Chronic systemic inflammation in dialysis patients: an update on causes and consequences

Despite marked improvements in dialysis technology during the last 20 years, the age-adjusted mortality rate in end-stage renal disease (ESRD) patients treated by dialysis is still unacceptably high and comparable to that of many cancer patients with metastases. The main cause of the increased mortality in ESRD patients is cardiovascular disease (CVD), which is twice as common and advances at twice the rate already in patients with early stages of chronic kidney disease as compared to the general population. Although traditional risk factors for CVD are common in dialysis patients, they can only in part explain the very high prevalence of CVD in this patient group. Recent evidence demonstrates that chronic inflammation, a non-traditional risk factor which is a commonly observed in dialysis patients, may cause progressive atherosclerotic CVD and malnutrition, itself an important risk factor for the development of CVD, by several pathogenetic mechanisms. The causes of inflammation in dialysis are multifactorial and include both dialysis-related and unrelated factors. While the long-term effects of chronic inflammation may be most important in the pathogenesis of CVD, the acute-phase reaction may also cause vascular damage by several pathogenic mechanisms. Indeed, it seems logical to speculate that suppression of the vicious cycle of malnutrition, inflammation, and atherosclerosis (MIA syndrome) in ESRD would improve survival and decrease co-morbidity in dialysis patients. As there are currently no established guidelines for the treatment of chronic inflammation in ESRD patients, more studies on the long-term effects of various anti-inflammatory treatment strategies on the nutritional and cardiovascular status, as well as outcome in this patient group, are clearly warranted and will be helpful in identifying precisely which pathways are most involved in the pathogenic process.     

Psychological factors in end-stage renal disease: an emerging context for behavioral medicine research

End-stage renal disease (ESRD) is a chronic, life-threatening condition afflicting over 300,000 Americans. Patient nonadherence and psychological distress are highly prevalent among ESRD patients, and both have been found to contribute to greater morbidity and earlier mortality in this population. A range of factors have been examined as potential determinants of adherence and adjustment. Evidence suggests that adherence and adjustment are maximized when a patient's preferred style of coping is consistent with the contextual features or demands of the renal intervention the patient is undergoing. Challenges for future clinical research include refining methodologies for the assessment of depression and adherence, more clearly evaluating the efficacy of psychological interventions, and clarifying the role that depression and social support play in influencing patient mortality.     

Is secondary hyperparathyroidism-related myelofibrosis a negative prognostic factor for kidney transplant outcome?

Secondary hyperparathyroidism (HP) presenting with hypocalcemia and subsequent increased parathormone (PTH), is mainly identified in patients with chronic renal failure, which has been associated with variable degrees of bone marrow fibrosis.For suitable patients with end-stage renal disease (ESRD), kidney transplantation is recognized as the therapy of choice, being superior to dialysis in terms of quality of life and long-term mortality risk; in this regard interesting data show that increased time on dialysis prior to kidney transplantation is associated with decreased graft and patient survival.In our opinion an important and until now underestimated determinant of graft survival is the proper activity of bone marrow because of the emerging role of hematopoietic stem cells (HSC) in repair of ischemia/reperfusion (IR) damage. We postulate that in ESRD patients, who usually undergo long dialytic treatment, a myelofibrosis caused by an overt secondary HP could drastically decrease the HSC potential for IR damage repair after kidney transplant; this could irremediably lead to a delay in graft function with all related complicances.If the curative role of bone marrow-derived stem cells was confirmed by more data obtained in experimental animal models, it could be possible to try a cellular-based therapeutic approach in the management of ESRD patients which are in waiting list for a kidney transplant.     

Renal disease disparities in Asian and Pacific-based populations in Hawai'i

The prevalence of end-stage renal disease (ESRD) in the United States is expected to double over the next 10 years. The identification of ethnic differences in the prevalence, treatment, morbidity, and mortality related to chronic kidney disease (CKD) is of great concern. Asian Americans comprise a rapidly expanding sector of the U.S. population and are reported to have ESRD growth rates that are approximately 50% higher than caucasians. Hawai'i has a large, well-established Asian and Pacific-based population that facilitates the examination of disparities in renal disease among the state's diverse ethnic groups. The prevalence of ESRD in Hawai'i has continued to rise due, in part, to high rates of diabetes, glomerulonephritis, and hypertension reported in Asian Americans and Pacific-based populations. ESRD patients in Hawai'i have a two-fold higher prevalence of glomerulonephritis, compared with the general ESRD population in the United States. Other potential sources of renal disparities-such as cultural factors, language barriers, and health access factors-among Hawaii's major ethnic groups are assessed. However, few studies have examined the relative contribution of these potential factors. Consequently, efforts to reduce and eventually eliminate renal disease disparities will require a better understanding of the major sources of health disparities, such as timely medical care, a diverse health workforce, and cultural/social barriers, that affect optimal health care practices in Asian and Pacific-based populations.     

Hyperhomocysteinemia in end-stage renal failure

The end-stage renal disease (ESRD) population experiences an excess morbidity and mortality due to arteriosclerotic cardiovascular disease (CVD) outcomes. Specifically, event rates for myocardial infarction and stroke are 5- to 10-fold in ESRD patients on maintenance dialysis than in the general population. Recently, there is controlled evidence that hyperhomocysteinemia occurs more commonly than any of the traditional CVD risk factors in ESRD patients. Prolonged exposure of endothelial cells to homocysteine impairs the production of nitric oxide and endothelium-dependent vasodilatation, they combine with low-density lipoprotein cholesterol to produce aggregates that are taken up by vascular macrophages in the arterial intima (foam cells), produce aggregatory effects on the platelets, and decrease endothelial antithrombotic activity due to changes in the thrombomodulin function. Current treatment regimens for ESRD hyperhomocysteinemia, which are based on the pharmacological doses of folic acid (5 to 15 mg/day), frequently result in suboptimal lowering of Hcy concentrations. Other potential therapeutic approaches (such as oral N-acetylcysteine at 1.2 g/day) merit controlled investigation.     

Hyperphosphatemia in dialysis patients: the therapeutic role of lanthanum carbonate

Phosphate overload is a dramatic consequence in end-stage renal disease (ESRD) patients. Recent studies have well documented that abnormalities in mineral and bone metabolism in these patients are associated with increased cardiovascular morbidity and mortality. Elevated serum phosphate and calcium-phosphate product levels play an important role in the pathogenesis of secondary hyperparathyroidism and extra-skeletal calcification in dialysis patients. Furthermore, inorganic phosphate may cause vascular calcification directly through a real "ossification" of the tunica media in the vasculature of ESRD patients. The "classical" treatment of secondary hyperparathyroidism and hyperphosphatemia in ESRD patients consists of either calcium- or aluminum-based phosphate binders and calcitriol administration. Unfortunately, this "old generation" therapy is not free of complications. This review paper suggests that new calcium- and aluminum-free phosphate binders, such as lanthanum carbonate, can be used to treat hyperphosphatemia and secondary hyperparathyroidism in ESRD patients.     

Disorders of hemostasis in chronic renal failure and renal transplantation

The presence of end-stage renal disease (ESRD) has been associated with profound clinical effects on hemostasis ranging from thrombosis to bleeding complications. The pathogenesis of uremic bleeding is multifactorial. It has been attributed to platelet dysfunction, the most important feature, particularly platelet-platelet and platelet-vessel wall interactions. Renal replacement therapy has helped reduce bleeding episodes, but the risk of morbidity and mortality due to hemorrhage persists. Abnormalities of blood coagulation and fibrinolysis predispose uremic patients to hypercoagulable state carrying the risk of atherosclerotic cardiovascular disease and thrombotic complications such as thrombosis of the vascular access wall. There are differences in the measurement of various hemostatic parameters in patients with ESRD concerning treatment with either hemodialysis (HD) or continuous ambulatory peritoneal dialysis (CAPD). Hemostatic disturbances are overlapped by changes in the coagulation/fibrinolytic system after renal transplantation (RT). Despite the etiology, renal transplant patients are at an increased risk of thromboembolic events as a consequence of prothrombotic clotting and fibrinolytic abnormalities. This hypercoagulable state is to a large extent associated with immunosuppressive drugs. This review will give a summary of views on hemostasis in patients with ESRD and after RT.     

Five-year survival in comparable HD and PD patients: one center's experience

Several studies have yielded conflicting results regarding morbidity and mortality in peritoneal dialysis (PD) and hemodialysis (HD) patients. We performed a retrospective analysis in end-stage renal disease (ESRD) patients in our department, who were equally distributed between HD and PD, in order to compare 5-year survival probabilities and hospitalization rates in the two modalities. Of the total 94 new ESRD patients who initiated dialysis in our department from January 1995 to December 2000, 48 were allocated to PD and 46 to HD. All patients were followed up for five years. There were no significant differences regarding demographics and serious co-morbidities upon dialysis initiation between HD and PD patients. Unadjusted 5-year survival probability in as-treated analysis was higher in PD patients (0.79 vs 0.6, p=0.04), whereas there was no significant difference in intent-to-treat analysis between HD and PD patients (p=0.5). Hospitalization rates were similar in both modalities. Despite the small number of patients included in our study, it seems that when HD and PD are both available in one department they have equivalent results regarding morbidity and mortality rates. Therefore we suggest that, when possible, PD and HD should be equally offered to all ESRD patients.     

End-stage renal disease and race: an overview and perspective

The epidemiology of end-stage renal disease (ESRD) in the United States is reviewed. Hypertension and diabetes as etiologic factors in ESRD in minorities are discussed, as is the question of a familial ESRD. It is hypothesized that diuretics as sole antihypertensive therapy in blacks may in the long term result in chronic volume contraction, increased sympathetic stimulation, and therefore, decreased renal function. As such, a rational basis for the long-term use of diuretics as the sole antihypertensive therapeutic in blacks becomes questionable at best.     

The association of diabetes with all-cause mortality in patients with end-stage renal disease compared to the general population in Poland – a comparative analysis

IntroductionEnd-stage renal disease (ESRD) is an important complication of diabetes, which is the leading cause of ESRD worldwide. The aim of the study was a comparative analysis of all-cause mortality in patients with ESRD with diagnosed diabetes mellitus (DM) and no diagnosed DM.Material and methodsData for the analysis were obtained from the resources of the Polish National Health Fund, and they concerned patients with end-stage renal disease from the entire population of Polish patients in the period from 1.01.2011 to 31.12.2013. In addition, the period from 1.01.2012 to 31.12.2012 was analysed for two subpopulations: diabetic and non-diabetic patients.ResultsThe all-cause mortality in patients with end-stage renal disease in Poland per 100,000 representatives of the general population was 17.7, 15.9, and 12.50 persons in 2011, 2012, and 2013, respectively. The all-cause mortality rates for patients with ESRD and diabetes in Poland in 2012 were more than 15 times higher, for both men and women, than the all-cause mortality rates for non-diabetic patients with ESRD. Mortality in the study group of diabetic men with ESRD amounted to 147.59 ±29.07/100,000 men, whereas in the study group of diabetic women with ESRD it was 105.13 ±26.77/100,000 women. Regarding non-diabetic men with ESRD and non-diabetic women with ESRD, mortality amounted to 9.58 ±6.29/100,000 and 6.87 ±2.27/100,000 men and women, respectively.ConclusionsThe occurrence of diabetes in patients with ESRD significantly increases the risk of death compared to patients with ESRD without diabetes.     

Long-term outcomes in lupus patients receiving different renal replacement therapy

Background/purposeTo compare the long-term outcomes and survival rates of patients with end stage renal disease (ESRD) caused by lupus nephritis who received three different modalities of renal replacement therapy, including hemodialysis (HD), peritoneal dialysis (PD), and kidney transplantation (KT).MethodsWe retrospectively analyzed 94 patients with ESRD caused by lupus nephritis. Among these, 42 received HD, 12 received PD, and 40 underwent KT. The adverse events, survival data and cause of mortality were recorded.ResultsThe mean age at onset of ESRD was younger in the KT group than in the HD group. Arteriovenous fistula (AVF) infection, sepsis, and AVF dysfunction were more common in the HD group than in the KT group. Peritonitis was more common in the PD group than in the HD group and KT group. Urinary tract infection was more common in the KT group than in the HD group. Cumulative survival rates were better in the KT group than in the HD or PD group.ConclusionThe patients with ESRD caused by lupus nephritis who underwent KT had better long-term outcomes and survival rates than those who received HD or PD. This implies that KT is the better choice of renal replacement therapy in the patients with ESRD caused by lupus nephritis.     

Illness and treatment cognitions and health related quality of life in end stage renal disease

Objectives. Patients' beliefs regarding illness and treatment are important to understand responses to chronic disease. The present study aimed (i) to assess the illness representations and treatment disruption beliefs of patients with end stage renal disease (ESRD), (ii) to determine whether beliefs about illness and treatment differ between different renal replacement therapies, and (iii) to examine whether these beliefs are associated with health related quality of life (HQoL). Method. A cross‐sectional sample of 262 ESRD patients, 145 dialysis and 117 kidney transplant recipients completed the illness perceptions questionnaire, the illness effects questionnaire, the treatment effects questionnaire and the short form 36 health survey. Measures of ESRD severity/co‐morbidity and biochemistry were also collected. Results. HQoL levels were higher in transplant patients. Dialysis patients reported more symptoms associated with ESRD (p<.001), stronger chronic timeline beliefs (p<.001), lower control beliefs (p<.05), and more illness and treatment disruptiveness (ps<.01). Illness and treatment disruptiveness, consequences and identity were inversely associated with HQoL whereas control was positively associated with HQoL. Multiple regressions indicated that treatment and illness disruptiveness, identity and consequences beliefs accounted for 22.9–67.6% of the variance HQoL although specific multivariate correlates differed across physical and emotional HQoL and between dialysis and transplantation. Conclusions. The beliefs that patients hold about their illness and treatment appear to be related to the type renal replacement therapy being undertaken. These cognitions have associations with HQoL in dialysis and transplantation that are independent of those of socio‐demographic and clinical factors.     

Sistemic calciphylaxis and thrombotic microangiopathy in a kidney transplant patient: Two mixing fatal syndromes?

Abnormalities in calcium and phosphorus metabolism are common and metabolic bone diseases develop often in patients with chronic renal failure (CRF). Effective clinical management includes measures to control phosphorus retention and prevent hyperphosphataemia, to maintain serum calcium concentrations within the normal range and to prevent excess parathyroid hormone (PTH) secretion by the judicious use of vitamin D sterols. Certain of these interventions, however, appear to increase the risk of soft tissue and vascular calcification in patients with End Stage Renal Disease (ESRD), so current therapeutic approaches are thus being re-evaluated in an effort to limit these risks. Patients with calciphylaxis have an extremely high mortality rate, diagnosis requires a high degree of clinical suspicion and the role and extent of parathyroidectomy in the management of this condition remain controversial. In some cases renal transplant patients could suffer from a comorbidity in which vascular function is compromised not only by secondary hyperparathyroidism-related calcification but also by other pathological condition as haemolytic uremic syndrome (HUS), leading to a fatal clinical outcome. We postulate that in these cases a secondary hyperparathyroidism not properly diagnosed in an early phase of the renal disease (probably before the kidney transplant) could cause a vascular calcification which, adding to the pre-existing HUS-related vascular compromission, gave rise to catastrophic clinical consequences. In the management of ESRD patients, in particular in the cases of pre-existing angiopathies, could be therefore crucial the early and proper diagnosis of an alteration of calcium-posphorus metabolism and effort of medicine could be oriented in these cases also towards identification of screening methodologies to undoubtedly assess such a diagnosis.     

Principles of iron therapy in hemodialysis patients

Anemia associated with chronic renal disease remains a major concern for nephrologists as it significantly increases the morbidity and mortality in this patient group. The introduction of erythropoietin has dramatically changed the treatment of anemia in uremic patients. However, some patients showed hyporesponsiveness to erythropoietin because of inadequate iron supply to the erythroid bone marrow. Patients undergoing chronic intermittent hemodialysis are especially vulnerable to iron deficiency due to blood loss during the hemodiaylsis sessions, gastrointestinal bleeding and compromised gastrointestinal absorption. Demand for iron is also increased by the treatment for anemia with erythropoietin. Intravenous administration is more effective than oral iron supplemantation in renal failure patients. Some studies have raised concerns of the potential serious side effects associated with intravenous iron administration. Besides anaphylactic reactions that were reported to occur in less than 1% of patients treated with iron dextran and have not been associated with other iron formulations, concerns about the long-term use of iron include the increased risk of infections and oxidative stress with consequent cardiovascular disease. Therapy with dextran-free iron formulations is an essential part of anemia treatment protocols, and was not found to be associated with either short- or long-term serious side effects.     

New mediators of vascular damage in dialysed patients

Cardiovascular events are the main causes of mortality in dialysed patients. Traditional risk factors such as hypertension, aging, smoking, diabetes, and abnormal lipid metabolism does not fully explain the high frequency of cardiovascular disease in renal patients, indicating that some other distinct pathogenesis may be involved. Vascular calcification have been associated with high cardiovascular morbidity and mortality in chronic kidney disease (CKD) patients. It is an active process that resembles osteogenesis, regulated by bone proteins and osteoblast-like cells. Elements involved in the pathogenesis are: the risk factors that initiates the process, the promoters released and overexpressed and the dysregulation of the inhibitor factors of extraskeletal calcifications. Although researches in the past decade have greatly improved our knowledge of the multiple factors and mechanisms involved in vascular calcification, many questions remain unanswered.     

Nonalcoholic fatty liver disease (NAFLD): A new risk factor for adverse cardiovascular events in dialysis patients

Non-alcoholic fatty liver disease (NAFLD) is the most common liver disease in Western countries. Today it is believed that NAFLD is a hepatic manifestation of metabolic syndrome, and thus it is closely related to the cardiovascular morbidity and mortality. Cardiovascular diseases (CVD) are the leading cause of morbidity and mortality in patients with end-stage-renal disease (ESRD). NAFLD and ESRD share some important cardiometabolic risk factors and possible common pathophyisiological mechanisms, and are linked to an increased risk of incident CVD events. We hypothesize that the coexistence of these two conditions could lead to much faster progress of the aterogenic process. Furthermore, patients with ESRD who suffer from NAFLD have a much higher risk for the development of adverse CVD events. Given the high prevalence of NAFLD, and its tight association with other manifestations of the metabolic syndrome and thus cardiovascular complications, it is important to recognize and aggressively treat this condition in ESRD patients. To evaluate this hypothesis, we propose the use of non-invasive methods such as transient elastography (TE) (Fibroscan-CAP) for the detection and quantification of liver steatosis and fibrosis, as well as an abdominal ultrasound for detecting liver steatosis. We focus on their correlation with carotid intima-media thickness (IMT) and plaque as surrogate measures of increased cardiovascular risk in HD patients in order to investigate the association of NAFLD and increase risk of adverse CVD events. This evaluation will prove useful in assessing the risk in HD patients with NAFLD for increase CVD mortality.     

Fludarabine-based nonmyeloablative stem cell transplantation for sickle cell disease with and without renal failure: clinical outcome and pharmacokinetics.

End-organ damage is common in patients with sickle cell disease (SCD) thereby limiting the use of allogeneic stem cell transplantation (SCT). We report the outcome of 2 adult SCD patients, 1 with end-stage renal disease (ESRD), who underwent fludarabine-based nonmyeloablative SCT from HLA-identical matched siblings. To prevent fludarabine toxicity, the patient with ESRD underwent aggressive dialysis following adjusted fludarabine dosing. Pharmacokinetics of the fludarabine metabolite F-Ara-A was studied on the patient with ESRD and 2 additional patients with normal renal function. Both patients with SCD achieved full donor erythroid chimerism, have normal blood counts, and are on no immunosuppressive medications. With a 20% dose reduction followed by daily dialysis, we achieved fludarabine drug exposure that is nearly identical to that achieved in patients with normal renal function. We conclude that fludarabine-based nonmyeloablative allogeneic SCT for adult patients with SCD is feasible, even in the setting of ESRD.     

Effects of Hemodialysis Therapy on Sit-to-Walk Characteristics in End Stage Renal Disease Patients

Patients with end stage renal diseases (ESRD) undergoing hemodialysis (HD) have high morbidity and mortality due to multiple causes; one of which is dramatically higher fall rates than the general population. In spite of the multiple efforts aiming to decrease the high mortality and improve quality of life in ESRD patients, limited success has been achieved. If adequate interventions for fall prevention are to be achieved, the functional and mobility mechanisms consistent with falls in this population must be understood. Human movements such as sit-to-walk (STW) tasks are clinically significant, and analysis of these movements provides a meaningful evaluation of postural and locomotor performance in elderly patients with functional limitations indicative of fall risks. In order to assess the effects of HD therapy on fall risks, 22 sessions of both pre- and post-HD measurements were obtained in six ESRD patients utilizing customized inertial measurement units (IMU). IMU signals were denoised using ensemble empirical mode decomposition and Savistky-Golay filtering methods to detect relevant events for identification of STW phases. The results indicated that patients were slower to get out of the chair (as measured by trunk flexion angular accelerations, time to peak trunk flexion, and overall STW completion time) following the dialysis therapy session. STW is a frequent movement in activities of daily living, and HD therapy may influence the postural and locomotor control of these movements. The analysis of STW movement may assist in not only assessing a patient’s physical status, but in identifying HD-related fall risk as well. This preliminary study presents a non-invasive method of kinematic measurement for early detection of increased fall risk in ESRD patients using portable inertial sensors for out-patient monitoring. This can be helpful in understanding the pathogenesis better, and improve awareness in health care providers in targeting interventions to identify individuals at risk for fall.     

Systemic fungal infections in renal diseases

Invasive fungal infections are a major challenge in the management of immunocompromised patients and those with renal dysfunction. These challenges are due to the immense morbidity and mortality in such situations. Also the management strategies for invasive mycosis in patients with renal dysfunction have narrow safety profile and involve high-cost. In this review we will discuss the issues involved in the management of invasive mycosis in the patients with renal dysfunction in the form of acute renal failure, chronic kidney disease, dialysis dependency of renal transplant recipients. We also emphasize that the use of Intravenous Liposomal Amphoterecin appears to be an effective alternative to the conventional Amphoterecin B for the treatment of invasive fungal infections in patients with renal dysfunction due to its greatly improved tolerability profile. Commercially two true liposomal preparations (Fungisome and Ambisome) are available. Judgement about the preferred formulation should be made on the basis of disease morbidity, severity of renal dysfunction and the cost involved.