylline prompted a randomized trial evaluating the effect of this agent in cardiac transplant recipients [113]. Twenty-nine patients received either pentoxifylline (400 mg three-times daily) or placebo for one year. No difference was observed in GFR or plasma creatinine concentration between the two groups.
●Thromboxane synthesis inhibitor – A proposed role for thromboxane in cyclosporine-induced renal vasoconstriction has led to the evaluation of thromboxane synthesis inhibitors. In one report, a thromboxane synthesis inhibitor was given for four weeks to stable patients with a low GFR of 45 mL/min that was presumed to reflect cyclosporine nephrotoxicity [114]. Despite an 80 to 90 percent reduction in the excretion of thromboxane metabolites, there was no improvement in either GFR or renal blood flow.
SUMMARY AND RECOMMENDATIONS
●Overview – Patients treated with the calcineurin inhibitors (CNIs) cyclosporine and tacrolimus are at high risk of developing kidney injury. Most data on CNI nephrotoxicity pertain to cyclosporine since it has been used for a much longer time. However, a similar pattern of kidney injury from cyclosporine is seen with the use of tacrolimus, thereby suggesting a drug class effect. (See 'Introduction' above.)
●Risk factors – Several factors may contribute to the risk of CNI nephrotoxicity, including high doses of cyclosporine or tacrolimus; older age of donated kidney; concomitant use of nephrotoxic drugs, particularly nonsteroidal antiinflammatory drugs (NSAIDs); salt depletion and diuretic use; drugs that inhibit cytochrome P-450 3A4/5 (CYP3A/5) or P-glycoprotein; and genetic polymorphisms in the genes encoding CYP3A4/5 (CYP3A4/5) and P-glycoprotein (ABCB1). (See 'Risk factors' above.)
●Clinical presentations – CNI nephrotoxicity encompasses several different clinical manifestations that reflect functional and/or morphologic changes in the kidney allograft (in kidney transplant recipients) or the native kidney (in non-kidney solid organ transplant recipients or nontransplant patients). Acute CNI nephrotoxicity commonly presents as an acute but typically reversible kidney function impairment and rarely as a thrombotic microangiopathy (TMA). Chronic CNI nephrotoxicity manifests as a chronic progressive deterioration in kidney function. In addition, CNIs have also been associated with a number of electrolyte and acid-base abnormalities that are a result of CNI-induced tubular dysfunction. (See 'Clinical presentations' above.)
●Prevention of chronic nephrotoxicity – The replacement of CNIs with non-nephrotoxic immunosuppressive agents may ameliorate kidney function impairment among patients with CNI nephrotoxicity. Benefits have been observed among kidney and non-kidney organ transplant recipients with decreased kidney function due to CNI therapy. Some studies, however, question whether CNI withdrawal is safe in those with adequate kidney function. A number of agents have been evaluated to help prevent chronic CNI nephrotoxicity, but none are clearly effective. (See 'Prevention of chronic calcineurin inhibitor nephrotoxicity' above.)
ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges William M Bennett, MD, who contributed to an earlier version of this topic review.
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