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Calcineurin Inhibitor-Induced Nephrotoxicity

CASE 34-2

QUESTION 1: C.C. is a 60-year-old man who received a deceased-donor kidney transplant 3 years ago. His

serum creatinine at 1 year after transplant was 1.5 mg/dL; at 2 years, it was 1.7 mg/dL; now it is 1.9 mg/dL.

He says he feels fine. His BP is controlled and urinalysis is negative for protein. A kidney biopsy conducted at

this time indicates that he has no signs of acute or chronic rejection, but has evidence of CNI nephrotoxicity.

His current regimen is cyclosporine 275 mg BID, MMF 500 mg BID, and prednisone 5 mg daily. His current

labs show the following:

Cyclosporine blood trough, 220 ng/mL (target 100–150 ng/mL)

K, 5.5 mEq/mL

Mg, 2.3 mg/dL

Uric acid 8.0 mg/dL

Why does C.C. have CNI nephrotoxicity?

CNI nephrotoxicity is one of the most common adverse effects and occurs to some

degree in all patients. The rise in the serum creatinine concentration is more gradual

than, and not as high as, that seen with rejection. CNI concentrations may be elevated,

although some patients may experience CNI nephrotoxicity even with levels below or

within the targeted therapeutic range. Two forms of CNI nephrotoxicity have been

identified: functional or acute renal dysfunction and chronic nephrotoxicity.

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Acute CNI nephrotoxicity is more likely to occur in the first months after

transplantation and associated with high CNI doses and levels. Functional renal

dysfunction or acute nephrotoxicity, the most common form of renal dysfunction, is

characterized by rapid reversal when the CNI dose is held or reduced. This

syndrome typically is not associated with histopathologic abnormalities. Repeated

episodes of transient acute renal dysfunction can result in protracted acute renal

dysfunction. Recovery of renal function after repeated episodes may not be complete

even if the CNI is withdrawn. Protracted acute renal dysfunction can lead to direct

tubular toxicity and can be associated with the development of thrombosis of

glomerular arterioles or diffuse interstitial fibrosis.

Chronic nephrotoxicity is associated with proteinuria and tubular dysfunction.

Renal biopsies in allograft patients with chronic CNI-related nephropathy show

tubulointerstitial abnormalities, sometimes with focal glomerular sclerosis. These

findings are considered nonspecific. Recently, the role of CNI chronic nephrotoxicity

in the development of irreversible chronic renal dysfunction has been challenged and

thought to be overdiagnosed in many patients. However, long-term use can result in

chronic nephrotoxicity, is usually seen after 6 months of therapy, and may be

irreversible. In this situation, renal function progressively declines to a point that

dialysis or retransplant is required. The pathophysiology of cyclosporine or

tacrolimus-induced transient acute renal failure is not understood completely, but

seems to be related to its effects on renal vessels. For example, CNI can induce

glomerular hypoperfusion secondary to vasoconstriction of the afferent glomerular

arterioles, thereby reducing glomerular filtration. One possible explanation for these

effects is that cyclosporine alters the balance of prostacyclin and thromboxane A2

in

renal cortical tissue. Increased thromboxane A2

results in renal vasoconstriction.

Endothelin release from renal vascular cells stimulated by CNI also may contribute

to this acute effect through its potent vasoconstrictive properties. Activation of the

renin–angiotensin–aldosterone system may also play a significant role. CNI also can

cause a reversible decrease in tubular function. The alterations in tubular function

reduce magnesium reabsorption and decrease potassium and uric acid secretion. This

may be a result of direct tubular toxicity and possibly the result of thromboxane A2

stimulation of platelet activation and aggregation.

C.C.’s rise in serum creatinine in conjunction with an elevated cyclosporine level

suggests acute cyclosporine toxicity as the most likely cause of his findings. In this

case, the total cyclosporine dose should be lowered by approximately 25% to 225

mg twice a day, to keep level in target range, and C.C. should be monitored closely

for resolution of any symptoms and decrease in serum creatinine or worsening if

rejection results from lowering the dose. His elevated potassium and uric acid and

low magnesium should correct themselves with this dose reduction if it is acute CNI

toxicity. If the nephrotoxicity is caused by cyclosporine, a decrease in the serum

creatinine may be evident when the cyclosporine dose is reduced. If no such

reduction occurs or if the serum creatinine continues to increase, then other

nonimmunologic or immunologic causes should be considered and also need to

substitute calcineurin inhibitor with an agent such as sirolimus, everolimus, or

belatacept.

Calcineurin Inhibitor Avoidance,

Withdrawal/Conversion, or Minimization

CASE 34-2, QUESTION 2: Would it be appropriate to withdraw cyclosporine in C.C.? If attempted, how

could this be accomplished?

Cyclosporine and tacrolimus are associated with a number of metabolic,

cardiovascular, neurologic, and cosmetic side effects but the most concerning is

nephrotoxicity, which is a contributor to graft loss. The potential benefit of

withdrawing cyclosporine would be to reduce toxicity, but this has to be weighed

against the risk for rejection, graft loss, and toxicities of replacement agents.

Concern for chronic nephrotoxicity, as well as other long-term side effects, has led

to the development of cyclosporine or tacrolimus minimization, withdrawal or

substitution/conversion protocols, using agents, such as mycophenolate or sirolimus,

everolimus, belatacept, or protocols using low doses of cyclosporine or tacrolimus.

Antibody induction, sirolimus, everolimus, mycophenolate, and belatacept, which

are not associated with nephrotoxicity, have been evaluated in combination protocols

that attempt to avoid, minimize, or withdraw CNI. Protocols completely avoiding

CNIs usually contain combinations of these agents. Studies, which were usually done

in low-risk populations, observed lower serum creatinine levels and fewer CNIinduced toxicities, but were associated with higher rates of acute rejection,

especially when CNI is not used at all. Other trials that compared combinations of

rabbit antithymocyte globulin, alemtuzumab, or basiliximab, sirolimus, everolimus,

mycophenolate, and steroids with either cyclosporine or tacrolimus withdrawal, or

minimization protocols have shown equal effectiveness compared to standard

therapy.

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In the case of early cyclosporine withdrawal, there is a 10% to 20% increased risk

of acute rejection, but no change in graft survival. Protocols are used that withdraw

the CNI or at least reduce the dose to a minimal level. Many attempts are within the

first 3 to 12 months after transplantation in the hope that the nephrotoxic effects can

be reversed before significant chronic damage occurs. These approaches add

mycophenolate, sirolimus, or both as the CNI is withdrawn or reduced in dose, but

they have been primarily tested in low-risk patients. Data with sirolimus suggest that

patients without proteinuria and an estimated glomerular filtration rate greater than

40 mL/minute in the first year had better renal function. Whether this applies to other

agents remains to be determined. Usually, when sirolimus

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is added to the CNI regimen, the CNI dose is reduced by 50% initially and in some

cases slowly withdrawn altogether during several weeks to months. Improvement in

serum creatinine may be seen initially, which may be attributed to the diminution of

the CNI vasoconstrictive effects.

CNI minimization or withdrawal may not reverse the nephrotoxicity observed in

C.C.’s biopsy, but it may slow the rate of deterioration of his renal function. Because

C.C. is currently receiving mycophenolate, one approach would be to continue to

reduce his cyclosporine, increase his mycophenolate, and maintain steroids. Another

approach would be to replace the mycophenolate with sirolimus/everolimus, because

he has no proteinuria and his eGFR is >40 ml/min, maintain steroids, and reduce or

withdraw slowly the cyclosporine. Belatacept could also be used as replacement for

cyclosporine, while continuing mycophenolate and steroids. Some studies indicate

better eGFR, lower incidence of new onset diabetes after transplant, lower blood

pressure, lower cholesterol, but no difference in survival compared to CNI.

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best regimen for someone such as C.C. has not been established, because the longterm consequences of these changes are not known. If this approach is attempted,

C.C. should be watched carefully for acute rejection, and side effects of these agents,

which some patients do not tolerate, and infections should be closely monitored. In

addition, BP control as well as control of hyperlipidemia and hyperglycemia could

improve with reduction or withdrawal of cyclosporine, depending on agent used, and

could also be important in minimizing renal injury.

STEROID AVOIDANCE OR WITHDRAWAL

CASE 34-3

QUESTION 1: D.T., a 65-year-old Caucasian woman, will receive a deceased-donor kidney transplant today.

She has a negative cross-match to this donor, and her previous cPRA was less than 10%. She will be given

alemtuzumab 30 mg IV × 1 and methylprednisolone 500 mg IV × 1, intraoperatively. After transplant, she will

be started on tacrolimus 0.05 mg/kg BID, adjusted to trough levels of 8 to 12 ng/mL for the first 3 months, along

with MMF 750 mg BID. Methylprednisolone IV will be given as 250 mg IV on postoperative day 1, 125 mg IV

on postoperative days 2 and 3, and no maintenance steroids thereafter. Is D.T. a good candidate for steroid

avoidance or withdrawal?

Another important issue after kidney transplantation is the role of short-term and

long-term steroid use. Most transplant protocols incorporate steroid therapy, although

approximately 30% of transplant centers use steroids only in the early postoperative

period.

2 The concept of either avoiding or discontinuing corticosteroids is appealing

because they cause significant adverse effects such as diabetes, cataracts, infection,

hypertension, hyperlipidemia, osteoporosis, avascular necrosis, and psychiatric,

neurologic, and cosmetic effects. Steroid withdrawal or avoidance, however, may

increase the risk of acute rejection, compromise long-term graft function, and

necessitate higher doses of the other immunosuppressives. Steroid avoidance is

defined as either no steroid use or steroid use only for the first few days after

transplant. Short-term studies, generally in low-risk patients, suggest no adverse

impact on short-term graft survival exists and no need is seen for higher doses of

other immunosuppressives when corticosteroids are not included in maintenance

regimens. These protocols have included regimens such as using induction agents,

alemtuzumab, basiliximab, or rabbit antithymocyte globulin along with tacrolimus

and cyclosporine, mycophenolate, sirolimus, or everolimus.