Endotoxemia in End‐Stage Kidney Disease

Chronic unexplained inflammation remains a prevalent and clinically significant problem for patients with end‐stage kidney disease (ESKD), especially in the dialysis population. The causes of persistent inflammation are likely to be multifactorial, but the underlying mechanisms remain to be elucidated. Endotoxins are reported to play a significant role in the pathogenesis of inflammation in patients with ESKD. However, blood endotoxin measurement with the Limulus amoebocyte lysate (LAL) assay is difficult with current detection systems. The reported degree and prevalence of endotoxemia varies in the literature. There are questions as to whether endotoxemia is truly present; whether the varied findings are due to methodological issues with the LAL assay and whether any endotoxemia that might be present plays a role in chronic inflammation frequently observed in ESKD patients. This review will discuss the challenges of accurate blood endotoxin detection, the potential source of blood endotoxins, and the significance of endotoxemia to patient with ESKD.     

Exercise in End‐Stage Renal Disease

This article will outline the clinical reasoning for exercise counseling in end‐stage renal disease (ESRD) patients and give healthcare providers detailed information on the different programs that can be implemented in this population according to patients’ specific needs. End‐stage renal disease patients often have other health problems that can be improved by participation in regular exercise programs. Research accumulated during the last 30 years on exercise for the ESRD population supports its numerous beneficial effects including those on cardiovascular capacity, sarcopenia, and health‐related quality of life. We describe the different types of exercise, aerobic and resistance programs (including their frequency, intensity and progression) that are recommended for the ESRD population, as well as the potential goals of each program. Groups with special needs among the ESRD population are considered, as well as safety, potential adverse events, and adherence to exercise programs. Finally, recommendations for future researches are highlighted.     

Clopidogrel Use in End‐Stage Kidney Disease

Clopidogrel irreversibly binds to the P2Y12 platelet receptor and acts as a potent inhibitor of platelet activation and aggregation. It is currently recommended for the prevention of cardiovascular events in patients with acute coronary syndromes, recent ischemic stroke, and peripheral arterial disease. Clopidogrel is a prodrug requiring hepatic conversion into its active metabolite. In the general population, genetic polymorphisms in the CYP2C19 gene interfering with hepatic conversion and the ABCB1 gene interfering with gut absorption of clopidogrel, account for the large interindividual response to clopidogrel and clopidogrel resistance. Chronic kidney disease (CKD) and ESKD are independent risk factors for clopidogrel resistance; 50–80% of patients with ESKD have high on‐treatment residual platelet reactivity when treated with clopidogrel. This may partially explain the abysmal outcomes for patients with kidney disease post coronary intervention. Several assays are used to determine residual on‐treatment platelet reactivity; however, their use in tailoring the suitability of clopidogrel treatment in patients with ESKD is unclear. Although clopidogrel decreased cardiovascular events in the general population after acute coronary syndromes and percutaneous intervention in the CURE and CREDO trials, a reanalysis of these studies in patients with CKD (eGFR <60 ml/minute) showed either a reduced or no benefit from clopidogrel treatment. ESKD patients were not represented in these two large trials; this is true for most of the trials that established clopidogrel as an integral part of the therapeutic armamentarium for cardiovascular disease. Furthermore, clopidogrel has been associated with an increased risk of death, death from bleeding, and hospitalization for bleeding in patients with ESKD. In conclusion, current evidence suggests that ESKD patients may not derive the same benefits from clopidogrel therapy as the general population and this therapy may be associated with harm. Properly designed observational studies and randomized controlled trials are needed to establish the role of clopidogrel in patients with ESKD, the use of platelet assays to tailor therapy, and the role of other antiplatelet agents such as prasugrel or ticagrelor in patients who exhibit high on‐treatment residual platelet reactivity.     

Antidiabetic Therapy in End‐Stage Renal Disease

There has been substantial growth in the variety of available antidiabetic agents during the last decade and a half. The role of these newer agents in patients with diabetes and end‐stage renal disease (ESRD) population, and their relative benefits and risks in this population compared to patients without ESRD are not yet clear. This stems from the altered state of glucose homeostasis in ESRD, which places patients at high risk for hypoglycemia and, in certain situations, hyperglycemia. In addition, there is a dearth of evidence to support a benefit of tight glycemic control on either micro‐ or macrovascular outcomes in ESRD patients; furthermore, the metrics by which glycemic control is conventionally measured are less valid in ESRD. In this review, we will discuss noninsulin and insulin‐based therapies as well as unique challenges, contraindications, advantages, and disadvantages to their use in ESRD. We will also review issues pertinent to both hemodialysis (HD) and peritoneal dialysis (PD) patients.     

Psychotherapeutic Agents in End‐Stage Renal Disease

Patients with end‐stage renal disease (ESRD) are often affected by many comorbid conditions, including mental health disorders. Psychiatric illness among patients with ESRD has been associated with increased risks for nonadherence, hospitalizations, suicide, and all‐cause mortality. We reviewed the pharmacokinetic data available with psychotherapeutic agents, focusing on physiologic data rather than specific dosing recommendations. Unfortunately data regarding the pharmacokinetics, efficacy, and safety of psychotherapeutic agents in ESRD remain rather limited. Of the agents available, it appears that the most data in this patient group were found with selective serotonin reuptake inhibitors and benzodiazepines. Given the small number of patients enrolled in many of the studies and the wide inter‐individual variability, it was difficult to interpret the significance of results in many instances. A number of agents, such as tricyclic antidepressants, were associated with adverse effects that would be imperative to avoid in patients with ESRD. Psychotherapeutic medications should be started at low doses and titrated carefully, while monitoring the efficacy and safety of each agent.     

Antihypertensive Medications in End‐Stage Renal Disease

Hypertension is almost universal in end‐stage renal disease (ESRD) and contributes to the substantial cardiovascular (CV) morbidity and mortality observed in these patients. The management of blood pressure (BP) in ESRD is complicated by a number of factors, including missed dialysis treatments, intradialytic changes in BP, medication removal with dialysis, and poor correlation of BPs obtained in the dialysis unit with those at home and with CV outcomes. Control of extracellular volume with ultrafiltration and dietary sodium restriction represents the principal strategy to manage hypertension in ESRD, and antihypertensive medications are subsequently added if this strategy is inadequate. While reduction in BP with medication improves CV outcomes, few head‐to‐head clinical trials have been performed to firmly establish the superiority of one antihypertensive medication class over another. Therefore, individualization of therapy is necessary, and patient comorbidities must be considered. Angiotensin‐converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), and beta‐blockers are reasonable first‐line agents for most patients. ACE inhibitors and ARBs exert cardioprotective effects that are independent of BP reduction. Medications that are removed with dialysis may be preferred in patients who are prone to develop intradialytic hypotension. Intradialytic hypertension can be managed with challenging the patient's dry weight and using nondialyzable medications. Within a class of antihypertensive medications, there may be large variability in drug removal with dialysis, which must be considered upon medication selection. Studies demonstrate that even thrice‐weekly dosing of medication after dialysis has robust BP‐lowering effects, which may be a useful regimen in nonadherent patients.     

Risk of End‐Stage Renal Disease in HIV‐Positive Potential Live Kidney Donors

New federal regulations allow HIV‐positive individuals to be live kidney donors; however, potential candidacy for donation is poorly understood given the increased risk of end‐stage renal disease (ESRD) associated with HIV infection. To better understand this risk, we compared the incidence of ESRD among 41 968 HIV‐positive participants of North America AIDS Cohort Collaboration on Research and Design followed for a median of 5 years with the incidence of ESRD among comparable HIV‐negative participants of National Health and Nutrition Examination III followed for a median of 14 years. We used risk associations from multivariable Cox proportional hazards regression to derive cumulative incidence estimates for selected HIV‐positive scenarios (no history of diabetes, hypertension, AIDS, or hepatitis C virus coinfection) and compared these estimates with those from similarly selected HIV‐negative scenarios. For 40‐year‐old HIV‐positive individuals with health characteristics that were similar to those of age‐matched kidney donors, viral load <400 copies/mL, and CD4⁺ count ≥500 cells/μL, the 9‐year cumulative incidence of ESRD was higher than that of their HIV‐negative peers, yet still low: 2.5 versus 1.1 per 10 000 among white women, 3.0 versus 1.3 per 10 000 among white men, 13.2 versus 3.6 per 10 000 among black women, and 15.8 versus 4.4 per 10 000 among black men. HIV‐positive individuals with no comorbidities and well‐controlled disease may be considered low‐risk kidney donor candidates.     

APOL1‐Associated End‐Stage Renal Disease in a Living Kidney Transplant Donor

Homozygosity for apolipoprotein‐L1 (APOL1) risk variants has emerged as an important predictor of renal disease in individuals of African descent over the past several years. Additionally, these risk variants may be important predictors of renal allograft failure when present in a living or deceased donor. Currently, there is no universal recommendation for screening of potential donors. We present a case of end‐stage renal disease with focal segmental glomerulosclerosis in a living donor 7 years following donor nephrectomy. Genetic assessment revealed homozygosity for the G1 high‐risk APOL1 variant.     

HIV and HCV Medications in End‐Stage Renal Disease

Human immunodeficiency virus (HIV) infection and hepatitis C virus (HCV) infection affect populations worldwide. With the availability of over 35 Food and Drug Administration approved medications for treatment of HIV, the morbidity and mortality associated with HIV has greatly improved. On the other hand, treatment options for HCV have been limited until very recently. While the use of protease inhibitors (such as boceprevir and telaprevir) has become standard of care for treatment of hepatitis C in the general population, data for individuals with impaired kidney function, particularly those on dialysis, are extremely limited. Use of medications in dialysis patients can be challenging given the dose adjustments that must be made for renally cleared molecules, and potentially increased impact of adverse effects such as anemia. Recommendations for dosing of marketed therapies for HIV and HCV are reviewed.     

Long‐Term Non–End‐Stage Renal Disease Risks After Living Kidney Donation

Despite generally positive outcomes and high rates of satisfaction, living kidney donors are at risk for both medical and psychosocial problems. In this review, the authors summarize non–end‐stage renal disease (ESRD) risks for donors and describe limitations to the data. We review the evidence of medical risks (e.g. increased cardiovascular disease and mortality, preeclampsia) and psychosocial risks (e.g. mood disturbance, financial burden). We then discuss the evidence of differential risks among subsets and the impact of postdonation events (e.g. development of diabetes). Collectively, available evidence indicates the following. (1) Recognizing the importance of non‐ESRD risks has been overshadowed by analyses of the reported risk of ESRD. This imbalance should be remedied. (2) There is little quantification of the true contribution of donation to medical and psychosocial outcomes. (3) Most studies, to date, have been retrospective, with limited sample sizes and diversity and with less‐than‐ideal controls for comparison of outcomes. (4) Many postdonation events (diabetes and hypertension) can now be reasonably predicted, and their association with adverse outcomes can be quantified. (5) Mechanisms and systems need to be implemented to evaluate and care for donors who develop medical and/or psychosocial problems. (6) Costs to donors are a significant burden, and making donation financially neutral should be a priority.     

Pericarditis and Pericardial Effusions in End‐Stage Renal Disease

Pericarditis and pericardial effusions are not uncommon in patients with end‐stage renal disease (ESRD). Etiologies include those found in the general population along with two entities unique to patients with kidney disease, namely uremic and dialysis‐associated pericarditis. Uremic pericarditis has been arbitrarily defined as pericarditis that develops before or within 8 weeks of initiation of dialysis, while dialysis‐associated pericarditis is used to define pericarditis in patients on dialysis for more than 8 weeks. Retention of uremic toxins is likely a major contributor to uremic and dialysis‐associated pericarditis although their exact cause is not known. Indeed, whether they are actually distinct entities is uncertain. Symptoms and signs of pericarditis differ in patients with ESRD compared to the non‐ESRD population. Management has not been well studied and ranges from initiation and intensification of dialysis to percutaneous or open drainage for large effusions. This review covers the literature on this topic but emphasizes that most of the data are old and of relatively poor quality, and therefore additional research is needed.     

Predicting End‐Stage Renal Disease After Liver Transplant

Few equations have been developed to predict end‐stage renal disease (ESRD) after deceased donor liver transplant. This retrospective observational cohort study analyzed all adult deceased donor liver transplant recipients in the Scientific Registry of Transplant Recipients (SRTR) database, 1995–2010. The prediction equation for ESRD was developed using candidate predictor variables available in SRTR after implementation of the allocation policy based on the model for end‐stage liver disease. ESRD was defined as initiation of maintenance dialysis therapy, kidney transplant or registration on the kidney transplant waiting list. We used Cox proportional hazard models to develop separate equations for assessing risk of ESRD by 6 months posttransplant and between 6 months and 5 years posttransplant. Variables in the 6‐month equation included recipient age, history of diabetes, history of dialysis before liver transplant, history of malignancy, body mass index, serum creatinine and liver donor risk index. Variables in the 6‐month to 5‐year equation included recipient race, history of diabetes, hepatitis C status, serum albumin, serum bilirubin and serum creatinine. The prediction equations have good calibration and discrimination (C statistics 0.74–0.78). We have produced risk prediction equations that can be used to aid in understanding the risk of ESRD after liver transplant.     

Calcium and Sudden Cardiac Death in End‐Stage Renal Disease

Sudden cardiac death (SCD) accounts for a quarter of all deaths in end‐stage renal disease (ESRD) patients. While causative mechanisms of SCD in this high risk population remain poorly defined, interaction of the vulnerable myocardium with dialysis‐related arrhythmic triggers is thought to play a major role. Recent evidence suggests that dialysis‐induced derangement of calcium concentrations contributes to the increased risk of all‐cause and cardiovascular mortality, vascular calcification, and SCD. Current KDIGO guidelines recommend avoiding high dialysate calcium concentrations as a precaution against adverse outcomes of increased calcium burden and vascular calcification. Conversely, low calcium concentration is also implicated in the development of SCD via increased QT dispersion and prolonged QT interval. Consequently, the optimal dialysate calcium concentration in dialysis patients remains debated and further studies are needed to establish the best strategy for managing calcium in dialysis patients.     

Neighborhood Poverty and Kidney Transplantation Among US Asians and Pacific Islanders with End‐Stage Renal Disease

The degree to which low transplant rates among Asians and Pacific Islanders in the United States are confounded by poverty and reduced access to care is unknown. We examined the relationship between neighborhood poverty and kidney transplant rates among 22 152 patients initiating dialysis during 1995–2003 within 1800 ZIP codes in California, Hawaii and the US‐Pacific Islands. Asians and whites on dialysis were distributed across the spectrum of poverty, while Pacific Islanders were clustered in the poorest areas. Overall, worsening neighborhood poverty was associated with lower relative rates of transplant (adjusted HR [95% CI] for areas with ≥20% vs. <5% residents living in poverty, 0.41 [0.32–0.53], p < 0.001). At every level of poverty, Asians and Pacific Islanders experienced lower transplant rates compared with whites. The degree of disparity increased with worsening neighborhood poverty (adjusted HR [95% CI] for Asians–Pacific Islanders vs. whites, 0.64 [0.51–0.80], p < 0.001 for areas with <5% and 0.30 [0.21–0.44], p < 0.001 for areas with ≥20% residents living in poverty; race–poverty level interaction, p = 0.039). High levels of neighborhood poverty are associated with lower transplant rates among Asians and Pacific Islanders compared with whites. Our findings call for studies to identify cultural and local barriers to transplant among Asians and Pacific Islanders, particularly those residing in resource‐poor neighborhoods.     

Ethnic and Gender Related Differences in the Risk of End‐Stage Renal Disease After Living Kidney Donation

There is limited data pertaining to the risk of End Stage Renal Disease (ESRD) after living kidney donation. The Organ Procurement and Transplantation Network and the Center for Medicare and Medicaid Services databases were used to identify living kidney donors (LKDs) who subsequently developed ESRD and to calculate LKD ESRD rates. We found 126 cases of ESRD among 56 458 LKDs (0.22%) who donated during October 1, 1987–March 31, 2003. The overall LKD ESRD rate was 0.134 per 1000 years at risk, with an average duration of follow‐up of 9.8 years. ESRD rates for LKDs overall and for Black, White, male and female donors compared favorably to the ESRD incidence in the general population. The LKD ESRD rate was nearly five times higher for Blacks than for Whites and two times higher for males than females. However, these ethnic and gender‐related differences were similar to those previously reported for ESRD in the general population. Our findings do not show an increase in the risk of ESRD for LKDs and support the current practice of living kidney donation. Further research is needed to determine if improved donor screening or follow‐up will reduce the risk of postdonation ESRD.     

Improving Outcomes in Patients with Lupus and End‐Stage Renal Disease

The development of lupus‐related end‐stage renal disease (ESRD) confers the highest mortality rates among individuals with lupus. Lupus‐related ESRD is also associated with higher morbidity and mortality rates compared with non‐lupus ESRD. We review the evidence that persistent lupus activity, hypercoagulability, and continuing immunosuppression may contribute to unfavorable outcomes in dialysis and renal transplantation among lupus patients. Robust epidemiologic studies are needed to develop individualized evidence‐based approaches to treating lupus‐related ESRD. In the meantime, managing lupus‐related ESRD presents a significant challenge for clinicians and requires a team approach involving nephrologists and rheumatologists. Goals of therapy after developing ESRD should include continuing monitoring of lupus activity, minimizing corticosteroid exposure, and choosing the most appropriate renal replacement therapy based on patient's risk profile and quality‐of‐life considerations.     

Update on the End‐Stage Renal Disease Quality Incentive Program

The End‐Stage Renal Disease Quality Incentive Program continues to evolve and expand. In this article, we will review the program's structure and critically assess the clinical metrics in place. In addition, we will discuss upcoming program changes to help prepare dialysis facilities and nephrologists to meet new proposed metrics.     

Immunization in End‐Stage Renal Disease: Opportunity to Improve Outcomes

Infection is the second most common cause of death in patients with end‐stage renal disease (ESRD), following cardiovascular causes. Immunization is a fairly simple, but underutilized, strategy for prevention of infectious morbidity and mortality in patients with kidney failure. It is imperative for nephrologists and primary care providers to have an understanding of immunization as an essential component of preventive healthcare measures in this high‐risk population. Patients with ESRD represent a unique population due to their immunosuppressed state, dialysis‐related exposures and suboptimal response to routine vaccines. While the Advisory Committee on Immunization Practices (ACIP) provides guidelines for vaccination of patients with renal disease against Hepatitis B, influenza and pneumococcal disease, the data on immunization against other commonly preventable infectious diseases are lacking. This article reviews the recent evidence on immunization in the ESRD population and synthesizes the related implications for maximizing prevention of infectious diseases in this high‐risk population.     

Characteristics of Elderly Patients with Diabetes and End‐Stage Renal Disease

Because of a combination of demographic and social factors, such as the aging of the population in general, increased incidence of diabetes, and more liberal criteria for renal replacement therapy initiation, the proportion of the end‐stage renal disease (ESRD) patients with diabetes who are considered elderly is currently the fastest growing segment of incident ESRD population. Despite the fast growth of this group, it is poorly characterized in current literature. In this review, we attempt to summarize the data available to date regarding demographic composition, outcomes, choice of renal replacement therapy, and other management issues including renal transplantation. There is significant evidence that the elderly diabetic patients might differ from the general dialysis population regarding renal replacement modality, vascular access for dialysis, and that guidelines addressing chronic kidney disease (CKD) issues such as nutrition and blood pressure may need modification in this ESRD subgroup. At the same time, other areas such as anemia and bone mineral metabolism have not been adequately studied. Lastly, despite lower rates of kidney transplantation in this population, it confers significant survival advantages, similar to that seen in younger populations. As the fastest growing group in the incident ESRD population, these patients have issues related to clinical management, which represent very important areas for future research.