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Saudi Journal of Kidney Diseases and Transplantation
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CASE REPORT Table of Contents   
Year : 2008  |  Volume : 19  |  Issue : 3  |  Page : 446-449
Confusion and Agitation after a Recent Kidney Transplantation

1 Department of Nephrology and Dialysis, Al Hada Armed Forces Hospital, Taif, Saudi Arabia
2 Department of Neurology, Al Hada Armed Forces Hospital, Taif, Saudi Arabia

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A 51-year-old man, who received a living related transplant from his wife and anti-thymocyte globulin (ATG) as induction therapy, developed delayed graft function after transplantation. One day after he received an i.v. dose of ganciclovir, the patient developed hallucinations, confusion and agitation, which worsened the following day. CT­scan of the brain and cerebrospinal fluid were unremarkable. Ganciclovir-induced encepha­lopathy was considered the most likely reason for the patient's neurological condition, since he recovered completely a few days after discontinuation of this drug. Since anti-CMV prophylactic treatment is now widely used after transplantation, a high index of suspicion is required to diagnose ganciclovir (or acyclovir) induced neurotoxicity.

Keywords: Confusion, Transplantation, Ganciclovir

How to cite this article:
Hussein MM, Mooij JM, Al Malki N, Ali Idriss D. Confusion and Agitation after a Recent Kidney Transplantation. Saudi J Kidney Dis Transpl 2008;19:446-9

How to cite this URL:
Hussein MM, Mooij JM, Al Malki N, Ali Idriss D. Confusion and Agitation after a Recent Kidney Transplantation. Saudi J Kidney Dis Transpl [serial online] 2008 [cited 2020 Dec 5];19:446-9. Available from: https://www.sjkdt.org/text.asp?2008/19/3/446/40509

   Introduction Top

Confusional state in patients after recent transplant surgery can be multifactorial that include neurotoxicity with cytomegalovirus (CMV) prophylaxis with drugs such as acy­clovir, ganciclovir, valganciclovir and valcy­clovir. [1],[2],[3],[4],[5],[6],[7],[8],[9],[10],[11]

We present a case of severe confusion and agitation one to two days after giving one dose of oral valganciclovir and one dose of intravenous (i.v.) ganciclovir, which resolved completely after discontinuation of the anti­viral medication. To make the diagnosis, a high index of suspicion will be needed, and timely discontinuation or dose reduction might prevent further deterioration.

   Case Report Top

A 51-year-old man with end-stage renal disease of uncertain etiology (shrunken kid­neys of around 5-6 cm in size), and diabetes mellitus controlled on diet only, was on main­tenance hemodialysis for the last 5 years in another hospital.

In August 2006, the patient was referred to our hospital for possible kidney transplan­tation from his wife. His pre-operative inves­tigations revealed atrial fibrillation with a ventricle rate of around 80 per minute. Echo­cardiogram revealed an ejection fraction of 40-45%, moderate aortic regurgitation and moderate mitral regurgitation with moderate pulmonary hypertension. Coronary angio­graphy illustrated normal coronary arteries. Patient was started on advice of the cardio­logist on warfarin as oral anticoagulant, biso­prolol as a beta-blocker, and digoxin.

Laboratory investigations included markers of active hepatitis that all were negative. The investigations of the donor were all normal. Cytotoxic crossmatch with the donor was negative, and panel reactive antibodies (PRA) of the recipient was negative. Both recipient and donor were seropositive for CMV-IgG.

Three days before transplantation the pa­tient was switched to heparin, which was discontinued 10 hours before surgery. Two days prior to the transplantation, the patient was started on immunosuppressive medi­cations that included cyclosporine, pred­nisone, and mycophenolate mofetil (MMF).

On December 17, 2006, the patient under­went transplantation that was complicated by delayed graft dysfunction, most likely due to hemodynamic instability during the ope­ration, and it required daily hemodialysis.

On the 1st post operative day, cyclosporine was discontinued and patient was started on anti-thymocyte globulin (ATG) with a dose of 1.5 mg/kg i.v. daily over 6 hrs. After the first 3 doses, it was reduced to 0.75 mg/kg in view of thrombocytopenia.

On the 3 rd postoperative day, anti- CMV­prophylaxis was initiated. The patient received one dose of valganciclovir 450 mg orally, followed the next day by ganciclovir i.v. in a dose of 1.25 mg/kg BW every 48 hours, the recommended dose for patient's degree of creatinine clearance.

On the 5 th post-operative day, the patient became confused, hallucinating and agitated pulling out his i.v. lines. The blood pressure was 160/80 mm Hg, temp 37°C, and 24-h urine output 211 ml. Laboratory investiga­tions revealed hemoglobin (Hgb) of 7.5 g/dl, white blood cell count (WBC) of 4.4 x 10 9 /l, and platelets count 104 x 10 9/l. Blood che­mistry showed serum sodium of 129 mmol/L, potassium: 5.5 mmol/L, bicarbonate: 14 mmol /L, blood urea nitrogen (BUN) 42 mmol/L, creatinine 924 µmol/L, and arterial blood gas (ABG): pH 7.30, pCO2 23 mm Hg, pO2 65 mm Hg. Chest X-ray (CXR) illustrated pulmonary congestion. A plain computerized tomography (CT) scan of the brain revealed normal findings.

On the 6 th post operative day, the patient was stuperous, but arousable and oriented to person, place, and time. He remained afeb­rile with blood pressure 135/74 mmHg, heart rate 110 per minute, and clear chest on aus­cultation. There were no focal neurological signs and no neck stiffness. Laboratory in­vestigations revealed Hgb of 7.7 g/dl, WBC of 7.7 x 10 9 /L, and platelets 119 x 10 9 /L. Serum sodium was 126 mmol/L, potassium 5.5 mmol/L, chloride 96 mmol/L, bicarbo­nate 11 mmol/L, blood glucose level was 4.8 mmol/L, BUN 49.9 mmol/l, serum crea­tinine 1076 µmol/L, corrected serum calcium 1.98 mmol/L, lactic acid 0.7 mmol/l, and ABG that included pH 7.13, pCO 2 35 mm Hg, HCO 3 13 mmol/L, and O2 96% on 2 liters of oxygen by nasal canula. The CXR was normal, and blood culture revealed no growth. Repeat CT-scan of the brain did not show any new changes, a lumbar puncture revealed clear, colorless cerebrospinal fluid with a white cell count 2 per mm 3 , protein 189 mg/L and glucose 3.3 mmol/L. Later that day, the patient's condition deteriorated further, and he had to be intubated and ventilated. A meta­bolic and/or drug-related cause of the con­usion and decreased level of consciousness was suspected. Because of its probable neu­rotoxicity, ganciclovir was discontinued, how­ever, its serum levels were not measured. In addition, ATG treatment was also withheld.

Over the next few days, there was a gradual improvement in the neurological condition of the patient. His mental status improved completely and he could be extu­bated on the 11 th postoperative day. The urine output increased to around 1.5 liters per day, but the patient remained dialysis de­pendent. A transplant biopsy was performed in a later stage, which revealed tubular nec­rosis with calcium oxalate deposits without signs of rejection.

   Discussion Top

Low level of consciousness post renal transplantation can be due to one or a com­bination of several factors such as he use of analgesics and/or sedatives, circulatory failure, respiratory insufficiency, sepsis, metabolic acidosis, hypo-and hyperglycemia, hypona­tremia, and central nervous system (CNS) insults.

Our patient initially recovered well from the anesthesia, and for the first three days post­operatively his mental status was normal. However, since the 4 th post operative day the patient became more drowsy and con­fused, agitated and hallucinating, together with worsening of the respiratory function, so that the patient had to be re-intubated again.

Several factors may have contributed to this process including fluid overload that re­sulted in hyponatremia, metabolic acidosis due to graft dysfunction, CNS insult, medi­cation side effects, and respiratory failure.

However, these parameters could not ex­plain the patient's condition completely, as the hyponatremia was mild (from 129 to 126 mmol/L), the symptoms started before the acidosis became prominent, and CT-scan of the brain was unremarkable. The use of mo­noclonal antibody anti-CD3 (OKT3), and possibly also of the polyclonal ATG has been occasionally associated with aseptic meni­ngitis, [8] however, cerebrospinal fluid findings were negative.

At present, ganciclovir or valganciclovir are routinely used post-solid organ transplan­tations in any case of CMV-seropositive do­nor and/or recipient to prevent CMV infec­tion and disease. [1],[2] This is especially needed when the patient receives induction therapy with polyclonal antibodies, as there is an in­creased risk of CMV-disease in these cases.

Neuropsychiatric side effects of ganciclovir and related compounds such as acyclovir and valacyclovir have been frequently reported, especially in patients with renal dysfunc­tion. [3],[4],[5],[6],[7],[8] The symptoms sometimes occur one day after stating the anti-viral treatment, [8],[10] while in our patient they developed 1-2 days after initiating it. The symptoms may vary from nightmares and hallucinations to agita­tion and delirium that may progress to coma. [8],[11] However, the process is usually rever­sible upon withdrawal of the drug. High levels of the metabolite 9-carboxymethoxy­methylguanine (CMMG) in patients receiving acyclovir may cause the neurological side effects. [12] In a reported case on a patient with acyclovir-associated coma, generalized slowing of the rhythm of electroencephalo­gram (EEG) was found. [11]

Although a serum level ganciclovir might have been helpful in the diagnosis, [7] the above considerations strongly suggested that our patient suffered from ganciclovir-induced encephalopathy. The contributions of other factors, although unlikely, could not be excluded.

Eventually, the patient's mental condition recovered fully in a few days after discon­tinuation of the drug, although the renal func­tion did not improve, and patient remained on dialysis.

With the wide use of anti-CMV prophy­lactic treatment after solid organ transplan­tation, it is important to pay attention to the neurological side effects of ganciclovir and acyclovir, which occur mainly in cases of renal dysfunction, even when the dose is adjusted to the degree of renal impairment according to the manufacturer's guidelines. [8]

As mentioned earlier, the symptoms may occur as early as one day after initiation of treatment. [8],[10]

As patients after recent transplantation sur­gery may often develop confusion and agi­tation, a high index of suspicion is required to diagnose ganciclovir or acyclovir neurotoxicity during course of therapy. [5] Timely discontinuation of these medications or dose reduction might prevent further deterioration.

   References Top

1.Hodson EM, Jones CA, Webster AC, et al. Antiviral medications to prevent cyto­megalovirus disease and early death in recipients of solid-organ transplants: A systematic review of randomised controlled trials. Lancet 2005;365(9477):2105-15.  Back to cited text no. 1    
2.Hodson EM, Barclay PG, Craig JC, et al. Antiviral medications for preventing cyto­megalovirus disease in solid organ transplant recipients. Cochrane Database Syst Rev 2005;(4):CD003774.  Back to cited text no. 2  [PUBMED]  [FULLTEXT]
3.Davis CL, Springmeyer S, Gmerek BJ. Central nervous system side effects of ganciclovir. N Engl J Med 1990;322(13):933-4.  Back to cited text no. 3    
4.Haefeli WE, Schoenenberger RA, Weiss P, Ritz RF. Acyclovir-induced neurotoxicity: Concentration-side effect relationship in acyclovir overdose. Am J Med 1993;94(2): 212-5.  Back to cited text no. 4    
5.Ernst ME, Franey RJ. Acyclovir-and ganci­clovir-induced neurotoxicity. Ann Pharma­cother 1998;32(1):111-3.  Back to cited text no. 5    
6.Linssen-Schuurmans CD, van Kan EJ, Feith GW, Uges DR. Neurotoxicity caused by valacyclovir in a patient on hemodialysis. Ther Drug Monit 1998;20(4):385-6.  Back to cited text no. 6    
7.Peyriere H, Jeziorsky E, Jalabert A, et al. Neurotoxicity related to valganciclovir in a child with impaired renal function: Use­fulness of therapeutic drug monitoring. Ann Pharmacother 2006;40(1):143-6.  Back to cited text no. 7    
8.Das V, Peraldi MN, Legendre C. Adverse neuropsychiatric effects of cytomegalovirus prophylaxis with valaciclovir in renal trans­plant recipients. Nephrol Dial Transplant 2006;21(5):1395-401.  Back to cited text no. 8    
9.Wilde MI, Goa KL. Muromonab CD3: A reappraisal of its pharmacology and use as prophylaxis of solid organ transplant rejection. Drugs 1996;51(5):865-94.  Back to cited text no. 9    
10.Saurina A, Ramirez de Arellano M, de las Cuevas X. Neurotoxicity after the first dose of oral administration of valaciclovir in a female hemodialyzed patient. Nefrologia 2002;22(1):83-4.  Back to cited text no. 10    
11.Rajan GR, Cobb JP, Reiss CK. Acyclovir induced coma in the intensive care unit. Anaesth Intensive Care 2000;28(3):305-7.  Back to cited text no. 11    
12.Hellden A, Odar-Cederlof I, Diener P, et al. High serum concentrations of the acyclovir main metabolite 9-carboxymethoxymethyl­guanine in renal failure patients with acyclovir-related neuropsychiatric side effects: An observational study. Nephrol Dial Transplant 2003;18(6):1135-41.  Back to cited text no. 12    

Correspondence Address:
Magdi M Hussein
Department of Nephrology and Dialysis, Al Hada Armed Forces Hospital, P.O. Box 1347, Taif
Saudi Arabia
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PMID: 18445909

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