Neurological complications of renal dialysis and transplantation

Kushan Karunaratne1, David Taube2, Richard Perry1,3, Nofal Khalil4, Paresh Malhotra1,3*

1 Department of Neurology, Imperial College Healthcare NHS Trust, London, United Kingdom.

2 Department of Renal and Transplantation Medicine, West London Renal and Transplant Centre, Imperial College Kidney and Transplant Institute, London, United Kingdom.

3 Division of Brain Sciences, Imperial College London, UK

4 Department of Neurophysiology, Imperial College Healthcare NHS Trust, London, United Kingdom.

*Corresponding author.

Correspondence: Dr Paresh Malhotra, Department of Neurology, Hammersmith Hospital, Du Cane Road, London, W12 OHS. Telephone number – 0203 311 7286

Email – [email protected]

Word count - 4740

ABSTRACT

Neurological complications with renal replacement therapy contribute significantly to morbidity and mortality in patients with renal failure. All levels of the nervous system can be affected, and can be classified as central or peripheral. Most neurological disturbances associated with the uraemic state fail to respond fully to renal replacement therapy and further complications are specifically associated with dialysis and transplantation. A multi-disciplinary approach involving both nephrologists and neurologists is critical in diagnosis and effective management of these disorders in these particularly vulnerable groups of patients.

Keywords – Haemodialysis, Dialysis, Renal transplant, Neurological complications

INTRODUCTION

In the most recent UK renal registry report, it was noted that there were approximately 60,000 patients receiving renal replacement therapy at the end of 2014 with 7,411 patients having started renal replacement therapy over the course of that year(1). Transplantation was the most common treatment modality (53%); haemodialysis was used in 41% and peritoneal dialysis in 6% of renal replacement therapy patients(1). The kidney and transplant service at Imperial College Healthcare NHS Trust, predominantly based at Hammersmith Hospital, looks after over 3500 patients on renal replacement therapy. In our experience a sizeable proportion of these individuals develop neurological problems. Although these can sometimes relate to systemic conditions, particularly diabetes mellitus and autoimmune diseases, which can lead directly to both neurological and kidney disease, they are often secondary to the introduction of dialysis or subsequent to renal transplantation. Thus, here we focus on neurological presentations in patients receiving renal replacement therapy (for descriptions of neurological presentations in chronic kidney disease see Kelly et al)(2).

Despite the therapeutic advances of dialysis and transplantation, the well- described neurological complications of uraemia such as encephalopathy, neuropathy and myopathy remain a serious concern and can lead to functional impairment(3). Although there are changes in the spectrum of neurological disease in the transition from pre-dialysis to dialysis, a considerable proportion of chronic uraemic complications remain. The underlying reasons for this are not clear, but some have postulated the inability to clear ‘middle molecules’ (a range of toxins consisting mostly of low molecular weight peptides and proteins; 300- 12000 Kilodaltons) with standard dialysis(4). The introduction of dialysis can also lead to a number of new neurological problems in these patients (See Table 1). With progression from dialysis to renal transplantation, immunosuppressive therapy engenders a variety of neurological disturbances(5) . From our own experience, it is important to note that neurological presentations in renal

replacement therapy patients are often multifactorial, and more than one problem may need to be addressed.

NEUROLOGICAL COMPLICATIONS ASSOCIATED WITH DIALYSIS

Peritoneal Dialysis versus Haemodialysis

The majority of neurological dialysis complications are observed in both haemodialysis and peritoneal dialysis. However, those complications associated with haemodynamic instability are more likely to occur in those undergoing haemodialysis. There is also some evidence to suggest that dialysis headache is less frequent, in peritoneal dialysis, although the underlying mechanisms explaining this difference are not yet clear(6).

Table 1

Neurological complications secondary to dialysis

Central nervous system Cerebral haemorrhage Cerebral thrombosis

Central pontine myelinolysis Wernicke’s encephalopathy Dialysis Cognitive impairment

Disequilibrium syndrome Anterior ischaemic optic neuropathy Posterior reversible encephalopathy syndrome

Peripheral nervous Vascular access related nerve injury system Carpal tunnel syndrome Peripheral neuropathy

Others Haemodialysis headache Dialysis induced hypotension

Drug toxicity

Central nervous system

Cerebral haemorrhage

Intracerebral haemorrhages (ICHs) cause significant morbidity and mortality in haemodialysis patients(3). Combinations of chronic uraemia, intradialytic anticoagulation, inadequate control of hypertension and concurrent use of blood thinners such as aspirin increase the risk of haemorrhagic events. Uraemia results in platelet dysfunction as well as abnormal interactions between platelets and the vessel wall, increasing bleeding tendency(7). Haemodialysis only partly corrects this pathophysiological abnormality. Techniques used to limit systemic bleeding risk include regional anticoagulation and minimal heparin use(8). Patients who have suffered a recent ICH, are actively bleeding from another site or are at a high risk of bleeding can undergo dialysis without anticoagulation (heparin-free dialysis).

A retrospective study in our centre with over 2500 patients on maintenance haemodialysis, found the prevalence of non-traumatic subdural haemorrhage was 0.4% with an overall annual incidence of 189 per 100 000 patients(9). No association was found with comorbidities such as hypertension and diabetes, or the use of anti-platelet and anticoagulant medication(9).

Cerebral thrombosis

Cerebral venous sinus thrombosis (CVST) is a relatively uncommon neurological complication in dialysis patients. Although dialysis patients have numerous predisposing factors to develop CVST, heparin anticoagulation used with haemodialysis most likely has a protective effect. If there is any clinical suspicion of CVST, magnetic resonance imaging (MRI) venogram is the preferable imaging method(10). If diagnosis is confirmed it is advisable to communicate with the haematology team with regards to acute and long-term anticoagulation therapy as dialysis patients are at a higher risk of haemorrhagic events. If no

contraindications, we would suggest acute treatment with therapeutic dose low molecular weight heparin.

Central pontine myelinolysis

Rapid plasma osmotic fluctuations during haemodialysis can result in central pontine myelinolysis also known as osmotic demyelination syndrome (11). Patients with chronic hyponatraemia and elevated serum osmolality are more likely to develop this complication. Initial symptoms such as dysarthria, dysphagia and limb weakness can mimic a . Characteristic oedema is observed in the pons and extrapontine regions on MRI scans. Caution must be exercised with slow correction of sodium levels (6-8 mmol/day) by reducing dialysate levels of sodium and slowing rate of blood flow during dialysis(3).

Wernicke’s encephalopathy

This is a particularly challenging clinical diagnosis, given the numerous differential diagnoses related to encephalopathy in haemodialysis patients (examples include hypertensive encephalopathy, drug toxicity, electrolyte and metabolic derangement and dialysis encephalopathy)(12). Wernicke’s encephalopathy manifests due to a combination of poor nutritional state commonly observed in dialysis patients, and increased loss of water-soluble vitamins during haemodialysis. Although classically characterised by the triad of confusion, ataxia and ophthalmoplegia, atypical features such as , peripheral neuropathy and myoclonus have also been observed(13). Assessment and advice from renal-specific dieticians is prudent to improve nutritional state. There is no widely available biochemical assay which aids diagnosis, so clinicians should always consider this reversible condition in patients undergoing dialysis, and treat empirically with parenteral vitamin replacement if in any doubt.

Dialysis dementia

Dialysis-associated dementia has been described ‘as an epidemic that came and went’, with aluminium neurotoxicity widely recognised as the causative factor (14).

Cognitive impairment

An increased incidence of cognitive impairment and dementia is observed in patients with ESRD compared to the general population(15). There is evidence that cognitive impairment starts to occur once estimated glomerular filtration rate (eGFR) is less than 60ml/min and faster eGFR decline is associated with global cognitive deterioration(16). However, compared to the general population, cognitive impairment secondary to vascular disease is thought to be more prevalent than Alzheimer’s disease in haemodialysis patients(15). High rates of cardiovascular risk factors contribute to development of cerebrovascular disease. Many studies have also noted the higher prevalence of cognitive impairment in haemodialysis patients compared to peritoneal dialysis patients (17,18). Rapid fluctuations in blood pressure, electrolytes and osmolality with haemodialysis may cause cerebral ischaemic injury leading to cognitive impairment. Although peritoneal dialysis does not result in such rapid changes, the high glucose based dialysate leading to secondary metabolic disorders is thought to contribute to cognitive impairment(15).

Disequilibrium syndrome

Cerebral oedema and raised intracranial pressure have been implicated in dialysis-related disequilibrium syndrome(3). First described over 50 years ago, but now very rare, it can present in any patient undergoing haemodialysis but most commonly occurs after the first session of dialysis. Initial symptoms can range from headache, muscle twitching, restlessness and nausea. Progression of cerebral oedema can result in coma and death. The simplest method to prevent disequilibrium syndrome is to perform haemofiltration instead of haemodialysis. This ensures a reduction in the rate of change of osmolalities compared to haemodialysis as solute is removed through convection rather than diffusion. If using haemodialysis, slowly reducing blood urea concentrations, taking a gentle approach with new dialysis patients, and using high sodium containing dialysates or other osmotic agents have been recommended to reduce the risk of occurrence(19).

Anterior ischaemic optic neuropathy

Anterior ischaemic optic neuropathy can be related to haemodialysis due to vascular compromise to the prelaminar optic nerve. Risk factors such as co- existing anaemia and dialysis-induced hypotension have been linked with this condition(20).

Posterior reversible encephalopathy syndrome

Posterior reversible encephalopathy syndrome (PRES) is a neurological disorder predominantly affecting cerebral white matter and is often associated with a rapid increase in blood pressure. PRES can also, rarely, be associated with systemic autoimmune diseases such as systemic . This clinico-radiologic entity commonly presents with symptoms such as headache, visual disturbances, altered mental state and . MRI findings are essential for diagnosis and typically (but not exclusively) show vasogenic oedema in the deep white matter of the occipital and parietal lobes. Early recognition and aggressive blood pressure control is crucial in management of this reversible neurological complication to prevent permanent neurological deficits(3).

Peripheral nervous system

Peripheral nervous system disorders are often directly related to haemodialysis and can involve mono and polyneuropathies. Mononeuropathies are mainly related to creation of arteriovenous fistulae.

Vascular access related nerve injury

Surgical nerve injury related to arteriovenous fistulae can occur in the immediate post-operative period or in the more chronic setting. The proximity of the median nerve to the brachial artery makes it susceptible during formation of brachio-cephalic fistulae. Disabling median nerve compression has been reported following a haematoma and a pseudoaneurysm formation relating to surgery(21). Pseudoaneurysms form due to repeated cannulation, and rotation of puncture sites helps to avoid this. Nerve compression related to surgical arteriovenous fistulae formation should be regarded as a surgical emergency to prevent long-term disability.

Ischaemic neuropathy following arteriovenous fistulae surgery has also been shown to affect the median nerve with one study reporting the frequency ranging from 1-10%(22,23). It is thought to be a form of ‘steal phenomenon’, where the vascular access site depletes blood supply to the distal nerve causing axonal loss(23). Risk factors included diabetes and severe peripheral vascular disease. If diagnosed, distal perfusion should be established without delay and this may require closure of the arteriovenous fistulae.

Carpal tunnel syndrome

Carpal tunnel syndrome commonly occurs in haemodialysis patients. Local amyloid deposition, venous hypertension distal to the arteriovenous fistulae, uraemic damage to median nerve and increased extracellular volume leading to nerve ischaemia have been implicated(21,24). Studies comparing results of surgical treatment in idiopathic carpal tunnel syndrome and dialysis related carpal tunnel syndrome suggest that carpal tunnel syndrome recurrence, higher post operative complication rates and longer recovery are more common in dialysis related carpal tunnel syndrome compared to idiopathic carpal tunnel syndrome(25).

Peripheral neuropathy

Peripheral neuropathy related to uraemic polyneuropathy is one of the most common neurological complications associated in pre-dialysis and dialysis patients(2,3). Unfortunately haemodialysis itself rarely improves neuropathy. In milder forms patients usually report distal paraesthesiae predominantly affecting the lower limbs. Loss of vibration sense and absent ankle reflexes are found on neurological examination. More severe forms can present with weakness. Neurophysiology typically shows a length-dependent predominantly axonal mixed sensory motor neuropathy(3).

It can be difficult to differentiate uraemic neuropathy from other causes of peripheral neuropathy in dialysis patients due to likely co-existing comorbidities such as systemic vasculitis and diabetes mellitus(3). In such cases neurophysiological findings alone are insufficient to distinguish one from the

other and the clinical history plays the most useful role. For instance a rapidly progressive motor neuropathy is unlikely to be related to uraemic neuropathy.

Folic acid and B Vitamin supplementation, and the use of neuropathic pain agents can be useful as symptomatic therapy (although note risk of possible drug toxicity as below). Non-uraemic peripheral neuropathies should also be considered

Others

Haemodialysis headache

This transient headache, thought to be related to intradialytic hypotension and changes in urea and magnesium levels, is reported to frequently occur towards the end of haemodialysis sessions and has an incidence of 5%(3). It is often described as a bilateral throbbing or non-pulsating headache usually lasting less than 4 hours. Diagnostic criteria (international headache classification system) include: >2 episodes of acute headache with each episode developing during a dialysis session, worsening headache during dialysis and headache resolution within 72 hours of completing dialysis. Following successful renal transplantation the headache must completely cease.

Few studies are available to provide evidence to support specific treatments. Angiotensive converting enzyme inhibitors and magnesium supplementation have been suggested as potential therapies(26).

Dialysis induced hypotension

Symptomatic hypotension is a common intradialytic complication, and increasingly recognised as a serious problem with the increasing number of elderly and diabetic patients undergoing haemodialysis. It can result in cerebral hypoperfusion and ischaemia. Risk factors in addition to rapid ultrafiltration include cardiovascular risks. Therapeutic strategies include close supervision and monitoring by dialysis staff and pharmacological management of co-existing cardiovascular and autonomic neuropathy(27).

Drug toxicity

One of the most common causes of neurological problems in patients with renal failure (pre-dialysis and dialysis) is drug toxicity, particularly penicillins, ciprofloxacin, acyclovir, gabapentin, pregabalin, benzodiazepines and opioids as these drugs (and often their active metabolites) are renally excreted and poorly removed by dialysis, particularly if protein bound(28,29) .

For these drugs, dose adjustments are often made by reducing the dose, increasing the interval between doses, or both. It may be safe to administer drugs with a wide therapeutic index without a dose reduction, if the drug is unlikely to cause harm although the drug concentration may be higher. However, in drugs with a low therapeutic index, significant dose adjustments may be required.

In all cases an approach must be taken to determine the importance of stable serum drug concentrations, whilst monitoring for adverse effects. There are many accessible sources for reference for dose adjustments in renal failure. The Renal Dosing Database is easily accessible online (http://www.globalrph.com/index_renal.htm) and provides guidance for both renal (based on creatinine clearance) and haemodialysis dosing. If in doubt, the renal unit pharmacist is a good source for advice and guidance.

NEUROLOGICAL COMPLICATIONS RELATED TO RENAL TRANSPLANTATION

Over the past decade robust evidence suggests the superiority of renal transplantation compared to haemodialysis with improvements, both in survival and quality of life(30,31). Advances in peri-operative care, surgical techniques and postoperative management have reduced the morbidity and mortality of transplant recipients. Despite this, recipients are at a high risk of developing neurological disorders(5).

The aetiology of most post-transplant neurological disorders relates to immunosuppressive medication. Some of these, such as opportunistic infections, are well-described but in our experience these medications have a very wide range of potential toxicities, not all of which have been frequently reported in the literature.

Opportunistic CNS infections, cerebrovascular events and de novo CNS are also more frequent in this population (See Table 2). Calcineurin inhibitors are amongst the most recognised immunosuppressive drugs causing neurotoxicity with complications ranging from fine tremor to seizures. Rapid identification of the underlying disorder and disease process particularly with neuroimaging, electrodiagnostic tests (Figure 3), laboratory tests including cerebrospinal fluid (CSF) analysis to complement history and clinical findings are crucial in these patients.

Table 2 Common neurological complications related to renal transplantation

Central nervous system Infections Toxicity of immunosuppressive therapy

Posterior reversible encephalopathy syndrome

Primary CNS lymphoproliferative disease Cerebrovascular disease

Peripheral nervous Peripheral Neuropathy system Post operative nerve injury

Central nervous system

Infection

Infection is the leading cause of mortality and morbidity in renal transplant patients and most common in the first 12 months following transplantation(32). Early diagnosis and treatment is crucial. Effects of immunosuppressive therapy often hinder the manifestation of typical signs and symptoms, leading to changes in presentation and difficulty in diagnosis. Hence the threshold for suspecting CNS infection in transplant patients must be lower than in the immunocompetent patient, and these must be differentiated from CNS vasculitis

or systemic lupus erythematosus (SLE) in patients with systemic forms of these diseases (whether or not they have previously had CNS involvement).

The most reliable symptom suggestive of CNS infection in the transplant patient is headache in the presence of an unexplained fever. Altered mental status, focal neurological signs and meningism may be suppressed by the anti-inflammatory properties of immunosuppressive medications. All recipients presenting with any of these symptoms should have an MRI scan with gadolinium contrast followed by lumbar puncture (provided no contraindications). Magnetic resonance imaging is the most sensitive modality to demonstrate leptomeningeal enhancement, cerebritis, hydrocephalus and abscesses(33).

Time frame post-transplant is an important factor relating to CNS infection susceptibility. In the first month, opportunistic pathogens such as gram-negative , staphylococcal species, Aspergillus fumigatus and Mycobacterium tuberculosis are common. There is always potential for CNS infections to be transmitted from donor to recipient, and although rare, clinicians must be aware of such occurrences.

Between one and six months, at peak levels of immunosuppression, there is increased susceptibility to organisms such as Cytomegalovirus (CMV), Epstein- Barr (EBV), Human herpes and atypical bacterial organisms such as Listeria monocytogenes(34). In this intermediate post transplant period, infections can precipitate organ rejection leading to a vicious cycle of increasing immunosuppressive therapy to prevent rejection, in turn precipitating difficulty controlling the infective process.

After 6 months there is generally a decreased risk of CNS infection with most cases reported as Cryptococcus neoformans, EBV and JC virus(34).

Neuroimaging with MRI is crucial in diagnosis. Aspergillus and Toxoplasma commonly present as mass lesions with ring enhancement. CNS aspergillosis is also often associated with haemorrhagic cerebral infarction as well as pulmonary involvement. Listeria and Cryptococcus, Epstein-Barr virus and Varicella-zoster virus most commonly are responsible for meningeal enhancement whilst CMV causes ventricular enhancement(34).

In addition to neuroimaging, lumbar puncture is also critical in establishing diagnosis. We suggest sending CSF for microbiology, culture and sensitivities, protein level, glucose (CSF and blood) level, extended viral PCR, cytology, Cryptococcal antigen, TB PCR, Bacterial 16S rDNA-PCR and an adequate sample for storage in the event further tests are required.

Cerebrospinal fluid PCR is sensitive and specific for organisms such as EBV, CMV, VZV and JC virus. Positive CSF culture is more useful in diagnosis of Cryptococcus neoformans and Mycobacterium tuberculosis.

Whilst investigating the rapidly deteriorating patient, we suggest empirical treatment with Ceftriaxone and Acyclovir and would recommending discussion with the infectious diseases and/or microbiology before and after initial test results are available.

Table 3

Organisms responsible for CNS infections in transplant patents and treatment options Organism Microbial therapy options

Bacterial Listeria monocytogenes Ampicillin + Gentamycin Ampicillin + Ceftriaxone + Vancomycin Cryptococcus Amphotericin B + neoformans Fluconazole/Flucytosine

Nocardia Asteroides Trimethoprim/sulfamethoxazole Toxoplasma gondii Pyrimethamine, Sulfadiazine + Folinic acid Mycobacterium Rifampicin, Isoniazid, Ethambutalol + Tuberculosis Pyridoxine, Amikacin, Dexamethasone

Viral Varicella Zoster Acyclovir

Human herpes virus 6 Ganciclovir Herpes simplex Acyclovir

Cytomegalovirus Ganciclovir/foscarnet Epstein-Barr Virus (No antiviral treatment available)

Fungal Aspergillus fumigatus Amphotericin B/fluconazole Histoplasma Itraconazole +- Amphotericin B capsulatum

Parasitic Strongyloides steroralis Ivermectin

Toxicity of immunosuppressive therapy

Numerous immunosuppressive drugs are used following transplantation to prevent organ rejection and these are associated with a number of neurotoxic effects (Table 4). Sudden exposure of the nervous system to toxic substances and the narrow therapeutic window increases the risk of neurotoxicity. Protocols for both induction and maintenance of immunosuppression vary according to centres with most using a combination of 1) glucocorticoids and calcineurin inhibitors or purine synthesis inhibitors or 2) monoclonal and calcineurin inhibitors.

The most well recognised neurotoxic effects are documented with calcineurin inhibitors expressed in several areas of the brain (35,36). A majority of transplant recipients suffer from mild neurological symptoms especially in the first few weeks following initiation of therapy. Common symptoms include fine resting and action tremors, headaches, paraesthesia and mood changes. More serious symptoms can include seizures, ataxia and motor deficits.

In our centre tacrolimus is the most commonly used immunosuppressive agent. The commonest neurotoxic side effects we have noticed are fine resting and action tremors. Drug level monitoring is important due to the narrow therapeutic index. Although many side effects are dose related, in our experience drug levels are not always raised even if there is clinical toxicity (See Figure 2).

Table 4

Immunosuppressive medication and common associated neurotoxic effects

Class Common neurotoxic effects Corticosteroids Acute - Insomnia, mood changes, , delirium Chronic – Proximal myopathy Purine synthesis inhibitors Usually none, rarely headache

Calcineurin inhibitors PRES, akinetic mutism, toxic encephalopathy, seizures

Headache, tremor, paraesthesia, mood changes

Antimetabolites, Target of rapamycin inhibitors and biologic agents are only rarely associated with neurotoxic effects (see Figure 2)

Posterior reversible encephalopathy syndrome

PRES (See section above) is also a complication of immunosuppressive therapy and can lead to permanent neurological deficits if misdiagnosed or inadequately managed(37). Neurotoxic effects of calcineurin inhibitors resulting in PRES may occur at therapeutic drug levels and even in the absence of hypertension. In most cases reducing dose or withdrawal of the offending immunosuppressive therapy (and control of any further exacerbating factor (e.g. hypertension)) can prevent permanent impairment. Electrolyte monitoring and replacement (including magnesium), treatment of hypertension and acute renal failure and supportive therapy are the mainstays of management. In the acute setting anti-epileptic drugs may be required(38).

Primary CNS lymphoproliferative disease

Post-transplant lymphoproliferative disease is a well-known complication developing in immunosuppressed transplant recipients. The vast majority are B- Cell phenotype, which are EBV driven. Patients commonly present with headaches, seizures, altered mental state and examination may reveal focal neurological deficits.

Both the type and level of immunosuppression are associated with risk in developing this disorder. One study showed, compared to the general public,

renal transplant recipients have been reported to have a relative risk of 12.6 of developing post-transplant lymphoproliferative disease (39). Treatment with anti-thymocyte globulin or Muromonab-CD3 for induction, or as an agent to prevent acute rejection, has been shown to increase post-transplant lymphoproliferative disease risk by approximately 9-fold(39) . Treatment with calcineurin inhibitors increased the risk approximately two fold(39).

Although post-transplant lymphoproliferative disease can affect any organ, CNS involvement has been reported in 10-15% of cases (39) . Additionally CNS lymphoma was found to be more common following renal transplantation compared to heart and lung transplant recipients. Prognosis largely depended of extent of disease dissemination and 5-year survival was 38%(40).

Cerebrovascular disease

Cardiovascular and cerebrovascular disorders remain the leading cause of mortality resulting in ‘death with a functioning allograft’(41). Most studies report an increased risk of ischaemic stokes compared to haemorrhagic but mortality is higher with haemorrhagic events(42,43). Risk factors for haemorrhagic stroke include diabetes mellitus, polycystic kidney disease (PKD), left ventricular hypertrophy and high systolic blood pressure(42).

A retrospective analysis of over 1000 patients from our unit found that that 4.53% of individuals who received a kidney alone or a simultaneous pancreas and kidney transplant had a stroke post-transplant(41). Predictors of stroke were age, diabetes, corticosteroid use and simultaneous pancreas and kidney transplant.

Transplant specific risk factors for stroke were identified as graft failure, immunosuppression, long duration on dialysis pre-transplant, and deceased donor transplantation(41). However, it has been observed that transplant leads to an overall improvement in cerebrovascular risk compared to dialysis patients(43).

Peripheral nervous system

Neuropathy

Peripheral nerves are susceptible to the toxic effects of immunosuppressive medication due to the absence of protective mechanisms such as the blood-brain barrier. An Australian study demonstrated abnormalities in nerve function induced by calcineurin inhibitors(44). A higher prevalence of clinical manifestations of neuropathy were noted in the calcineurin inhibitor therapy group (68%) compared to the calcineurin inhibitor free-group (37%,) where sirolimus and mycophenolate were used in combination or either as monotherapy. Further there were significant differences in nerve excitability parameters suggestive of membrane depolarisation.

Neuropathy could also be due to pre-existing uraemia related nerve damage or as a new manifestation due to graft failure related uraemia. It can often be difficult to differentiate between uraemic neuropathy and calcineurin inhibitor induced peripheral neuropathy. In our experience with uraemic neuropathy, motor symptoms and signs tend to only occur when uraemic neuropathy is very advanced.

Post-operative nerve injury

Sensory and motor impairment following renal transplantation is relatively common with lateral cutaneous nerve of the thigh and femoral nerves mostly affected(45).

Instrument related injury is likely the most common explanation even though the surgical site is usually distant from the path of lateral cutaneous nerve of the thigh and femoral nerves. Postoperative haematoma and compression due to retractors can also cause nerve palsy. Local steal syndrome resulting in femoral nerve ischaemia has also been postulated in acute femoral nerve palsy(46). These changes are usually temporary.

Useful neurological investigations is renal dialysis and transplant patients

In these susceptible groups of patients, early identification and prompt treatment of the disease process is crucial. Particularly with immunosuppressed

patients, symptoms and signs may be masked due to therapy and there must a low threshold for diagnostic investigations (Table 5).

Table 5

Neurological investigations in renal dialysis and transplant patients Investigations Indication

Imaging

Computed tomography Unwell patient in acute setting

Magnetic resonance imaging Stroke Suspected CNS infections or focal lesion

Encephalopathy

Primary CNS malignancy

Ultrasound Doppler Suspected ischaemic neuropathy

Electrophysiological tests Electroencephalogram Encephalopathy Episodic confusion Nerve conduction studies Suspected mononeuropathy or polyneuropathy

Fatiguable weakness (Repetitive nerve stimulation) Electromyography Suspected myopathy or Neuromuscular junction pathology

Computed tomography and magnetic resonance imaging MRI is the most useful diagnostic investigation in early detection of cerebrovascular disease in dialysis and transplant patients, and is the preferred imaging modality.

Patients receiving dialysis treatment should be scheduled to undergo dialysis as soon as practical, preferably within 24 hours following administration of

gadolinium contrast. In transplant patients, creatinine levels should be closely monitored and in event of acute deterioration of renal function, provisions for haemodialysis or haemofiltration should be in place. The development of nephrogenic systemic sclerosis is rare and not usually seen with the newer forms of gadolinium(47). It should be noted that a large number of patients with chronic kidney disease have significant cerebral small vessel disease.

MRI however has many limitations, particularly in the acutely unwell and restless patient. These include scanner availability and image degradation due to movement artefact. In these situations CT is very useful to rule out cerebral haemorrhages, hydrocephalus and space occupying lesions. CT arteriograms and venograms are also useful for acute vascular imaging and in the diagnosis of venous sinus thrombosis (Figure 1).

Electroencephalogram

Electroencephalogram (EEG) can be helpful in patients with impaired consciousness or altered mental status and is particularly of use in early detection of dialysis dementia, metabolic encephalopathy associated with renal failure and seizures occurring in severe encephalopathy(48) . Triphasic waves and diffuse slow activity are observed in such encephalopathies (48). In acute uraemic encephalopathy, EEG changes are usually more severe and may help to distinguish from -related impairment of consciousness (48). Correlations between degree of EEG slowing and level of serum creatinine may also be seen (48).

Lumbar puncture Cerebrospinal fluid analysis is useful in patients with new-onset severe headache, altered mentation, seizures and essential in the accurate diagnosis of CNS infections and malignancies. In many dialysis patients with altered mental state and no fever, lumbar puncture will not be necessary as clinical improvement usually develops within 48 hours. Intracranial hypotension secondary to haemodialysis can be confirmed by measuring CSF pressure. CSF in uraemia may be abnormal with a pleocytosis and raised protein level in approximately 50% of patients(49). History, examination and investigations

need to be considered in the interpretation of abnormal CSF results (for instance when distinguishing uraemic encephalopathy from a CNS infection). Although there is theoretical increased risk associated with lumbar puncture because of bleeding tendency, we have not experienced this, and recommend prompt LP when indicated.

Nerve conduction studies and Electromyography

Uraemic neuropathy is predominantly axonal, although sensory and motor conduction velocities are often reduced. With chronic renal failure a Guillain- Barre type of neuropathy can be observed with conduction block, conduction slowing and prolonged F wave latencies. Electromyography with uraemic myopathy is usually normal.

Conclusion

Numerous neurological complications are induced by dialysis and renal transplantation. Neurological manifestations occur in both the central and peripheral nervous systems resulting in morbidity and mortality. It is likely that dialysis-specific complications are underreported compared to transplant related complications. This is most likely due to the closer monitoring of transplant recipients by physicians. Clinicians should recognise that symptoms that may be perceived to be less alarming, such as headache or commonly reported by haemodialysis patients, may be an early warning sign of more serious complications. Nephrologists will appreciate the difficulty and frustration of patients on haemodialysis reporting ‘aches, pains and headaches’ and in identifying which patients to examine more thoroughly.

Following transplantation a majority of neurological complications are related to immunosuppressive therapy. It is important to be aware that agents even at therapeutic levels result in neurotoxicity.

A close relationship between nephrologists and neurologists is critical to effectively deal with neurological complications in these vulnerable and susceptible groups of patients. Early identification of the disease process and rapid treatment is crucial to ensure a good long-term outcome.

Learning points

1. Immunosuppressive medications often have a narrow therapeutic index. Drug levels may not always be raised even with evidence of clinical toxicity. 2. Neurological presentations in renal replacement therapy patients are often multifactorial, and more than one problem may need to be addressed. 3. Unless contraindicated magnetic resonance imaging is the preferred modality of neuroimaging for these groups of patients. 4. A healthy working relationship between neurologists and nephrologists is crucial to diagnose and effectively manage these patients.

LEGENDS

Legend to Figure 1a CT venogram from a 53-year-old man with an ABO incompatible renal transplant presented with a sudden onset occipital headache. Plain CT did not show any clear abnormality, but CSF opening pressure was 47cm CSF. There is thrombus at the junction of the left transverse and sigmoid sinuses

Legend to Figure 1b Thrombus in the inferior superior sagittal sinus (in the same patient)

Legend to Figure 2 Abnormal EEG (Predominantly anterior spike and wave) in an encephalopathic transplant patient on tacrolimus (therapeutic levels). Other causes of encephalopathy were ruled out and she recovered after tacrolimus was replaced with sirolimus.

Legend to Figure 3 Repetitive nerve stimulation with recording from abductor digiti minimi in a 65 year old patient with fatiguable ocular and limb weakness which developed 12 months after renal transplant which was carried with alemtuzumab induction. Acetylcholine receptor antibodies were negative. There is a clear decrement of responses to repeated stimulation at 2 Hz (Panel A) and 3Hz (Panel B). Stimulation single fibre EMG of Orbicularis oculi showed increased mean jitter (MCD 36 usec) and 10% blocking.. The patient responded well to pyridostigmine. Alemtuzumab is associated with autoimmune complications and myasthenia has previously been reported one year following renal transplant with Alemtuzumab induction (50).

.

Legend to Table 2 CNS, central nervous system

Legend to Table 4 PRES, posterior reversible encephalopathy syndrome

Legend to Table 5 CNS, central nervous system;

CONTRIBUTORSHIP

KK wrote the first draft. DT, RP and NK contributed in the writing of the paper. PM contributed to writing and final approval of the paper.

ACKNOWLEDGEMENTS

This work is supported by the National Institute for Health Research (NIHR) Imperial Biomedical Research Centre. Thanks to Dr Gemma Dawe for her help with the Figures.

CONFLICTS OF INTEREST

None

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