Keywords: Chronic kidney disease, dialysis, encephalopathy, neurology
Chronic kidney disease (CKD) is a critical and rapidly growing global health problem. Neurological complications occur in almost all patients with severe CKD, potentially affecting all levels of the nervous system, from the central nervous system (CNS) through to the peripheral nervous system (PNS). Cognitive impairment, manifesting typically as a vascular dementia, develops in a considerable proportion of patients on dialysis, and improves with renal transplantation. Patients on dialysis are generally weaker, less active, and have reduced exercise capacity compared with healthy individuals. Peripheral neuropathy manifests in almost all such patients, leading to weakness and disability. Better dialysis strategies and dietary modification could improve outcomes of transplantation if implemented before surgery. Patients with CKD exhibit tremendously high levels of symptomatic and occult cerebrovascular disease and associated inflammatory factors, high homocysteine levels, anemia, hypertension, and diabetes.,,, As these risk factors overshadow aging and nonvascular factors, patients with CKD represent a potential model of accelerated vascular cognitive impairment. In this article, the disease-related and treatment-related neurological complications of renal disorders will be reviewed.
With the introduction of dialysis and renal transplantation, the spectrum of neurological complications has changed. Dialytic therapy or kidney transplantation has also induced neurological complications. Dialysis dementia, dialysis dysequilibrium syndrome, hypertensive encephalopathy, and cerebrovascular accident caused by ultrafiltration-related arterial hypotension can occur as a direct consequence of dialysis. Furthermore, dialysis is associated with aggravation of atherosclerosis and can contribute to the development of Wernicke's encephalopathy, hemorrhagic stroke, subdural hematoma, osmotic myelinolysis, opportunistic infections, intracranial hypertension, and neuropathy. Neurological complications related to treatment of renal failure have a wide spectrum of manifestations [Table 1].
Manifestations of neurologic dysfunction may occur as a direct consequence of the uremic state, its treatment, or both. As therapeutic options for renal failure have grown, so has the spectrum of neurologic complications related to kidney transplantation and the use of immunosuppressant medications. Neurologic complications of renal failure can involve the CNS, PNS, or both.
In patients with renal failure, encephalopathy is a common problem that may be caused by uremia, thiamine deficiency, dialysis, transplant rejection, hypertension, fluid and electrolyte disturbances, or drug toxicity. In general, encephalopathy presents with a symptom complex progressing from mild sensorium clouding to delirium and coma [Table 2].
Acute disturbances in cognitive function are often related to metabolic abnormalities common in patients with renal disease. Electrolyte disturbances, such as hypercalcemia, hypophosphatemia, hyponatremia, and hypermagnesemia, can produce CNS depression with encephalopathy as the major clinical manifestation. Correction of the underlying metabolic abnormality typically leads to resolution of symptoms. Uremic encephalopathy may accompany acute or chronic renal failure; however, in patients with acute renal failure, the symptoms are generally more pronounced and progress more rapidly. In addition to the general symptom complex of encephalopathy, focal motor signs and the “uremic twitch-convulsive” syndrome may also be seen., Wernicke's encephalopathy typically presents with the triad of ophthalmoplegia, ataxia, and cognitive symptoms or with disturbances of consciousness. Wernicke's encephalopathy in uremic patients is rare but hemodialysis patients are especially at risk, not only due to their lower thiamine intake but probably also because of an accelerated loss of thiamine during the procedure.,
Patients with CKD are at an increased risk of ischemic and hemorrhagic stroke. The magnitude of relative risk is estimated to be between four-folds and ten-folds when patients with CKD are compared to those without CKD. The risk of hemorrhagic stroke, including subdural, intraparenchymal, and subarachnoid hemorrhage, is increased in patients with renal disease. Qualitative platelet dysfunction with altered aggregability resulting from the uremic state leads to an increase in bleeding tendency. However, Krishna et al., studied a total of 1369 patients of CKD and concluded that, out of 1369 CKD patients studied in the 2-year period from December 2004 to December 2006, stroke was found to be more frequent in males and in the middle age groups. Hypertension, anemia, and diabetes were found to be important risk factors for stroke. Brain infarcts were more prevalent than brain hemorrhage. Active management improved the outcome in 62.9% of the patients. All those patients who succumbed developed hemorrhage, an observation that highlights the sinister significance of hemorrhage in CKD patients. Therefore, clinicians should have a high index of suspicion for CKD in stroke patients.
Recent studies have described a graded, cross-sectional association between estimated glomerular filtration rate (eGFR) or proteinuria (albumin/creatinine ratio = 30 mcg/mg) and brief cognitive screening tests, tests of specific cognitive domains, or dementia.,, Longitudinal analyses have measured the relation between eGFR and dementia, or incident cognitive decline on the Modified Mini-Mental State (3MS) examination., None had measured the effect of eGFR on the rate of cognitive decline globally, using a detailed cognitive battery, and also the effect of eGFR within multiple cognitive domains. In the Rush Memory and Aging Project (n = 886 community-dwelling adults without dementia; mean age 80.6 years), a lower eGFR (eGFR = 60 mL/min/1.73 m2) or having CKD was associated with a rapid rate of global cognitive decline over approximately 3.4 years.
Neurological infections in patients with renal failure mainly present as acute, subacute, or chronic meningitis, encephalitis, myelitis, or brain abscess., Opportunistic bacterial infections include pathogens such as Nocardia asteroides, Mycobacterium tuberculosis, and Listeria monocytogenes. Fungi are often represented by Cryptococcus neoformans, Aspergillus fumigatus, Candida, Pneumocystis carinii, Histoplasma, Mucor, and Paracoccidioides species. Reactivation of latent viral infection with herpes simplex, cytomegalovirus, and JC (John Cunnigham) polyomavirus are not uncommon., Infection with cytomegalovirus is the most frequent opportunistic infection following renal transplantation. It is usually asymptomatic; however, invasive forms with meningitis, encephalitis, myelitis, and involvement of nerve roots can develop. Reactivation of the JC polyomavirus and infection of oligodendrocytes results in progressive multifocal leukoencephalopathy.
Action myoclonus and stimulus-sensitive myoclonus have been described in uremic encephalopathy. In addition, a “twitch-convulsive” syndrome consisting of intense asterixis and myoclonic jerks accompanied by fasciculations, muscle twitches, and seizures has been described. Restless leg syndrome occurs in approximately 15–20% of patients with CKD. Drug-induced involuntary movements in patients with chronic renal failure are more frequently seen in patients after a kidney transplantation. Neurotoxic effects of immunosuppressive agents such as cyclosporine and tacrolimus may manifest as tremors or as other extrapyramidal signs.
Osmotic myelinolysis in patients with renal failure mainly occurs within the central basis pontis; however, extrapontine regions including the midbrain, thalamus, basal nuclei, and cerebellum can be affected as well. Osmotic myelinolysis after rapid correction of prolonged hyponatremia—or less frequent hypernatremia—by dialysis is a known problem.
The peripheral nerves are susceptible to compression and local ischemia in patients with renal disease. The ulnar, median, and femoral nerves are most often affected. A compressive ulnar neuropathy in the Guyon canal can occur by uremic tumoral calcinosis at the wrist. A compressive median neuropathy at the wrist in the carpal tunnel is common. Clinical manifestations include weakness of the thenar groups with associated atrophy. Sensory symptoms include burning pain and paresthesias involving the ventral surface of the hand and the lateral three digits and the lateral border of the fourth digit.
The adverse effects of CKD on the PNS are minimal as long as the glomerular filtration rate exceeds roughly 12 mL/min. At glomerular filtration rates below this value, nerve conduction studies become abnormal, and the patients begin to demonstrate clinical signs of peripheral nerve dysfunction when the glomerular filtration rate of about 6 mL/min is reached. Babu et al., studied patients with CKD and concluded that, CKD was found to cause peripheral neuropathy, including overt and subclinical neuropathy, of which distal symmetrical sensory motor neuropathy was the commonest in CKD. The prevalence of peripheral neuropathy was directly proportional to the duration and severity of CKD. Uremic polyneuropathy occurs in approximately 60% of the patients with chronic renal failure. Both large and small fiber peripheral neuropathies in addition to cranial neuropathies have been described. Uremic neuropathy may stabilize or even improve during chronic dialysis. Paresthesias may improve rapidly after the initiation of hemodialysis, but other symptoms may persist. Renal transplantation can result in recovery from uremic neuropathy through remyelination if significant axonal loss has not occurred. Improvement after supplementation with biotin, pyridoxine, cobalamin, and thiamine has been reported.,
Uremic myopathy usually appears in patients with a glomerular filtration rate under 25 mL/min and its progression parallels the decline of renal function. The overall prevalence is estimated at 50% in patients undergoing dialysis. It manifests as proximal limb weakness, with muscle wasting, limited endurance, exercise limitation, and rapid fatigability. Decreased clearance of the uremic toxins, disorders of vitamin D metabolism, insulin resistance, carnitine deficiency, and malnutrition have been proposed as possible pathophysiologic mechanisms for uremic myopathy.,
Thrombotic microangiopathy (TMA) is a well-recognized and a serious complication of renal transplantation. Renal ischemia by itself is an initiating event for the development of TMA. Prolonged ischemia is a proapoptotic factor and endothelial cells acquire procoagulant properties upon activation of apoptosis. The time from transplantation to diagnosis of TMA is variable; it has been reported to vary between a few days to years after transplantation, suggesting that different mechanisms are involved. TMA may occur de novo in the transplanted kidney without previous history of TMA as a cause of end-stage renal disease (ESRD). Calcineurin inhibitors, humoral (C4b positive) rejection, ischemia, and less frequently, viral infections, are all proposed etiological factors. The clinical presentation of posttransplantation TMA is variable; it often manifests clinically as the hemolytic uremic syndrome (HUS), with classical findings of renal failure, hemolytic anemia, schistocytes, and thrombocytopenia, with worsening renal function or delayed graft function (DGF). Literature review reveals a spectrum of TMA neuroimaging findings including parenchymal hematoma, posterior reversible encephalopathy syndrome (PRES), ischemic infarction, and venous thrombosis, with a case report also reporting multifocal hemorrhagic infarctions.
Neurological side effects of immunosuppressive drugs
Side effects relating to immunosuppressive therapy, especially cyclosporine, are some of the most common neurological problems encountered in the transplant recipient [Table 3]. Some 15–40% of the patients receiving cyclosporine experience neurological side effects. Higher blood concentrations of cyclosporine are associated with an increased risk of complications, although the correlation is not a close one, and metabolites which are not assayed may also be important. More recently, a reversible posterior leukoencephalopathy syndrome has been described in a heterogeneous group of patients, including those undergoing renal, liver, and bone marrow transplantation and immunosuppressive treatment with either tacrolimus (FK506) or cyclosporine.
Neurological complications have a major impact on the final outcome of patients with renal disorders. It is of paramount importance to vigilantly diagnose and manage such neurological complications in patients with renal disorders. Even with all the modern modalities of treatment, most of the neurological complications of dialysis fail to respond to dialysis and some are even aggravated after performing dialysis or transplantation.
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[Table 1], [Table 2], [Table 3]