Clinical Case Scenario

A 56-year-old female has a recent history of undergoing a heart transplant. She is admitted to the intensive care unit with new-onset oliguria. Her baseline serum creatinine prior to her heart transplant was 0.8 mg/dL. She had a stable post-transplant serum creatinine at 1.2 mg/dL on her maintenance immunosuppression regimen of cyclosporine and mycophenolate mofetil. However, over the past 48 hours, her serum creatinine has increased to 2.8 mg/dL, and her urine output has decreased to less than 20 mL/hour. Her BUN/serum creatinine ratio is noted to be 10. She is hemodynamically stable, and a renal ultrasound shows no evidence of obstruction. Her most recent cyclosporine trough level was 200 ng/mL.

This scenario represents a post-heart transplant patient on cyclosporine who develops acute kidney injury. The general therapeutic trough level range for cyclosporine is 100-400 ng/mL. Our patient has got a trough level of 200 ng/mL, which is in the therapeutic range.

Wrong Answer: a) Acute tubular necrosis (ATN) due to sepsis:
This scenario has the patient who does not have any overt signs of sepsis (e.g., fever, significant hypotension, elevated white blood cell count with a left shift). This rules out ATN due to sepsis.

Wrong Answer: b) Pre-renal azotemia secondary to dehydration:
Pre-renal azotemia occurs from dehydration or hypovolemia. The clinical scenario states the patient is haemodynamically stable, along with a normal BUN/serum creatinine ratio, making significant dehydration less probable as the sole cause of the acute kidney injury. The rapid and significant rise in creatinine, coupled with oliguria in a transplant patient on a nephrotoxic drug, points more towards intrinsic renal damage.

Wrong Answer: c) Acute interstitial nephritis related to mycophenolate mofetil:
Mycophenolate mofetil (MMF) can cause gastrointestinal side effects and myelosuppression. Acute interstitial nephritis (AIN) is a less common adverse effect of MMF. Additionally, if AIN due to MMF were the primary issue, other signs like fever, rash, or eosinophilia might be present.

Right Answer:d) Calcineurin inhibitor (cyclosporine) nephrotoxicity:

The history of cyclosporine use, even with therapeutic trough levels, makes calcineurin inhibitor nephrotoxicity the MOST likely cause. Cyclosporine can cause both acute and chronic nephrotoxicity through various mechanisms, such as vasoconstriction (primary mechanism), tubular injury, and endothelial dysfunction.

The general therapeutic trough level range for cyclosporine is 100-400 ng/mL. Our patient has a trough level of 200 ng/mL, which is in the therapeutic range. But this does not entirely rule out nephrotoxicity. Although therapeutic drug monitoring (TDM) can help to keep drug levels in the target range, individual sensitivity can vary.

TDM for cyclosporine can be done by 2 methods:
● 12 hours trough level (prior to the morning dose)
● C2 level (2 hours after the morning dose) The following factors may produce cyclosporine nephrotoxicity despite the therapeutic range of cyclosporine trough levels.
● Prior subclinical renal injury (e.g., exposure to other nephrotoxic medications, donor kidney quality in transplant recipients)
● Genetic polymorphisms in genes coding for drug transporters and metabolizing enzymes
● Variations in drug distribution, which may lead to localized toxicity at the level of the kidney, even though systemic levels are acceptable
● Exacerbation of the vasoconstrictive effects of cyclosporine on renal arterioles even with minor hemodynamic instability

Clinical pearl:
Early AKI post-transplant can be due to the following causes:
1. ATN
2. Dehydration and hypovolemia
3. Acute rejection
4. Medication-induced AKI (including calcineurin inhibitor toxicity)
5. Infections