Neurological complications in chronic kidney disease patients

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Abstract

Chronic kidney disease (CKD) is associated with a high prevalence of cerebrovascular disorders such as stroke, white matter diseases, intracerebral microbleeds and cognitive impairment. This situation has been observed not only in end-stage renal disease patients but also in patients with mild or moderate CKD. The occurrence of cerebrovascular disorders may be linked to the presence of traditional and non-traditional cardiovascular risk factors in CKD. Here, we review current knowledge on the epidemiological aspects of CKD-associated neurological and cognitive disorders and discuss putative causes and potential treatment. CKD is associated with traditional (hypertension, hypercholesterolaemia, diabetes etc.) and non-traditional cardiovascular risk factors such as elevated levels of oxidative stress, chronic inflammation, endothelial dysfunction, vascular calcification, anaemia and uraemic toxins. Clinical and animal studies indicate that these factors may modify the incidence and/or outcomes of stroke and are associated with white matter diseases and cognitive impairment. However, direct evidence in CKD patients is still lacking. A better understanding of the factors responsible for the elevated prevalence of cerebrovascular diseases in CKD patients may facilitate the development of novel treatments. Very few clinical trials have actually been performed in CKD patients, and the impact of certain treatments is subject to debate. Treatments that lower LDL cholesterol or blood pressure may reduce the incidence of cerebrovascular diseases in CKD patients, whereas treatment with erythropoiesis-stimulating agents may be associated with an increased risk of stroke but a decreased risk of cognitive disorders. The impact of therapeutic approaches that reduce levels of uraemic toxins has yet to be evaluated.

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A trial of darbepoetin alfa in type 2 diabetes and chronic kidney disease.

Marc Pfeffer, Emmanuel A. Burdmann, Chao-Yin Chen … (2009)

Anemia is associated with an increased risk of cardiovascular and renal events among patients with type 2 diabetes and chronic kidney disease. Although darbepoetin alfa can effectively increase hemoglobin levels, its effect on clinical outcomes in these patients has not been adequately tested. In this study involving 4038 patients with diabetes, chronic kidney disease, and anemia, we randomly assigned 2012 patients to darbepoetin alfa to achieve a hemoglobin level of approximately 13 g per deciliter and 2026 patients to placebo, with rescue darbepoetin alfa when the hemoglobin level was less than 9.0 g per deciliter. The primary end points were the composite outcomes of death or a cardiovascular event (nonfatal myocardial infarction, congestive heart failure, stroke, or hospitalization for myocardial ischemia) and of death or end-stage renal disease. Death or a cardiovascular event occurred in 632 patients assigned to darbepoetin alfa and 602 patients assigned to placebo (hazard ratio for darbepoetin alfa vs. placebo, 1.05; 95% confidence interval [CI], 0.94 to 1.17; P=0.41). Death or end-stage renal disease occurred in 652 patients assigned to darbepoetin alfa and 618 patients assigned to placebo (hazard ratio, 1.06; 95% CI, 0.95 to 1.19; P=0.29). Fatal or nonfatal stroke occurred in 101 patients assigned to darbepoetin alfa and 53 patients assigned to placebo (hazard ratio, 1.92; 95% CI, 1.38 to 2.68; P<0.001). Red-cell transfusions were administered to 297 patients assigned to darbepoetin alfa and 496 patients assigned to placebo (P<0.001). There was only a modest improvement in patient-reported fatigue in the darbepoetin alfa group as compared with the placebo group. The use of darbepoetin alfa in patients with diabetes, chronic kidney disease, and moderate anemia who were not undergoing dialysis did not reduce the risk of either of the two primary composite outcomes (either death or a cardiovascular event or death or a renal event) and was associated with an increased risk of stroke. For many persons involved in clinical decision making, this risk will outweigh the potential benefits. (ClinicalTrials.gov number, NCT00093015.) 2009 Massachusetts Medical Society

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Phosphate regulation of vascular smooth muscle cell calcification.

S Jono, M McKee, C Murry … (2000)

Vascular calcification is a common finding in atherosclerosis and a serious problem in diabetic and uremic patients. Because of the correlation of hyperphosphatemia and vascular calcification, the ability of extracellular inorganic phosphate levels to regulate human aortic smooth muscle cell (HSMC) culture mineralization in vitro was examined. HSMCs cultured in media containing normal physiological levels of inorganic phosphate (1.4 mmol/L) did not mineralize. In contrast, HSMCs cultured in media containing phosphate levels comparable to those seen in hyperphosphatemic individuals (>1.4 mmol/L) showed dose-dependent increases in mineral deposition. Mechanistic studies revealed that elevated phosphate treatment of HSMCs also enhanced the expression of the osteoblastic differentiation markers osteocalcin and Cbfa-1. The effects of elevated phosphate on HSMCs were mediated by a sodium-dependent phosphate cotransporter (NPC), as indicated by the ability of the specific NPC inhibitor phosphonoformic acid, to dose dependently inhibit phosphate-induced calcium deposition as well as osteocalcin and Cbfa-1 gene expression. With the use of polymerase chain reaction and Northern blot analyses, the NPC in HSMCs was identified as Pit-1 (Glvr-1), a member of the novel type III NPCs. These data suggest that elevated phosphate may directly stimulate HSMCs to undergo phenotypic changes that predispose to calcification and offer a novel explanation of the phenomenon of vascular calcification under hyperphosphatemic conditions. The full text of this article is available at http://www.circresaha.org.

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Low glomerular filtration rate and risk of stroke: meta-analysis

Meng-Luen Lee, Jeffrey L Saver, Kuo-Hsuan Chang … (2010)

Objective To qualitatively and quantitatively investigate the link between a low estimated glomerular filtration rate (eGFR) at baseline and risk of future stroke. Design Systematic review and meta-analysis of prospective studies. Data sources PubMed (1966-October 2009) and Embase (1947-October 2009). Selection criteria Inclusion criteria were studies that prospectively collected data within cohort studies or clinical trials, estimated glomerular filtration rate at baseline using the modification of diet in renal disease or Cockcroft-Gault equations, assessed incident stroke, had a follow-up of at least one year, and reported quantitative estimates of multivariate adjusted relative risk and 95% confidence interval for stroke associated with an eGFR of 60-90 ml/min/1.73 m2 or <60 ml/min/1.73 m2. Data abstraction Two investigators independently abstracted data from eligible studies. Estimates were combined using a random effects model. Heterogeneity was assessed by P value of χ2 statistics and I2. Publication bias was assessed by visual examination of funnel plots. Results 21 articles derived from 33 prospective studies: 14 articles assessed eGFR <60 ml/min/1.73 m2 and seven assessed eGRF at both <60 ml/min/1.73 m2 and 60-90 ml/min/1.73 m2 for a total of 284 672 participants (follow-up 3.2-15 years) with 7863 stroke events. Incident stroke risk increased among participants with an eGFR <60 ml/min/1.73 m2 (relative risk 1.43, 95% confidence interval 1.31 to 1.57; P<0.001) but not among those with an eGFR of 60-90 ml/min/1.73 m2 (1.07, 0.98 to 1.17; P=0.15). Significant heterogeneity existed between estimates among patients with an eGFR <60 ml/min/1.73 m2 (P<0.001). In subgroup analyses among participants with an eGFR <60 ml/min/1.73 m2, heterogeneity was significant in Asians compared with non-Asians (1.96, 1.73 to 2.23 v 1.25, 1.16 to 1.35; P<0.001), and those with an eGFR of 40-60 ml/min/1.73 m2 v <40 ml/min/1.73 m2 (1.28, 1.04 to 1.56 v 1.77, 1.32 to 2.38; P<0.01). Conclusions A baseline eGFR <60 ml/min/1.73 m2 was independently related to incident stroke across a variety of participants and study designs. Prompt and appropriate implementation of established strategies for reduction of vascular risk in people with know renal insufficiency may prevent future strokes.