Cognitive impairment in the aging dialysis and chronic kidney disease populations: an occult burden

The high burden of cognitive impairment in hemodialysis and chronic kidney disease (CKD) patients has only recently become recognized. Up to 70% of hemodialysis patients aged 55 years and older have moderate to severe chronic cognitive impairment, yet it is largely undiagnosed. Recent studies describe the strong graded relation between estimated glomerular filtration rate and cognitive function in CKD patients. The process of conventional hemodialysis may induce recurrent episodes of acute cerebral ischemia, which, in turn, may contribute to acute decline in cognitive function during dialysis. Thus, the worst time to communicate with dialysis patients may be during the hemodialysis session. Both symptomatic and occult, subclinical ischemic cerebrovascular disease appears to play a large role in a proposed model of accelerated vascular cognitive impairment in these populations. Severe cognitive impairment or dementia among hemodialysis patients is associated with an approximately 2-fold increased risk of both mortality and dialysis withdrawal. Predialysis cognitive screening and adding dementia to the list of comorbidities on Form 2728 would provide critical information regarding the benefit versus risks of receiving dialysis. It could also improve quality of care and outcomes by raising clinicians' awareness of the potential effects of cognitive impairment on medication, fluid, and dietary compliance and the ability to make advance directive decisions among dialysis patients. Although much remains to be learned regarding the pathophysiology of cognitive impairment in kidney disease, the public health implications of this substantial burden are immediate.     

Epidemiology and prevention of cardiovascular complication in chronic kidney disease patients

The risk for cardiovascular disease is significantly higher among patients with chronic kidney disease (CKD) than among the general population, considering that cardiovascular disease is the prominent cause of both morbidity and mortality in dialysis patients. This is explained mainly by the considerable prevalence of cardiovascular risk factors among CKD patients since the earliest stages of renal impairment, which include not only the so-called traditional risk factors, but also a number of additional risk factors that are specific to CKD and to the dialytic treatment itself. Considering the multiplicity of cardiovascular risk factors operating in CKD patients, as well as the crucial impact of their cardiovascular condition on long-term outcome, it is mandatory that all the available interventions aimed at the correction of all the modifiable risk factors for cardiovascular disease are performed as early as possible in the progression of the disease. In particular, the results of several controlled clinical trials have shown that a timely correction of anemia and of calcium-phosphate disorders leads to a significant improvement in the cardiovascular conditions of CKD patients. Evidence also is growing regarding the benefits of intervention of newly recognized risk factors for cardiovascular disease such as inflammation and oxidant stress.     

Anemia and the heart in chronic kidney disease

Cardiovascular disease is highly prevalent at all stages of chronic kidney disease (CKD) and is the leading cause of morbidity and mortality. Individuals with CKD commonly have multiple risk factors for the development of cardiovascular disease, including both traditional and nontraditional risk factors. Anemia is a nontraditional cardiovascular risk factor found in CKD that contributes to the development and progression of structural abnormalities of the heart, namely left ventricular hypertrophy and dilation. In addition, a deficiency of erythropoietin per se also may have important pathophysiologic consequences. In this review we summarize the evidence from observational studies showing an association between anemia and adverse cardiac outcomes at all stages of CKD. In addition, we provide an overview of the evidence accumulating from randomized controlled trials conducted in both nondialysis and dialysis CKD populations evaluating the effect of anemia correction on cardiac outcomes such as changes in left ventricular hypertrophy.     

A Rational Guide to Reducing Fracture Risk in Dialysis Patients

Extrapolation of evidence-based management of disorders in the general population to patients with chronic kidney disease (CKD) is not always appropriate, and the prevention of bone fracture and reduction of fracture risk in CKD stages 3–5 is one example. Compared to the general population, fracture risk is greater in CKD patients, especially those on dialysis (CKD-5D). Fractures in CKD-5D are associated with a marked increase in morbidity and mortality and with an aging dialysis population the burden of disease caused by fracture is likely to increase. Patients with CKD-5D have distinct risks for fracture, as well as sharing risks identified in the general population. The development of the CKD mineral and bone disorder constitutes a significant cause for these differences. Literature addressing the determination of fracture risk and the efficacy of treatments to reduce fracture in patients on dialysis is limited. While some tools used for the diagnosis and monitoring of osteoporosis are applicable to patients on dialysis, bone mineral density measurement by dual-energy X-ray absorptiometry is generally not helpful and therapeutic interventions that reduce fracture risk in the nonuremic population cannot be generalized to patients on dialysis. This review outlines available evidence on the incidence, risk factors, and management of fractures in CKD-5D with recommendations for strategies to reduce fracture risk.     

Different kidney function trajectory patterns before dialysis in elderly patients: clinical implications and outcomes

Background. Identifying trajectories of kidney disease progression in chronic kidney disease (CKD) patients may help to deliver better care. We aimed to identify and characterize trajectories of renal function decline in CKD patients and to investigate their association with mortality after dialysis.Methods. This retrospective cohort study included 378 CKD patients who initiated dialysis (aged 65 years and over) between 2009 and 2016. Were considered mixed models using linear quadratic and cubic models to define the trajectories, and we used probabilistic clustering procedures. Patient characteristics and care practices at and before dialysis were examined by multivariable multinomial logistic regression. The association of these trajectories with mortality after dialysis was examined using Cox models.Results. Four distinct groups of eGFR trajectories decline before dialysis were identified: slower decline (18.3%), gradual decline (18.3%), early rapid decline (41.2%), and rapid decline (22.2%). Patients with rapid eGFR decline were more likely to have diabetes, more cognitive impairment, to have been hospitalized before dialysis, and were less likely to have received pre-dialysis care compared to the patients with a slower decline. They had a higher risk of death within the first and fourth year after dialysis initiation, and after being more than 4 years in dialysis.Conclusions. There are different patterns of eGFR trajectories before dialysis initiation in the elderly, that may help to identify those who are more likely to experience an accelerated decline in kidney function, with impact on pre ESKD care and in the mortality risk after dialysis.     

Clinical epidemiology of cardiovascular disease in chronic kidney disease prior to dialysis

Cardiovascular disease (CVD) remains the leading cause of morbidity and mortality in patients with end-stage renal disease (ESRD). Both in dialysis and in transplant patients, CVD remains the leading cause of death. There is accumulating evidence that the increase in CVD burden is present in patients prior to dialysis, due to both conventional risk factors as well as those specific to kidney disease. Of importance is that even in patients with mild kidney disease, the risk of cardiovascular events and death is increased relative to patients without evidence of kidney disease. The new classification system proposed by the National Kidney Foundation as part of the Dialysis Outcomes Quality Initiative (DOQI) process describes the five stages of kidney disease, as well as those complications associated with chronic kidney disease (CKD), in particular cardiovascular risk factors and disease. Patients with kidney disease are deemed to be at highest cardiovascular risk. CVD, defined as the presence of either congestive heart failure (CHF), ischemic heart disease (IHD), or left ventricular hypertrophy (LVH), is prevalent in cohorts with established CKD (8-40%). The prevalence of hypertension, a major risk factor for coronary artery disease (CAD) and LVH is high in patients with CKD (87-90%). At least 35% of patients with CKD have evidence of an ischemic event (myocardial infarction or angina) at the time of presentation to a nephrologist. The prevalence of LVH increases at each stage of CKD, reaching 75% at the time of dialysis initiation, and the modifiable risk factors for LVH include anemia and systolic blood pressure, which are also worse at each stage of kidney disease. Even under the care of nephrologists, a change in cardiac status (worsening of heart failure or anginal symptoms) occurs in 20% of patients. The presence of CVD predicts a faster decline of kidney function and the need for dialysis, after controlling for all other factors including glomerular filtration rate (GFR), age, and the presence of LVH. This article describes the new classification system for staging of CKD, defines and describes CVD in CKD, and reviews the evidence and its limitations with respect to the current understanding of CKD and CVD. Specifically, methodologic issues related to survival and referral bias limit our current understanding of the complex interaction of conventional and nonconventional kidney disease-specific risk factors. We identify the importance of well-conducted studies of patient groups with and without CVD, with and without CKD, in order to better understand the complex physiology so that treatment strategies can be appropriately applied.     

The epidemics of cardiovascular disease in elderly patients with chronic kidney disease – Two facets of the same problem

There is increasing evidence that even mild renal dysfunction is a novel potent cardiovascular risk factor in the general elderly population. With more severe renal impairment, cardiovascular risk increases proportionately. This issue deserves attention, as chronic kidney disease (CKD) is predominantly a disease of the elderly, and the mean age of end-stage renal disease patients entering dialysis is growing constantly. In the dialysis population, when clinically significant cardiovascular disease (CVD) (particularly congestive heart failure) is present, survival is worse. Thus, every effort should be made to identify and treat cardiovascular risk factor in the early stages of CKD. However, elderly renal patients receive less proper cardiovascular therapy compared to non-renal subjects of the same age. This review deals briefly with the most significant data published in the last decade on CVD in elderly with CKD.     

Cardiovascular risk in stage 4 and 5 nephropathy

Severity of heart disease of almost all types, as well as mortality risk associated with heart disease, increases in step with severity of kidney disease, although not necessarily in a linear fashion. Heart failure is more common and just as lethal as ischemic heart disease in patients with severe chronic kidney disease (CKD). The incidence of nonfatal heart disease in dialysis and transplant populations has now been described in detail. Although standard risk factors for heart disease that are more common among patients with CKD than in the general population do not adequately explain the greatly increased risk of heart disease in patients with severe CKD, neither do as yet identified "nontraditional" risk factors. However, in addition to the factors not common in the general population, such as anemia, hyperphosphatemia, and markers of systemic inflammation, patients with CKD in the modern era may also exhibit excessive thrombotic tendencies. Screening for heart disease in this population relies mainly on dobutamine stress echocardiography or nuclear scintigraphy. The role of electron beam CT (EBCT) scanning is currently controversial. The indications for coronary angiography are the same for patients with CKD as for the general population, but patients with CKD are at greatly increased risk for contrast-associated nephropathy, the least controversial preventive therapy, which consists of isotonic saline and N-acetylcysteine. Finally, patients with CKD do not currently receive adequate medical therapy for prevention and treatment of heart disease.     

Cardiovascular risk assessment in children with chronic kidney disease

Chronic kidney disease (CKD) is a major factor contributing to cardiovascular (CV) morbidity and mortality with the highest risk in patients on dialysis. An estimation of CV risk is important not only to identify potential modifiable risk factors but also to evaluate the effect of treatments aimed to reduce the risk. Non-invasive methods of measuring vascular changes and circulating biomarkers are available to assess the presence and severity of cardiovascular damage. These include measures of structural (carotid intima-media thickness and coronary artery calcification score) and functional (aortic pulse wave velocity, 24-h ambulatory blood pressure monitoring, ambulatory arterial stiffness index, heart rate variability and flow-mediated dilatation) changes in the vessel wall. In addition, a number of circulating biomarkers of vascular damage and its progression have been studied. Many of these tests are well validated as surrogate markers of future cardiovascular events and death in adult CKD patients, but need technical adaptation, standardization and validation for use in children. With our current state of knowledge, these are best reserved for research studies and scarce clinical resources may be better utilized for preventative strategies to reduce the modifiable risk factors for calcification from early CKD stages.     

Controversies in Timing of Dialysis Initiation and the Role of Race and Demographics

Dialysis remains the predominant form of renal replacement therapy in the United States, but the optimal timing for the initiation of dialysis remains poorly defined. Not only clinical factors such as signs/symptoms of uremia, co‐existing cardiovascular disease, and presence of diabetes but also key demographic characteristics including age, gender, race/ethnicity, and socioeconomics have all been considered as potential modifying factors in the decision for the timing of dialysis initiation. The 2012 Kidney Disease: Improving Global Outcomes (KDIGO) Clinical Practice Guideline for the Evaluation and Management of chronic kidney disease (CKD) suggests that dialysis be initiated when signs/symptoms attributable to kidney failure such as serositis, acid‐base or electrolyte abnormalities, pruritus, poorly controlled volume status or blood pressure, deteriorating nutritional status despite dietary intervention, or cognitive impairment are visible or noted. These signs/symptoms typically occur when the glomerular filtration rate (GFR) is in the range of 5–10 ml/minute/1.73 m², although they may occur at higher levels of GFR. We review recent data on the timing of dialysis initiation, their implications for managing patients with late‐stage CKD, and the important role of considering key demographics in making patient‐centered decisions for the timing of dialysis initiation.     

Dyslipidemia in children with CKD: should we treat with statins?

Dyslipidemia has been shown to be a risk factor for increased cardiovascular morbidity and mortality in adult patients with chronic kidney disease (CKD) stages 2–4. In patients on dialysis, a paradoxical correlation has been found between low cholesterol values and increased mortality rates. No data exist in children. Treatment with statins has been convincingly shown to both reduce blood lipid levels and mortality rates from cardiovascular disease in adult patients in CKD stages 2–4. There is no strong literature support for treating patients on dialysis or after having had a transplant. Data on benefits of statin therapy do not exist in children with CKD. There are many differences between adult and paediatric kidney patients, and I caution on extrapolating the findings in adult patients to children. Studies are thus needed to evaluate the benefits and potential problems of statin treatment in children with CKD.     

Anemia and left ventricular hypertrophy in chronic kidney disease populations: a review of the current state of knowledge

The increasing awareness of the high prevalence of cardiovascular disease (CVD) in the dialysis population has led clinical nephrologists and researchers to focus their attention on processes and factors that are present in patients prior to dialysis. It is clear that many of the risk factors for kidney disease and cardiovascular disease are similar: This may account for the high prevalence of CVD within the dialysis population. However, it is evident that there are unique risk factors for CVD that are present in patients with chronic kidney disease (CKD). These unique uremia-related risk factors for CVD include anemia, hyperparathyroidism, abnormalities of mineral metabolism, and acidosis. Of note, the association of anemia, or lower levels of hemoglobin, have been consistently described in all populations with kidney disease. Left ventricular hypertrophy has long been known as an independent risk factor for death and CV events, in both the dialysis and general populations. There have been accumulating data that LVH and left ventricular (LV) growth occur prior to dialysis in patients with kidney disease, and that the prevalence of LVH in that group of patients is caused by, conventional risk factors for LVH (e.g., hypertension) as well as nonconventional risk factors such as anemia.     

Should we quantify insulin resistance in patients with renal disease? (Review Article)

Cardiovascular disease is a major cause of morbidity and mortality in dialysis patients. Vascular disease develops before the initiation of dialysis, and it is now recognized that chronic kidney disease (CKD) is an independent risk factor for cardiovascular disease. Death from cardiovascular disease is a more common endpoint of CKD than progression to dialysis. There are multiple mechanisms that contribute to the increased vascular risk of CKD, one of which is the presence of insulin resistance (IR). CKD is characterised by many features of the metabolic syndrome, and features of IR are also observed in dialysis and transplant patients. IR may be quantified by several different methods. One such method is homeostatic model assessment (HOMA) technique, which derives a measurement of IR from fasting plasma glucose and insulin concentrations. The HOMA index has been demonstrated to be an independent predictor of survival in dialysis patients. CKD is characterised by a chronic inflammatory response and abnormalities in the production and regulation of adipose tissue derived proteins, which may contribute to the development of IR. There are a range of interventions including diet and exercise programmes or medications that may influence IR; however, the impact of these interventions in the context of CKD has not been systematically evaluated.     

Chronic kidney disease and cognitive impairment in the elderly: the health, aging, and body composition study

Previous studies suggest a link between chronic kidney disease (CKD) and cognitive impairment. Whether the longitudinal course of cognitive impairment differs among people with or without CKD is unknown. Data collected in 3034 elderly individuals who participated in the Health, Aging, and Body Composition study were analyzed. Cognitive function was assessed with the Modified Mini-Mental State Exam (3MS) at baseline and then 2 and 4 yr after baseline. Cognitive impairment was defined as a 3MS score <80 or a decline in 3MS >5 points after 2 or 4 yr of follow-up among participants with baseline 3MS scores > or =80. Participants with CKD, defined as an estimated GFR (eGFR) <60 ml/min per 1.73 m2, were further divided into two eGFR strata. Unadjusted mean baseline 3MS scores and mean declines in 3MS scores over 4 yr were significantly more pronounced for participants with lower baseline eGFR. More advanced stages of CKD were associated with an increased risk for cognitive impairment: Odds ratio (OR) 1.32 (95% confidence interval [CI] 1.03 to 1.69) and OR 2.43 (95% CI, 1.38 to 4.29) for eGFR 45 to 59 ml/min per 1.73 m2 and <45 ml/min per 1.73 m2, respectively, adjusted for case mix, baseline 3MS scores, and other potential confounders. CKD is associated with an increased risk for cognitive impairment in the elderly that cannot be fully explained by other well-established risk factors. Studies aimed at understanding the mechanism(s) responsible for cognitive impairment in CKD and efforts to interrupt this decline are warranted.     

Gene polymorphism association studies in dialysis: cardiovascular disease

Cardiovascular disease (CVD) is the most important cause of morbidity and mortality in dialysis patients. The high prevalence of CVD is due to the cumulative effects of multiple risk factors from the early stages of chronic kidney disease (CKD). Familial predispositions to CVD, CKD, and their respective risk factors are well known, and it is likely that genetic factors determine the interindividual variability in risks for disease. Advances in genomic technology have facilitated the study of genetic variation--most commonly single nucleotide polymorphisms (SNPs) in candidate genes--and their associations with disease. This review examines CVD in dialysis patients as a model of a complex disease, discusses the approach to gene polymorphism association studies, including the roles of gene-environment and gene-gene interactions and provides an overview of available studies.     

Cigarette Use and Cardiovascular Risk in Chronic Kidney Disease: An Unappreciated Modifiable Lifestyle Risk Factor

Tobacco use is a major modifiable cardiovascular risk factor in the general population and contributes to excess cardiovascular risk. Emerging evidence from large‐scale observational studies suggests that continued tobacco use is also an independent cardiovascular risk factor among patients with chronic kidney disease (CKD). The benefits of smoking cessation programs on improving the heath status of patients and reducing mortality are unequivocal in the general population. Despite this, there has been little effort in pursuing tobacco cessation programs in dialysis cohorts or those with lesser degrees of kidney impairment. Most of our attention to date has focused on the development of “kidney‐specific” interventions that reduce rates of renal disease progression and improve dialysis outcomes. The purpose of this current review is to describe the epidemiology of tobacco use among patients with CKD, draw attention to its negative impact on cardiovascular morbidity and mortality, and finally highlight potential strategies for successful intervention. We hope that this study heightens the importance of tobacco use in CKD, stimulates renewed interest in the barriers and challenges that exist in achieving smoking cessation, and endorses the efficacy of intervention strategies and the immeasurable benefits of quitting on cardiovascular and noncardiovascular outcomes.     

How to manage HIV-infected patients with chronic kidney disease in the HAART era

As human immunodeficiency virus (HIV)-infected patients now live longer while receiving highly active antiretroviral therapy (HAART), chronic kidney disease (CKD) has emerged as a significant cause of morbidity and mortality among urban HIV population. Risk factors associated with CKD in such HIV-infected population include aging, hypertension, diabetes mellitus, co-infection with hepatitis C virus, low CD4 cell count, and high HIV viral load. Clinical experience has shown that HIV-infected individuals often have one or more concurrent risk factors for CKD. The cumulative effect of multiple risk factors on the development of CKD should be noted in this population. Glomerular disease directly related to HIV infection, so-called HIV-associated nephropathy, remains an important cause of CKD among limited HIV population of African descent. The impact of exposure to nephrotoxic antiretroviral agents on the development of kidney disease is both an old and a new concern. In particular, the association of tenofovir with kidney disease has been an area of great interest. The findings regarding tenofovir's adverse effect on long-term kidney function vary among studies. Early identification and treatment of kidney disease is imperative for reducing the burden of patients requiring dialysis in HIV-infected populations. Periodic monitoring of urinary albumin excretion, tubular parameters such as low-molecular-weight proteinuria, and the estimated glomerular filtration rate may be useful for early diagnosis of patients at risk for incident CKD. This review focuses on recent developments in epidemiology, risk factors, identification, estimation, and management of CKD in HIV-infected population in the HAART era.     

Racial and survival paradoxes in chronic kidney disease

Most of the 20 million people in the US with chronic kidney disease (CKD) die before commencing dialysis. One of every five dialysis patients dies each year in the US. Although cardiovascular disease is the most common cause of death among patients with CKD, conventional cardiovascular risk factors such as hypercholesterolemia, hypertension and obesity are paradoxically associated with better survival in hemodialysis populations. Emerging data indicate the existence of this 'reverse epidemiology' in earlier stages of CKD. There are also paradoxical relationships between outcomes and race and ethnicity. For example, the survival rate of African American dialysis patients seems to be superior to that of whites on dialysis. Paradoxes-within-paradoxes have been detected among Hispanic and Asian American CKD patients. These survival paradoxes might evolve and change over the natural course of CKD progression as a result of the time differentials of competing risk factors and the overwhelming impact of malnutrition, inflammation and wasting. Reversal of the reverse epidemiology as a result of successful kidney transplantation underscores the role of nutritional status and kidney function in engendering these paradoxes. The observation of paradoxes and their reversal might lead to the formulation of new paradigms and management strategies to improve the survival of patients with CKD. Such movement away from the use of targets set on the basis of data gathered in general populations (e.g. the Framingham cohort) would be a major paradigm shift in clinical medicine and public health.     

Ethical issues in the care of vulnerable chronic kidney disease patients: the elderly, cognitively impaired, and those from different cultural backgrounds

Numerous ethical issues such as the appropriate initiation or withdrawal of dialysis are inherent when one cares for patients with chronic kidney disease (CKD). Conflicts concerning decisions to withhold or withdraw dialysis often involve particularly vulnerable CKD patients such as the elderly, those with cognitive impairment, or those who come from different cultural backgrounds. Issues related to renal replacement therapy in vulnerable or special CKD populations will be explored within an ethical framework based on the principles of autonomy (self-determination), beneficence (to maximize good), nonmaleficence (to not cause harm), and justice (what is due or owed).     

Risk factors for cognitive dysfunction in CKD and hypertensive subjects

Purpose

Cognitive dysfunction (CO/DY) in chronic kidney disease (CKD) patients has long been recognized. Hypertension is also associated with CO/DY. The study describes associated factors with CO/DY in CKD patients compared to hypertensive subjects.

Methods

Ninety-six hypertensive subjects without CKD, 19 patients with CKD stages I–II, 33 with CKD III, 42 with CKD stage IV, 33 on hemodialysis (HD) and 33 on peritoneal dialysis (PD) were included in our study. Cognitive impairment measured by MMSE, clock-drawing test and IADL was considered as primary outcome.

Results

In all groups tested, age was significantly associated with CO/DY by almost all cognitive function tests. Among CKD patients, CKD stage and DM were significantly associated with CO/DY by all three cognitive function tests. PTH levels were also associated with CO/DY by MMSE and clock-drawing tests. In hypertensives, pulse pressure (PP) was associated with CO/DY by clock-drawing and IADL tests, while those receiving CCBs as monotherapy were less likely to have CO/DY by IADL test. For dialysis patients, DM was significantly related to CO/DY by MMSE and clock-drawing tests. In the same group of patients Hb <11 g/dl was significantly correlated with CO/DY by MMSE, dialysis modality and Kt/V >1.2 by IADL test. PD patients were less likely to present with CO/DY by clock-drawing test.

Conclusions

In every CKD stage, the risk of CO/DY increased significantly. Low Hb levels (Hb <11 g/dl) and increased serum PTH levels were associated with CO/DY while DM plays also a significant role in cognitive function deterioration. Among hypertensive subjects, those with PP ≤60 mmHg or receiving CCBs showed a better executive function.