Nephrotoxicity of Calcineurin Inhibitors

The introduction of the calcineurin inhibitor (CNI) cyclosporine in the 1980s revolutionized the field of organ transplantation, and the CNIs cyclosporine and tacrolimus remain a cornerstone of immunosuppression in recipients of nonrenal allografts.¹ However, there is little doubt that CNIs contribute significantly to both acute kidney injury (AKI) and chronic kidney disease (CKD) in these recipients. There is speculation that CNI nephrotoxicity is more severe in nonrenal than in renal transplantation because (1) dosage and blood concentrations of CNIs tend to be higher in nonrenal transplantation and (2) the lack of normal innervation of the transplanted kidney may protect it from early CNI injury. CNIs also exacerbate post-transplantation hypertension and diabetes mellitus, which cause renal damage in the long term.

Acute CNI nephrotoxicity is thought to be mainly a pre-renal syndrome caused by vasoconstriction of the afferent glomerular arteriole (see also Chapter 101). Tubular damage and microvascular disease may occur in more severe cases. In the early post-transplantation period, AKI is usually multifactorial, and it is difficult to quantify the degree to which CNI toxicity is contributing to the problem. In practice, doses of CNIs are often temporarily reduced in the setting of AKI. Acute CNI-induced thrombotic microangiopathy (TMA) is rare in nonrenal transplant recipients. Chronic CNI nephrotoxicity is probably a result of prolonged renal ischemia and other effects, such as direct stimulation of renal fibrogenesis. Typically the patient is hypertensive (CNIs worsen hypertension) and there is a steady fall in GFR, most marked in the first 6 to 12 months after transplantation (Fig. 111-1).⁵ Dipstick urinalysis shows minimal or no hematuria and minimal or mild proteinuria. Urine protein-creatinine ratio or 24-hour urine collections confirm low-grade proteinuria. Renal histology shows interstitial fibrosis, arteriolar hyalinosis, arteriosclerosis, and secondary focal glomerulosclerosis.⁶ There may also be features of chronic TMA.⁶ In practice, renal biopsies are rarely performed unless there are clinical features suggestive of a renal disorder other than CNI toxicity.

It is not surprising that the presumed high prevalence of chronic CNI nephrotoxicity has generated interest in low-dose or zero-dose CNI protocols. Just as in renal transplantation, these typically involve use of mycophenolate mofetil (MMF) or mammalian target of rapamycin (mTOR) inhibitors.^1,3,7 However, there is still understandable reluctance to pursue such protocols because CNIs are considered such effective immunosuppressive agents, and organ replacement therapy analogous to dialysis is not available for other organ transplant recipients if severe rejection occurs. MMF has the advantage of being non-nephrotoxic. mTOR inhibitors have several disadvantages; they impair wound healing, potentiate the nephrotoxicity of cyclosporine, and sometimes induce proteinuria. Although some studies suggest that everolimus is better tolerated than sirolimus, similar nephrotoxic interactions have been reported between both sirolimus and everolimus with cyclosporine.⁸ CNI-sparing strategies are discussed in more detail later.

Another strategy is to use tacrolimus as the de novo CNI or to switch from cyclosporine to tacrolimus if there is evidence of nephrotoxicity (cyclosporine is still commonly prescribed as the de novo CNI in heart and lung transplantation). The rationale here is that tacrolimus provides equivalent or even better immunosuppression at doses and concentrations that are less nephrotoxic than cyclosporine. Furthermore, tacrolimus is associated with less hypertension and hyperlipidemia (which might exacerbate CKD) than cyclosporine. Conversely, it is associated with more post-transplantation diabetes mellitus. Studies in nonrenal transplant recipients have yielded conflicting results as to which is more nephrotoxic.

The usefulness of calcium channel blockers in ameliorating CNI nephrotoxicity in renal transplantation remains controversial, and there is limited evidence of such benefit in nonrenal transplantation. Experimental studies suggest that agents that block the renin-angiotensin system (RAS) may provide protection against the arteriolar hyalinosis and tubulointerstitial injury associated with chronic CNI use. Control of hypertension per se is probably more important than use of any particular antihypertensive agent.

Acute Kidney Injury in the Immediate Pretransplantation Period

It is not surprising that AKI can occur in the days to weeks immediately before liver, heart, or (less commonly) lung transplantation. Typically, the cause of AKI is either pre-renal (e.g., renal hypoperfusion or hepatorenal syndrome) or intrarenal (ischemic or toxic acute tubular necrosis) or a combination of both. AKI may develop on a background of CKD. A mildly elevated serum creatinine may mask a significant fall in GFR in malnourished patients with severe organ failure.³ Reported rates of AKI vary widely; rates may be modified by varying definitions of AKI, organ-specific risks of AKI, and center variability in the type of patients listed for transplantation.

Management of AKI focuses on treatment of the underlying cause and provision of dialytic support according to standard criteria. Because the patients are critically ill, continuous renal replacement therapy (CRRT) may be preferred to intermittent hemodialysis, but there are no randomized controlled trials showing improved outcomes with this modality in this setting. When severe or prolonged AKI occurs before planned transplantation, estimation of the degree of reversibility becomes very important, because presumed irreversible severe kidney injury is generally a contraindication to transplantation or shifts the management toward simultaneous dual-organ (e.g., liver and kidney) transplantation. This is an area of ongoing debate in liver and, to a lesser extent, cardiac transplan­tation and is discussed in detail later. The general advantages and disadvantages of simultaneous dual-organ transplantation are shown in Table 111-1.

Acute kidney injury is also common in the days to weeks after transplantation. This reflects several factors: pretransplant renal function may have been compromised, the transplanted organ may have poor initial function, high doses of CNIs and other nephrotoxic agents may be prescribed, and the invasive surgery and high-dose immunosuppression predispose to severe infection (Table 111-2). AKI is associated with higher mortality in the early postoperative period.^9–11 This is likely to reflect both the association of AKI with other severe complications and also its direct effects on mortality. In those who survive, AKI is associated with an increased risk of developing CKD.¹²

With the increasing number of solid organ transplants being performed worldwide and the longer survival of recipients, the absolute number of recipients with CKD has increased. In the largest and most comprehensive study to date, the cumulative incidence of post-transplant CKD (defined as estimated glomerular filtration rate [eGFR] <30 ml/min/1.73 m²) at 5 years varied from 7% to 21% (Fig. 111-2).¹² By multivariate analysis, the following pretransplant variables increased the risk of development of CKD: increasing age, female gender, white or black (as opposed to Asian) ethnicity, lower GFR, diabetes mellitus, hypertension, hepatitis C virus infection, and need for dialysis. The following post-transplant variables were also implicated: postoperative AKI and initial use of cyclosporine (as opposed to tacrolimus).¹² These risk factors have been confirmed in other studies.

Many studies have also confirmed that whatever the transplanted organ, development of CKD, and especially of end-stage renal disease (ESRD), portends a poor prognosis (Fig. 111-3). Recipients with CKD have a relative risk of death of 4.6 compared with those without CKD.¹² The risk is highest in those with ESRD, but even in those not on dialysis, the relative risk of death was doubled.¹²

BK Virus Nephropathy

BK virus nephropathy is a much-feared complication of kidney transplantation. Fortunately, although BK viruria is occasionally noted after liver, heart, or lung transplantation, the absolute risk of BK viremia and BK virus nephropathy remains low. This probably reflects the lack of a “second hit” to the native kidneys, such as human leukocyte antigen (HLA) mismatching or inflammation. Nevertheless, BK virus nephropathy should be considered in the differential diagnosis of “unexplained” renal dysfunction after solid organ transplantation, especially because more intensive maintenance immunosuppressive protocols involving combined MMF and tacrolimus are being increasingly used.

Acute Kidney Injury in the Late Post-transplantation Period

Severe AKI occasionally occurs late after transplantation. The major causes are shown in Table 111-2. Severe rhabdomyolysis has been reported, usually when statins are prescribed with cyclosporine and an inhibitor of the cytochrome P-450 system, such as diltiazem or ketoconazole and other azole-based antifungal agents. Treatment of late AKI is of the underlying cause plus the usual supportive measures.