Tacrolimus toxicity in kidney transplant recipient after wedge liver resection: A case report and review of literature

Abstract

BACKGROUND

Tacrolimus is a key immunosuppressive agent used to prevent allograft rejection in kidney transplant recipients. Due to its narrow therapeutic index, careful monitoring is essential to avoid adverse effects, particularly neurotoxicity and nephrotoxicity. Hepatic metabolism is an important part of tacrolimus pharmacokinetics. This case report highlights the impact of liver resection on tacrolimus pharmacokinetics in a kidney transplant recipient.

CASE SUMMARY

A 61-year-old male with end-stage kidney disease underwent a living-unrelated donor kidney transplant at age 46 and has maintained a stable tacrolimus regimen for 15 years. He was later diagnosed with hepatocellular carcinoma and underwent an open wedge liver resection. Despite stable preoperative tacrolimus levels, he developed acute kidney injury and neurotoxicity (manifested as new-onset tremors and headache) postoperatively. Tacrolimus levels rose from 3.4 ng/mL before surgery to 19.5 ng/mL postoperatively, despite no changes in dosage. This increase was most likely due to reduced liver mass and function following resection, in addition to ischemic injury of the remaining liver parenchyma, leading to impaired drug metabolism and acute toxicity. Liver function tests showed transient abnormalities postoperatively, with transaminase levels peaking at 30 times the normal range before gradually returning to normal, coinciding with the decline in tacrolimus levels. The patient’s symptoms and acute kidney injury improved as tacrolimus concentration returned to normal.

CONCLUSION

This is the first reported case of acute tacrolimus neurotoxicity and nephrotoxicity in a kidney transplant recipient following liver resection. It highlights the critical need for vigilant therapeutic drug monitoring of tacrolimus after liver surgery to prevent severe adverse effects.

Key Words: Tacrolimus; Kidney transplant; Liver resection; Hepatectomy; Nephrotoxicity; Neurotoxicity; Case report

Core Tip: We report the first case of tacrolimus toxicity in a kidney-transplant recipient after wedge liver resection for hepatocellular carcinoma. Reduced liver mass and transient ischemic injury impaired metabolism of tacrolimus, a calcineurin inhibitor, causing rapid rises in trough concentration, acute kidney injury, and neurotoxicity that reversed with dose interruption. The case underscores the need for proactive therapeutic drug monitoring, early dose adjustment, and structured evaluation of postoperative acute kidney injury in transplant recipients undergoing hepatic surgery.

INTRODUCTION

Tacrolimus is currently the backbone of immunosuppressive medications after solid organ transplantation because of its excellent efficacy in preventing allograft rejection and improving allograft survival[1,2]. Tacrolimus is a calcineurin inhibitor (CNI) that suppresses T-cell activation by inhibiting calcineurin phosphatase, thereby reducing interleukin-2 transcription and production in T lymphocytes[3]. However, tacrolimus is considered a narrow therapeutic index medication, which necessitates therapeutic drug monitoring to ensure that the concentrations stay within the therapeutic range to avoid its toxicity[4-6]. Among these toxicities, neurotoxicity and nephrotoxicity are the two most concerning adverse effects of tacrolimus[3].

Since tacrolimus in the blood is metabolized mainly in the liver via cytochrome P450 3A5 (CYP3A5) as a major metabolizing enzyme, any factors that affect CYP3A5 or liver function can alter tacrolimus whole-blood concentration[3]. In this case report, we describe a case of acute tacrolimus toxicity immediately after a liver resection operation in a kidney transplant recipient who was on a stable dose of tacrolimus. This case report is the first to demonstrate the potential effect of reduced total liver tissue and intraoperative ischemic injury on tacrolimus whole-blood concentration and clearance.

CASE PRESENTATION

Chief complaints

Increased serum creatinine (Cr) levels after wedge liver resection.

History of present illness

A 61-year-old Thailand male with end-stage kidney disease due to diabetic nephropathy underwent a living-unrelated donor kidney transplantation from his wife 15 years ago, at the age of 46. At 14 years after transplantation, abdominal ultrasonography showed a hypoechoic mass in the right hepatic lobe, prompting further investigation. His viral hepatitis profiles were negative except for the positive isolated hepatitis B core antibody. The hepatitis B virus-deoxyribonucleic acid level was undetectable. Magnetic resonance imaging of the liver confirmed hepatocellular carcinoma (HCC), measuring 5.6 cm in diameter at segment VI and 2.8 cm in diameter at segment II. Mycophenolate mofetil (MMF) was reduced to 1000 mg/day, and tacrolimus was decreased to a target trough concentration (C₀) of 2-4 ng/mL (Prograf 3.5 mg/day). The patient’s tacrolimus trough level had been steady for 2 weeks before surgery. He then proceeded to wedge liver resection of segments VI and II/III under the Pringle maneuver (clamping the hepatoduodenal ligament to control bleeding from the liver) for 121 minutes. The total operation time was 5 hours and 50 minutes with total blood loss of 600 mL. One unit of packed red cell was intraoperatively administered. On postoperative day 1, the patient developed oliguria, with serum Cr increasing from 2.51 mg/dL to 4.98 mg/dL by postoperative day 3, despite stable vital signs and consistent intraoperative to postoperative hemodynamics (Figure 1).

Figure 1 Time course of the patient showing tacrolimus concentration, tacrolimus dosage, and serum creatinine. Cr: Creatinine; AST: Aspartate aminotransferase; ALT: Alanine aminotransferase.

History of past illness

The human leukocyte antigen mismatches were 2-2-2 with 0% panel reactive antibodies and negative cytotoxic-dependent cross-match. Basiliximab and methylprednisolone were the induction regimen. There were no complications during the perioperative period. The patient was discharged with a serum Cr level of 1.28 mg/dL. The maintenance immunosuppressive regimen included tacrolimus, MMF, and prednisolone.

Seven years after transplantation, his serum Cr level increased from 1.50 mg/dL to 1.81 mg/dL with increased proteinuria from 200 mg/day to 2400 mg/day; therefore, allograft biopsy was performed. The pathology revealed focal glomerulitis and moderate peritubular capillaritis compatible with antibody-mediated rejection (ABMR) (glomerulitis score 2, peritubular capillaritis score 2, vasculitis score 0, complement C4d deposition score 1). Donor-specific human leukocyte antigen class II antibody was positive against DQ7, with a median fluorescence intensity of 4200. The patient was treated with plasma exchange, intravenous immunoglobulin, and rituximab. Serum Cr after ABMR ranged from 1.74 mg/dL to 1.88 mg/dL. Five years later, his serum Cr level increased from 1.88 mg/dL to 2.22 mg/dL. Transplant kidney biopsy revealed a suspicion of chronic active ABMR (chronic glomerulopathy grade 1b, glomerulitis grade 1, peritubular capillaritis grade 2, vasculitis grade 0, complement c4d deposition grade 1), borderline acute T-cell-mediated rejection (t1, i2), and secondary focal segmental glomerulosclerosis. The dose of MMF was increased from 1500 mg/day to 2000 mg/day. The tacrolimus trough level was targeted at 5-8 ng/dL. The patient’s serum Cr level was stable at 2.5-3.0 mg/dL, and 24-hours urine protein levels were steady at 3-4 g/day.

Personal and family history

No significant personal or family history was found.

Physical examination

He was afebrile; his blood pressure, heart rate, and respiratory rate were 138/86 mmHg, 80 beats/minutes, and 16 breaths/minutes, respectively. The remainder of the physical examination was unremarkable, except for an action tremor of both upper extremities. The postoperative surgical incision was clean, dry, and intact without active bleeding.

Laboratory examinations

On postoperative day 1, transient abnormal liver function was observed, with alanine transaminase increasing from 19 U/L to 980 U/L and aspartate aminotransferase increasing from 20 U/L to 771 U/L. Both enzymes returned to normal levels by postoperative day 10 following supportive intravenous fluid administration, with alanine transaminase at 24 U/L and aspartate aminotransferase at 36 U/L. The maximum serum total bilirubin level was 5.8 mg/dL on postoperative day 3, before decreasing to 2.1 mg/dL on postoperative day 12.

The tacrolimus C₀ was elevated to 12.6 ng/mL on the morning of postoperative day 1, despite no change in the tacrolimus dosage on postoperative day 0. As the C₀ tacrolimus result was available only after the morning dose, the evening dose of tacrolimus was withheld on postoperative day 1. On postoperative day 2, the patient developed a new tremor in both upper extremities and a tension-type headache, and tacrolimus C₀ increased further to 15.8 ng/mL despite not having received the previous evening dose. Tacrolimus was stopped from postoperative days 2-5. By postoperative day 6, tacrolimus C₀ decreased to 6.8 ng/mL, at which point a 0.5 mg evening dose was restarted, with a target C₀ of 2-4 ng/mL.

Imaging examinations

No imaging examinations were performed.

FINAL DIAGNOSIS

HCC in a kidney transplant recipient with tacrolimus toxicity after wedge liver resection and transient ischemic liver injury.

TREATMENT

The primary management consisted of supportive care, and tacrolimus was temporarily withheld during the period of transient liver injury and ischemic hepatitis. It was reinitiated when the trough concentration returned to the target range and the liver function tests had improved.

OUTCOME AND FOLLOW-UP

During the period of elevated tacrolimus C₀, serum Cr also increased, peaking at 4.98 mg/dL on postoperative day 3. It gradually returned to baseline by postoperative day 7, coinciding with the normalization of tacrolimus C₀ and liver function test, as previously mentioned. Hemoglobin levels remained stable at 10.5-11.5 g/dL throughout the postoperative period. On postoperative day 2, supportive treatment with intravenous furosemide at 20 mg/hour was initiated to promote urine output and was tapered off by postoperative day 4. Headache and tremor symptoms gradually improved after postoperative day 4 and resolved by postoperative day 7.

DISCUSSION

We report the case of a kidney transplant recipient with HCC who developed acute CNI toxicity following liver resection. Tacrolimus C₀ was significantly elevated, accompanied by new-onset tremor, headache, and acute kidney injury (AKI). Other than tacrolimus toxicity, no other identifiable causes for the patient’s symptoms were found. After tacrolimus was withdrawn and its concentration returned to therapeutic levels, both AKI and the tremor resolved, supporting the diagnosis of tacrolimus-induced kidney injury and neurotoxicity following liver resection.

Tacrolimus is recognized as a drug with a narrow therapeutic index, where its concentrations are closely related to both its efficacy (e.g., prevention of rejection) and its potential toxicities. It is well documented that the long-term use of tacrolimus in kidney and non-kidney transplantations causes nephrotoxicity and neurotoxicity[7-9]. However, the toxicity observed in specific circumstances, such as in this case, warrants further investigation and discussion to improve patient care and outcomes.

Several factors have been reported in the literature that contribute to the development of AKI after liver surgery in non-transplant patients, including massive intraoperative blood loss leading to renal hypoperfusion, liver failure after hepatectomy, hepatorenal syndrome, sepsis, and nephrotoxic drugs[10,11]. However, CNI nephrotoxicity is an additional important factor in kidney transplant recipients. The differential diagnosis and approach to AKI after liver surgery are shown in Table 1[12-14].

Table 1 Approach to acute kidney injury after liver surgery.

Conditions	Clinical clues
Renal hypoperfusion from intraoperative blood loss	Prolonged MAP < 65 mmHg, oliguria, history of large volume loss, improvement with fluids/transfusion
Abdominal compartment syndrome	Tense abdomen, rising airway pressures, refractory oliguria, large-volume resuscitation/bleeding/packing in major liver resection (IAH ≥ 12 mmHg; ACS > 20 mmHg + organ dysfunction)
Hepatorenal syndrome	Bland urine; no shock/nephrotoxins; no response after adequate volume resuscitation, low FENa, decompensated liver disease, usually with ascites
Ischemic ATI	Persistent creatinine rise with history of poor renal perfusion, granular casts, FENa > 2% (caution with diuretics), slow recovery, poor response to fluid resuscitation
Sepsis-associated AKI	Sepsis definition (based on Sepsis-3 criteria; infection + SOFA score) with AKI
Bile cast nephropathy	Marked cholestasis (total bilirubin usually > 20 mg/dL), bilirubinuria, bland or bile-pigmented casts
Nephrotoxic drugs (non-CNI)	Recent exposure: IV contrast, aminoglycosides, amphotericin, NSAIDs, etc. (also considered antibiotics or other drugs-associated AIN)
Acute CNI nephrotoxicity	Acute, dose-dependent afferent arteriolar vasoconstriction, temporal relation to high troughs, improves with dose reduction/cessation, biopsy rarely needed if rapid reversal

MAP: Mean arterial pressure; IAH: Intra-abdominal hypertension; ACS: Abdominal compartment syndrome; FENa: Fractional excretion of sodium; ATI: Acute tubular injury; AKI: Acute kidney injury; SOFA: Sequential Organ Failure Assessment; CNI: Calcineurin inhibitor; IV: Intravenous; NSAIDs: Non-steroidal anti-inflammatory drugs; AIN: Acute interstitial nephritis.

Tacrolimus is metabolized by CYP3A5 isoenzymes in the liver and intestinal wall, with highly variable expression among individuals. It is primarily eliminated via the biliary route, with more than 95% of its metabolites being excreted this way[15,16]. Therefore, hepatic dysfunction is one of the most critical factors affecting tacrolimus pharmacokinetics. Poor liver function can reduce tacrolimus clearance by up to two-thirds and prolong its elimination half-life by up to threefold[15]. Our patient underwent liver surgery involving an estimated 30%-40% resection of total liver tissue, along with prolonged cold ischemia time and reperfusion injury. These factors could have significantly impaired tacrolimus clearance, leading to systemic accumulation and subsequent toxicity.

A previous study reported a 19% incidence of tacrolimus-induced neurotoxicity in the early post-liver transplant period[17]. This is likely due to the slow recovery of the donor liver graft, resulting in reduced metabolism and clearance of tacrolimus. Supporting this, studies have identified increasing donor age and prolonged operative time as significant risk factors for tacrolimus neurotoxicity following liver transplantation[18,19]. Additionally, the impact of the donor CYP3A5 genotype on the concentration-to-dose ratio of tacrolimus becomes more pronounced after the first 3 months, whereas the recipient CYP3A5 genotype is the predominant factor in the early post-transplant period[20]. This suggests that in the early post-liver transplant phase, tacrolimus metabolism is primarily driven by the recipient’s intestinal CYP3A5, gradually shifting to the donor liver CYP3A5 as the graft recovers.

Although the effect of the donor CYP3A5 genotype on liver allografts has been well documented, its impact on kidney allografts remains inconclusive. Some studies have suggested that the donor CYP3A5*3/*3 genotype (non-expressor phenotype) is associated with increased CNI nephrotoxicity due to reduced intra-allograft tacrolimus clearance. Conversely, the donor CYP3A5*1 allele (expressor phenotype) has been linked to a higher risk of allograft loss[21-23].

Importantly, no prior reports have described CNI toxicity in a kidney transplant recipient following liver resection, as in the present case. However, tacrolimus toxicity following liver surgery has been frequently reported in liver transplant recipients[17-19,24]. Furthermore, tacrolimus toxicity has been reported in cases of cholestasis and biliary tract obstruction in combined liver-kidney transplant recipients[25], emphasizing the crucial role of hepatic metabolism and biliary excretion in tacrolimus clearance. Notably, an animal model of bile duct ligation demonstrated a marked increase in tacrolimus whole-blood concentrations following oral administration but not intravenous administration. This effect was attributed to the impaired pre-systemic metabolism of tacrolimus after bile duct ligation, leading to increased bioavailability[26].

Several mechanisms have been proposed for tacrolimus-induced neurotoxicity, including the dysregulation of vasoconstrictive pathways and alterations in blood-brain barrier permeability[27,28]. Interestingly, among solid organ transplants, liver transplantation has the highest reported incidence of neurotoxicity, likely due to impaired tacrolimus metabolism in the early post-transplant period. Most evidence suggests a correlation between peak tacrolimus concentrations and neurotoxicity[27]. A study demonstrated that extended-release tacrolimus, which produces lower peak concentrations, was associated with a lower incidence of tremors compared with immediate-release tacrolimus[29]. However, the relationship between tacrolimus concentrations and nephrotoxicity remains less well-defined and may involve the free form of tacrolimus found in anemic patients or local tacrolimus metabolism within the kidney allograft in addition to systemic exposure[21,30]. Approximately 85% of tacrolimus partitions into erythrocytes. The erythrocyte-bound fraction decreases and the plasma free fraction increases in patients with anemia. If standard whole-blood trough targets are applied without adjustment for anemia, the higher free fraction can lead to overexposure and toxicity; therefore, reduced whole-blood targets may be appropriate in patients with anemia[3,31]. Decreased intragraft tacrolimus metabolism - observed in kidneys from CYP3A5 non-expressing donors - is associated with an increased risk of tacrolimus nephrotoxicity, likely due to impaired allograft clearance[21].

We hypothesized that the tacrolimus toxicity in our patient was driven by abnormally high peak concentrations, reflected by elevated tacrolimus C₀ levels. Although other perioperative factors may have contributed to tacrolimus toxicity, the rapid postoperative increase in tacrolimus concentration, along with the onset and resolution of symptoms correlating with drug levels, strongly suggests an operative impact on tacrolimus pharmacokinetics.

CONCLUSION

To the best of our knowledge, this is the first report of CNI-induced neurotoxicity and nephrotoxicity in a kidney transplant recipient following wedge liver resection - a scenario distinct from previously reported cases in liver transplant recipients. Because tacrolimus is primarily metabolized in the liver, a reduction in liver mass and ischemic injury to the remaining liver tissue may impair drug metabolism and clearance, leading to prolonged elevations in whole-blood tacrolimus concentrations, even after the drug is discontinued. This case highlights the need for close monitoring of tacrolimus levels following non-transplant liver surgery as part of therapeutic drug management in such patients.