Printer Friendly

Neurological complications after renal transplantation: a retrospective clinical study.


Neurological complications (NCs) after transplantation are still a major problem and cause significant mortality and morbidity despite improvements in organ preservation, surgical techniques, and immunosuppressive treatment. These complications may be caused by an underlying primary disorder particularly diabetes mellitus, owing to renal failure, neurotoxicity of immunosuppressive drugs or surgical procedures, or their combination (1,2,3,4,5). These complications may involve the central or peripheral nervous system (PNS). NCs after renal transplantation (RT) were described in the previous studies, but their electrophysiological findings were not evaluated. The aim of this study was to evaluate the types of NC and their electrophysiological findings in RT patients. Besides, treatment methods of NC after RT were also investigated under the light of the English literature.


In this study, 344 patients who had RT performed at the Ondokuz Mayis University Hospital between January 2005 and July 2014 were retrospectively evaluated. All patients were administered tacrolimus, mycophenolate mofetil, and prednisolone with induction treatment initially comprising basiliximab or antithymocyte globulin. In case of tacrolimus toxicity it was switched to cyclosporine or sirolimus.

File records of the patients revealed '9 cases having 22 episodes of NC, of which three cases had more than one episode. Electroneuromyography (EMG) was performed on six patients with signs of polyneuropathy, and electroencephalography (EEG) was performed on six other patients.

Descriptive statistics regarding age, gender and frequency of NCs were analyzed. NCs were classified as central or peripheral. This study was performed according to the tenets of the Declaration of Helsinki.


A total of 22 episodes of NC was identified in 19 patients (8 females, 11 males), three of whom had more than one episode. The mean age of the 19 patients enrolled in the study was 37.52+13.08 (range, 18-65) years. The demographic data of the patients and their NCs are summarized in Table 1. Central nervous system involvement was found in 16 (84.2%) patients. Seven (36.8%) of the 19 patients had tremors. Generalized tonic-clonic status epilepticus, tonic-clonic seizures, and encephalopathy were observed in two (10.5%) cases. One had delirium and dementia (5.2%), one had agitated depression (5.2%), and one had headache (5.2%).

Polyneuropathy appeared after encephalopathy in one of the three patients who had multiple episodes of NCs. Other two patients had tremor and agitated depression or polyneuropathy

Seven of the 22 (31.8%) episodes of NCs were tremor Six of the seven patients with tremor were using tacrolimus, and one patient was using cyclosporine. All of these patients had bilateral postural hand tremor; in advanced cases, additional kinetic tremor was observed. However none of them had resting tremor Three patients (No. 1,2, 6) had tremor prior to RT but it did not affect their daily lives. Tremor of these patients increased after RT to a degree that it prevented eating. In the other four patients, tremor emerged after RT Three of the seven patients had tremors in the limbs, and one of these patients also had lower-extremity neuropathy

Two of the 22 episodes of NCs (9.0%) were generalized tonic-clonic status epilepticus, and two (9.0%) were generalized tonic-clonic seizures. All four patients were taking tacrolimus. They are still under the antiepileptic drug treatment. One (4.5%) of the 22 episodes of NCs was diagnosed as agitated depression and responded immediately to a change in medication from tacrolimus to sirolimus. Delirium occurred in one patient because of infection, and the patient recovered after antibiotic treatment; one patient had a migraine-type headache with a history of 2 weeks that was relieved with beta-blocker therapy

Six patients (26.3%) had a PNS involvement; one case had numbness of hands but normal EMG. Four patients were diagnosed with polyneuropathy according to clinical and electrophysiological findings, three of whom had polyneuropathy caused by immunosuppressive drugs (cyclosporine, two patients; tacrolimus, one patient) and one had polyneuropathy caused by amyloidosis. In the other patient with lumbar plexopathy the cause is being investigated.

Sensory ataxia and progressive sensory polyneuropathy were observed in one patient (No. 12) who received cyclosporine for 4 years. Neurological examination revealed deep sensory impairment, normal somatosensory evoked potentials (SEP) and cervical MRI, and low vitamin B12 and ferritin levels; however, even after the correction of these parameters, progression in clinical and EMG findings was observed. The administration of cyclosporine, which was considered as the cause of polyneuropathy was discontinued. There was improvement in symptoms after the discontinuation of cyclosporine.

In another patient (No.8) with acute axonal mixed polyneuropathy cyclosporine level was very high, i.e., 1138 (100-400) ng/dL. When the concentration of the drug in the blood decreased to 213 ng/dL, the patient's symptoms almost completely disappeared.

Another cachectic patient who had meralgia paresthetica and severe sensory symptoms (No. 11) was considered to have polyneuropathy because of amyloidosis. The patient was administered codeine for severe pain in one thigh. This patient, who also had autonomic gastrointestinal symptoms (diarrhea) and pituitary deficiency had the most severe clinical symptoms of all the patients and died from cardiac arrest.

Fourteen of 22 NC were considered to be caused by the immunosuppressant tacrolimus and three were caused by cyclosporine. Amyloidosis, infection, septic emboli, and hypoglycemia were other causes of NCs. In one patient, the etiology was unknown.


Our study evaluated NCs after RT There are few studies on this issue in the literature; neurological signs and symptoms after RT, such as encephalopathy the PNS involvement, tremor and headache, have been reported (1,2,3,4,5).

Tremor is one of the most common neurological symptoms after RT and different incidence rates of tremor have been reported (4). Yardimci et al. (5) reported a tremor rate of 11.1%. whereas in our study it was 36.8%, which is much higher In a multi-center study conducted in Europe, 448 RT patients were randomly selected. In their immunosuppressive therapy they were receiving either cyclosporine (n = 145) or tacrolimus (n=303) (6). The incidence of tremor in patients receiving tacrolimus (34.7%) was higher than that in patients receiving cyclosporine (11.7%) (p<.001). In another study, 412 patients were receiving either tacrolimus (n=205) or cyclosporine (n=207) for immunosuppression. In that study the incidence of tremor in patients who received tacrolimus (54.1%) was higher than that in patients who received cyclosporine (33.8%) (p<.001) (7).

The mechanism by which tacrolimus causes tremor is not fully understood; however, there has been a study indicating that the level of calcineurin inhibitors (CNI) is associated with the tremor (8). Calcineurin inhibition by cyclosporine and tacrolimus alters sympathetic outflow, which may play a role in the mediation of tremor (9).

Diffuse encephalopathy is diagnosed with mental illness, generalized tonic-clonic status, seizures, or encephalopathic EEG and normal cranial MRI findings. Posterior leukoencephalopathy syndrome (PLES) is a reversible encephalopathy, which partially affects the cerebral cortex, and the symmetric involvement of posterior regions has been commonly reported. PLES is clinically characterized by altered mental status, seizures, and frequent visual disturbances, and it is generally reported in patients who receive immunosuppressive drugs after transplantation (10,11,12,13,14). In our study the sudden onset of drowsiness, diffuse delta and theta waves in EEG, and a suicide attempt in one patient suggested diffuse encephalopathy The absence of clinical hypertension, blurred vision, or headache and other focal neurological findings also indicated diffuse encephalopathy However a limitation of unilateral diffusion in the right cerebellum in the cranial MRI of the patient suggested PLES. In the study by Kastrup et al. (10), there was not only unilateral cerebellar involvement but also additional cerebral lesions in all of the 50 patients with PLES. The clinical condition and EEG improved after tacrolimus was switched to cyclosporine in one of our patient with a normal tacrolimus level. However she developed acute axonal polyneuropathy after cyclosporine treatment. PNP findings that occurred while receiving cyclosporine improved when the dosage was reduced. There was axonal involvement in both the central nervous system (CNS) gray matter and the PNS of the patient, suggesting it was not a demyelinating process but a direct attack on neurons. In this patient, the toxic effects appeared in response to two CNI (cyclosporine and tacrolimus). In our opinion, the monitoring of drug levels is very important and medication should not be changed in polyneuropathies, which can improve by the reduction of drug doses.

We assert that the neuropathic symptoms of this patient resulted from dose-dependent toxic effects of the cyclosporine because the patient had been using the same drug for 5 years.

One patient with both CNS and neuropathy was reported in the literature; however the involvement of both systems was observed while the patient was taking tacrolimus and inadvertently had an overdose of the drug (11).

Cyclosporine and tacrolimus (CNI) are known to be a substrate of cytochrome P450 (CYP) 3A5 and P-glycoprotein (P-gp), which are encoded by CYP3A5 gene and ATP-binding cassette subfamily B member 1 (ABCB1) gene, also known as multidrug-resistant gene 1 (MDR1), respectively (15,16,17,18). Yanagimachi et al. (19) showed an association between CNI-related neurotoxicity and gene polymorphism in the ABCB1 and CYP3A5 genes in patients with hematopoietic stem cell transplantation. These gene polymorphisms may explain the reason for CNS side-effect patterns in some patients. However, we did not search gene polymorphism in our study population; two of our patients with severe encephalopathy may have had gene polymorphism. CYP3A5 gene polymorphism results in the inhibition of the metabolism of two different CNIs and may cause encephalopathy and polyneuropathy.

In our study the other tacrolimus-induced the CNS involvement was agitated depression, which was switched to sirolimus. Headache was recorded in 56% of the patients in another study but it was 5.2% in our study (5).

There are usually case reports regarding PNP after RT and femoral neuropathy is the most common type of neuropathy (20,21,22,23,24,25,26,27). However there was no femoral neuropathy in our patients.

In the literature, cyclosporine-induced axonal sensory and sensorimotor polyneuropathy after RT have been reported in two patients (21,22). In our study cyclosporine-induced sensorimotor axonal polyneuropathy was diagnosed by EMG and clinical findings in two patients. Although cyclosporine-induced axonal neuropathies are very rare, Guillain-Barre Syndrome (GBS) was reported in one patient and CIDP was reported in another patient after transplantation (23,24).

Bhagavati et al. (25) reported that two patients developed tacrolimus-induced polyneuropathy after RT; one had block with axonal neuropathy in the left ulnar nerve and the other had demyelinating neuropathy. Another demyelinating polyneuropathy was reported in one patient who received tacrolimus after RT by Echaniz-Laguna (24). In one of our patients who developed tacrolimus-induced neuropathy, there were axonal and demyelinating (mixed-type) neuropathy findings. These findings appeared while the patient was receiving therapeutic doses of tacrolimus. Tacrolimus may have increased his polyneuropathic symptoms because this patient had undergone dialysis for many years and had neuropathic symptoms before RT.

Uremic neuropathies are generally reported to be sensorimotor and axonal (28). In the literature, the symptoms of uremic neuropathy are reported to resolve after RT (29,30), while in our patients, these symptoms emerged or progressed after RT despite modification or reduction of the dosage of medications.

This is a retrospective study. Because the patients were followed up for 1-9 years at our center, this facilitated the close monitoring of clinical and electrophysiological responses of patients to the modifications in medication. Different neurological disorders can be seen after RT and most of them are caused by immunosuppressive drugs and can be treated by decreasing the dose or switching the immunosuppressive drugs.

Prospective studies, which focus on the assessment of neurological complication of patients who undergo RT, can help to achieve better patient outcomes.

DOI: 10.5152/npa.2015.9876

Acknowledgements: The authors thank Gregory T Sullivan for editing the English in an earlier version of this manuscript,

Conflict of Interest: No conflict of interest was declared by the authors,

Financial Disclosure: The authors declared that this study has received no financial support,


(1.) Ponticelli C, Campise MR, Neurological complications in kidney transplant recipients, J Nephrol 2005; 18:521-528,

(2.) Bruno A, Adams HP Jr Neurologic problems in renal transplant recipients, Neurol Clin 1988; 6:305-325,

(3.) Lee JM, Raps EC, Neurologic complications of transplantation, Neurol Clin 1998; 16:21-33, [CrossRef]

(4.) Ce P Koskderelioglu A, Coban G, Gedizlioglu M, Nart A, Uslu A, Neurologic complications of renal transplant, Exp Clin Transplant 2012; 10:243-246, [CrossRef]

(5.) Yardimci N, Colak T Sevmis S, Benli S, Zileli T Haberal M, Neurologic complications after renal transplant, Exp Clin Transplant 2008; 6:224-228,

(6.) Mayer AD, Dmitrewski J, Squifflet JP Besse T Grabensee B, Klein B, Eigler FW Heemann U, Pichlmayr R, Behrend M, Vanrenterghem Y Donck J, van Hooff J, Christiaans M, Morales JM, Andres A, Johnson RW, Short C, Buchholz B, Rehmert N, Land W, Schleibner S, Forsythe JL, Talbot D, Pohanka E, Multicenter randomized trial comparing tacrolimus (FK506) and cyclosporine in the prevention of renal allograft rejection: a report of the European Tacrolimus Multicenter Renal Study Group, Transplantation 1997; 64:436-443, [CrossRef]

(7.) Neylan JF Sullivan EM, Steinwald B, Goss TF Assessment of the frequency and costs of posttransplantation hospitalizations in patients receiving tacrolimus versus cyclosporine. Am J Kidney Dis 1998; 32:770-777. [CrossRef]

(8.) Veroux P Veroux M, Puliatti C, Morale W, Cappello D, Valvo M, Macarone M. Tacrolimus-induced neurotoxicity in kidney transplant recipients. Transplant Proc 2002; 34:3188-3190. [CrossRef]

(9.) Bechstein WO. Neurotoxicity of calcineurin inhibitors: impact and clinical management. Transpl Int 2000; 13:313-326. [CrossRef]

(10.) Kastrup O, Schlamann M, Moenninghoff C, Forsting M, Goericke S. Posterior Reversible Encephalopathy Syndrome: The Spectrum of MR Imaging Patterns. Clin Neuroradiol 2014 Feb 20.

(11.) Wu G, Weng FL, Balaraman V Tacrolimus-induced encephalopathy and polyneuropathy in a renal transplant recipient. BMJ Case Rep 2013; 2013.

(12.) Cadavid-Aljure D, Caicedo-Paredes A, Meza JC, Granados-Sanchez AM, Posada-Chavez JG, Mesa-Ramfrez L, Schweineberg-Lopez J. Tacrolimus associated to posterior reversible atypical encephalopathy syndrome and brain haemorrhage in renal transplant recipient. Nefrologia 2012; 32:861-863.

(13.) Chegounchi M, Hanna MG, Neild GH. Progressive neurological disease induced by tacrolimus in a renal transplant recipient: case presentation. BMC Nephrol 2006; 7:7. [CrossRef]

(14.) Kastrup O, Gerwig M, Frings M, Diener HC. Posterior reversible encephalopathy syndrome (PRES):electroencephalographic findings and seizure patterns. J Neurol 2012; 259:1383-1389. [CrossRef]

(15.) Fredericks S, Holt DW, MacPhee IA. The pharmacogenetics of immunosuppression for organ transplantation: a route to individualization of drug administration. Am J Pharmacogenomics 2003; 3:291-301. [CrossRef]

(16.) Mourad M, Wallemacq P De Meyer M, Malaise J, De Pauw L, Eddour DC, Goffin E, Lerut J, Haufroid V. Biotransformation enzymes and drug transporters pharmacogenetics in relation to immunosuppressive drugs: impact on pharmacokinetics and clinical outcome. Transplantation 2008; 85:19-24. [CrossRef]

(17.) Eichelbaum M, Fromm MF Schwab M. Clinical aspects of the MDRI (ABCBI) gene polymorphism. Ther Drug Monit 2004; 26:180-185. [CrossRef]

(18.) Yamauchi A, Ieiri I, Kataoka Y Tanabe M, Nishizaki T Oishi R, Higuchi S, Otsubo K, Sugimachi K. Neurotoxicity induced by tacrolimus after liver transplantation: relation to genetic polymorphisms of the ABCBI (MDRI) gene. Transplantation 2002; 74:571-572. [CrossRef]

(19.) Yanagimachi M, Naruto T Tanoshima R, Kato H, Yokosuka T Kajiwara R, Fujii H, Tanaka F Goto H, Yagihashi T Kosaki K, Yokota S. Influence of CYP3A5 and ABCBI gene polymorphisms on calcineurin inhibitor-related neurotoxicity after hematopoietic stem cell transplantation. Clin Transplant 2010; 24:855-861. [CrossRef]

(20.) Junaid I, Kwan JT Lord RH. Femoral neuropathy in renal transplantation. Transplantation 1993; 56:240-241. [CrossRef]

(21.) Sayin R, Soyoral YU, Erkoc R. Polyneuropathy due to cyclosporine A in patients with renal transplantation: a case report. Ren Fail 2011; 33:528-530. [CrossRef]

(22.) Etemadi J, Shoja MM, Ghabili K, Talebi M, Namdar H, Mirnour R. Multiple etiologies of axonal sensory motor polyneuropathy in a renal transplant recipient: a case report. J Med Case Rep 2011; 5:530. [CrossRef]

(23.) Falk JA, Cordova FC, Popescu A, Tatarian G, Criner GJ. Treatment of Guillain-Barre syndrome induced by cyclosporine in a lung transplant patient. J Heart Lung Transplant 2006; 25:140-141. [CrossRef]

(24.) Echaniz-Laguna A, Anheim M, Wolf P Kessler R, Massard G, Mohr M, Moulin B, Braun-Parvez L, Jaeck D, Tranchant C. Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) in patients with solid organ transplantation: a clinical, neurophysiological and neuropathological study of 4 cases. Rev Neurol (Paris) 2005; 161:1213-1220. [CrossRef]

(25.) Bhagavati S, Maccabee P Muntean E, Sumrani NB. Chronic sensorimotor polyneuropathy associated with tacrolimus immunosuppression in renal transplant patients: case reports. Transplant Proc 2007; 39:3465-3467. [CrossRef]

(26.) Patel MK, Rashed A, Mesraoua B, Khaddash S, Romeh SA. Cyclosporine neurotoxicity presenting as an unilateral foot drop in a renal transplant patient. Nephron 1991; 58:116. [CrossRef]

(27.) Bulsara KR, Baron PW, Tuttle-Newhall JE, Clavien PA, Morgenlander J. Guillain-Barre Syndrome in organ and bone marrow transplant patients Transplantation 2001; 71:1169-1172. [CrossRef]

(28.) Raskin NH. Neurological aspects of renal failure. Aminoff MJ, ed. Neurology and general medicine. 2. Ed. New York Chuchill Livingstone 1989; 231-246.

(29.) Ho DT Rodig NM, Kim HB, Lidov HG, Shapiro FD, Raju GR Kang PB. Rapid reversal of uremic neuropathy following renal transplantation in an adolescent. Pediatr Transplant 2012; I6:E296-E300. [CrossRef]

(30.) Bolton CF Electrophysiologic changes in uremic neuropathy after successful renal transplantation. Neurology 1976; 26:152-161. [CrossRef]

Nilgun CENGIZ [1], Zelal ADIBELLI [2], Yarkin Kamil YAKUPOGLU [3], Hande TURKER [1]

[1] Department of Neurology, Ondokuz Mayis University, Faculty of Medicine, Samsun, Turkey

[2] Department of Nephrology, Ataturk State Hospital, Antalya, Turkey

[3] Department of Urology, Ondokuz Mayis University, Faculty of Medicine, Samsun, Turkey

Correspondence Address: Dr Nilgun Cengiz, Ondokuz Mayis Oniversitesi Tip Fakultesi, Noroloji Anabilim Dali, Samsun, Turkiye E-mail:

Received: 12.07.2014 Accepted: 19.11.2014
Table 1. The demographic data of
patients and their neurological complications

Patient     Age     Development     Type of NC(s)
          (years)     of NCs

1          40/M      Before RT          Tremor
2          32/F      Before RT          Tremor
3          33/M       15 days           Tremor
4          56/M       15 days           Tremor
                      15 days       Polyneuropathy

5          37/F       15 days           Tremor
6          35/M      Before RT          Tremor
7          23/F       1 week            Tremor
                     4 months         Depression
8          32/F     1.5 months      Encephalopathy
                     2 months       Polyneuropathy
9          65/M      7 months     Dementia Delirium
10         55/M       4 years           Lumbar
11         18/M       5 years       Polyneuropathy

12         36/M       4 years       Polyneuropathy
13         48/M      4 months          Sensory
14         26/M       2 years          Seizure
15         42/F       5 years     Status epilepticus
16         36/M       4 years     Status epilepticus
17         23/F       6 years          Headache
18         22/F       10 days          Seizure

19         54/F       4 days        Encephalopathy

Patient          Symptoms            Indication for RT

1              Hand tremor          Glomerulonephritis
2              Hand tremor             Polycystosis
3          Hand and Leg tremor     Chronic renal failure
4          Hand and Leg tremor         Polycystosis
             Leg weakness and          Polycystosis
           sensory disturbances
5          Hand and Leg tremor              UTI
6              Hand tremor                Unknown
7              Hand tremor             Hypertension
                Depression             Hypertension
8               Confusion                 Unknown
            Weakness in limbs             Unknown
9                Delirium              Hypertension
10        Unilateral thigh pain      Diabetes mellitus
                                     and hypertension
11        Unilateral thigh pain     Amyloidosis and FMF
             and leg weakness
12            Sensory ataxia              Unknown
13            Hand numbness              Bilateral
14             GTC seizure             Policystosis
15             GTC seizures          Diabetes mellitus
16             GTC seizures              Nephritis
17               Headache                 Unknown
18             GTC seizure            Bilateral renal
19        Confusion GTC seizures          Unknown

Patient    Cause(s) of    Diagnostic tools used
                          EMG    EEG    MRI

1          Tacrolimus      --     --     --
2          Tacrolimus      --     --     --
3          Tacrolimus      --     --     --
4          Tacrolimus      --     --     --
           Tacrolimus      +      --     --

5          Tacrolimus      --     --     --
6         Cyclosporine     --     --     --
7          Tacrolimus      --     --     --
           Tacrolimus      --     --     --
8          Tacrolimus      --     +      +
          Cyclosporine     +      --     --
9           Infection      --     +      --
10           Unknown       +      --     --

11         Amyloidosis     +      --     --

12        Cyclosporine     +      --     --
13         Tacrolimus      +      --     --

14         Tacrolimus      --     +      +
15        Hypoglycemia     --     +      --
16         Tacrolimus      --     +      --
17         Tacrolimus      --     --     --
18        Septic emboli    --     +      --

19         Tacrolimus      --     +      +

RT: renal transplantation; EEG: electroencephalography;
EMG: electroneuromyography; MRI: brain magnetic resonance
imaging; NCs: neurological complications; UTI: urinary
tract infection; PNP: polyneuropathy; FMF: familial
Mediterranean fever
COPYRIGHT 2015 Galenos Yayinevi Tic. Ltd.
No portion of this article can be reproduced without the express written permission from the copyright holder.
Copyright 2015 Gale, Cengage Learning. All rights reserved.

Article Details
Printer friendly Cite/link Email Feedback
Title Annotation:Research Article
Author:Cengiz, Nilgun; Adibelli, Zelal; Yakupoglu, Yarkin Kamil; Turker, Hande
Publication:Archives of Neuropsychiatry
Article Type:Clinical report
Date:Dec 1, 2015
Previous Article:Prevalence of intimate partner violence and associated factors.
Next Article:Psychiatric features in neurotic excoriation patients: the role of childhood trauma.

Terms of use | Privacy policy | Copyright © 2021 Farlex, Inc. | Feedback | For webmasters |