Cognitive impairment in patients on dialysis: can we prevent it?

Chronic kidney disease (CKD) is among the leading causes of morbidity and mortality as it affects more than 10% of the global adult population. Cognitive impairment has a positive correlation with the stage of CKD. It has been recorded in more than half of CKD patients undergoing kidney replacement therapy. The assessment of cognitive function in dialysis patients presents challenges due to various patient limitations. Such a common debilitating comorbidity of CKD has no approved treatment option, highlighting the importance of preventive measures and screening modalities. Erythropoietin therapy, exercise training, cognitive stimulation or behavioral therapies, alterations in dialysis frequency, dialysate cooling and kidney transplantation have been proposed as potential preventive and/or therapeutic options with variable efficiency at a clinical level. Regular screening, such as yearly, for cognitive impairment in maintenance dialysis patients is not only beneficial for timely and accurate diagnosis but also crucial for effective management and improved patient care. However, current practices face challenges, including the absence of validated tools specific for kidney failure and complications arising from patient conditions.

Treatment strategies of the thromboembolic risk in kidney failure patients with atrial fibrillation.

The incidence and prevalence of atrial fibrillation (AF) in patients affected by kidney failure, i.e. glomerular filtration rate <15 ml/min/1.73 m2, is high and probably underestimated. Numerous uncertainties remain regarding how to prevent thromboembolic events in this population because both cardiology and nephrology guidelines do not provide clear recommendations. The efficacy and safety of oral anticoagulant therapy (OAC) in preventing thromboembolism in patients with kidney failure and AF has not been demonstrated for either vitamin K antagonists (VKAs) or direct anticoagulants (DOACs). Moreover, it remains unclear which is more effective and safer, because estimated creatinine clearance <25-30 ml/min was an exclusion criterion in the randomized controlled trials (RCTs). Three RCTs comparing DOACs and VKAs in kidney failure failed to reach the primary endpoint, as they were underpowered. The left atrial appendage is the main source of thromboembolism in the presence of AF. Left atrial appendage closure (LAAC) has recently been proposed as an alternative to OAC. RCTs comparing the efficacy and safety of LAAC versus OAC in kidney failure were terminated prematurely due to recruitment failure. A recent prospective study showed a reduction in thromboembolic events in haemodialysis patients with AF and undergoing LAAC compared with patients taking or not taking OAC. We review current treatment standards and discuss recent developments in managing the thromboembolic risk in kidney failure patients with AF. The importance of shared decision-making with the multidisciplinary team and the patient to consider individual risks and benefits of each treatment option is underlined.

Practical guide on left atrial appendage closure for the non-implanting physician: an international consensus paper.

A significant proportion of patients who suffer from atrial fibrillation (AF) and are in need of thromboembolic protection are not treated with oral anticoagulation or discontinue this treatment shortly after its initiation. This undertreatment has not improved sufficiently despite the availability of direct oral anticoagulants which are associated with less major bleeding than vitamin K antagonists. Multiple reasons account for this, including bleeding events or ischaemic strokes whilst on anticoagulation, a serious risk of bleeding events, poor treatment compliance despite best educational attempts, or aversion to drug therapy. An alternative interventional therapy, which is not associated with long-term bleeding and is as effective as vitamin K anticoagulation, was introduced over 20 years ago. Because of significant improvements in procedural safety over the years, left atrial appendage closure, predominantly achieved using a catheter-based, device implantation approach, is increasingly favoured for the prevention of thromboembolic events in patients who cannot achieve effective anticoagulation. This management strategy is well known to the interventional cardiologist/electrophysiologist but is not more widely appreciated within cardiology or internal medicine. This article introduces the devices and briefly explains the implantation technique. The indications and device follow-up are more comprehensively described. Almost all physicians who care for adult patients will have many with AF. This practical guide, written within guideline/guidance boundaries, is aimed at those non-implanting physicians who may need to refer patients for consideration of this new therapy, which is becoming increasingly popular.

Prescribing the dialysis dose and treatment frequency in home haemodialysis.

BACKGROUND: There is growing interest in home haemodialysis (HHD) performed with low-flow dialysate devices and variable treatment schedules. The target standard Kt/V (stdKt/V) should be 2.3 volumes/week, according to KDOQI guidelines (2015). The current formula for stdKt/V does not help prescribe the dialysis dose (eKt/V) and treatment frequency (TF). The aim of this study was to obtain a formula for stdKt/V that is able to define the minimum required values of eKt/V and TF to achieve the targeted stdKtV. METHODS: Thirty-eight prevalent patients on HHD were enrolled. A total of 231 clinical datasets were available for urea modelling using the Solute-Solver software (SS), recommended by KDOQI guidelines. A new formula (stdKt/V = a + b × Kru + c × eKt/V) was obtained from multivariable regression analysis of stdKt/V vs eKt/V and residual kidney urea clearance (Kru). The values of coefficients a, b and c depend on the treatment schedules and the day of the week of blood sampling for the kinetic study (labdayofwk) and then vary for each of their foreseen 62 combinations. For practical purposes, we used only seven combinations, assuming Monday as a labdayofwk for each of the most common schedules of the 7 days of the week. RESULTS: The stdKt/V values obtained with SS were compared with the paired ones obtained with the formula. The mean ± standard deviation stdKt/V values obtained with SS and the formula were 3.043 ± 0.530 and 2.990 ± 0.553, respectively, with 95% confidence interval +0.15 to -0.26. A 'prescription graph' was built using the formula to draw lines expressing the relationship between Kru and required eKt/V for each TF. Using this graph, TF could have been reduced from the delivered 5.8 ± 0.8 to 4.8 ± 0.8 weekly sessions. CONCLUSIONS: The new formula for stdKtV is reliable and can support clinicians to prescribe the dialysis dose and TF in patients undergoing HHD.

Dialysis after kidney transplant failure: how to deal with this daunting task?

The best treatment for patients with end-stage kidney disease is kidney transplantation, which, if successful provides both a reduction in mortality and a better quality of life compared to dialysis. Although there has been significant improvement in short-term outcomes after kidney transplantation, long-term graft survival still remains insufficient. As a result, there has been an increase in the number of individuals who need dialysis again after kidney transplant failure, and increasingly contribute to kidney transplant waiting lists. Starting dialysis after graft failure is a difficult task not only for the patients, but also for the nephrologists and the care team. Furthermore, recommendations for management of dialysis after kidney graft loss are lacking. Aim of this narrative review is to provide a perspective on the role of dialysis in the management of patients with failed kidney allograft. Although numerous studies have reported higher mortality in patients undergoing dialysis following kidney allograft failure, reports are contrasting. A patient-centered, individualized approach should drive the choices of initiating dialysis, dialysis modality, maintenance of immunosuppressive drugs and vascular access.

Shared decision making in patients with kidney failure.

'Elderly' is most commonly defined as an individual aged 65 years or older. However, this definition fails to account for the differences in genetics, lifestyle and overall health that contribute to significant heterogeneity among the elderly beyond chronological age. As the world population continues to age, the prevalence of chronic diseases, including chronic kidney disease (CKD), is increasing and CKD frequently progresses to kidney failure. Moreover, frailty represents a multidimensional clinical entity highly prevalent in this population, which needs to be adequately assessed to inform and support medical decisions. Selecting the optimal treatment pathway for the elderly and frail kidney failure population, be it hemodialysis, peritoneal dialysis, or conservative kidney management is complex, because of the presence of comorbidities associated with low survival rates and impaired quality of life. Management of these patients should involve a multidisciplinary approach including doctors from various specialties, nurses, psychologists, dieticians, and physiotherapists. Studies are mostly retrospective and observational, lacking adjustment for confounders or address selection and indication biases, making it difficult to use these data to guide treatment decisions. Throughout this review we discuss the difficulty of making a one-size-fits-all recommendation for the clinical needs of older patients with kidney failure. We advocate that a research agenda for optimization of the critical issues we present in this review be implemented. We recommend prospective studies that address these issues, and systematic reviews incorporating the complementary evidence of both observational and interventional studies. Furthermore, we strongly support a shared decision making process matching evidence with patient preferences to ensure that individualized choices are made regarding dialysis vs. conservative kidney management, dialysis modality, and optimal vascular access.

Dialysis in Pregnancy: An Update Review.

Chronic kidney disease and end-stage kidney disease (ESKD) are important public health problems with increased rates of morbidity, mortality, and social costs. Pregnancy is rare in patients with ESKD, with reduced fertility rates in women undergoing dialysis. Although current advances have led to an increase in live births in pregnant dialysis patients, this modality still has an increased risk of multiple adverse events in pregnant women. Despite these existing risks, large-scale studies investigating the management of pregnant women on dialysis are lacking, resulting in the absence of consensus guidelines for this patient group. In this review, we aimed to present the effects of dialysis during pregnancy. We first discuss pregnancy outcomes in dialysis patients and the development of acute kidney injury during pregnancy. Then, we discuss our recommendations for the management of pregnant dialysis patients, including the maintenance of pre-dialysis blood urea nitrogen levels, the ideal frequency and duration of hemodialysis sessions, as well as the modality of renal replacement therapies, the difficulty of maintaining peritoneal dialysis in the third trimester of pregnancy, and optimization of prepregnancy modifiable risk factors. Finally, we present our recommendations for future studies investigating dialysis among pregnant patients.

Chronic kidney disease in the elderly and frail patient: perspectives with opinions and comments.

Chronic kidney disease is common in elderly and frail people. The importance of age in staging chronic kidney disease is discussed as well as the possible constraints of staging what is actually a 'continuum' of disease progression. Frailty is a biological state characterized by the decline of several physiological systems and strongly correlated with adverse health outcomes, including mortality. Frailty is measured by the Comprehensive Geriatric Assessment, which focuses on quantitative rating scales that determine not only the clinical profile and pathological risk of frail individuals, but also their residual capacities, functional status, and quality of life. There is circumstantial evidence that Comprehensive Geriatric Assessment can improve both survival and quality of life in elderly chronic kidney disease patients. Despite the long list of emerging risk factors and markers of chronic kidney disease progression, it is the authors' opinion that a single biochemical parameter can hardly cover the complexity of chronic kidney disease in elderly and frail patients. Among the numerous clinical scores proposed, the European Renal Best Practice guidelines recommend the Renal Epidemiology and Information Network score and the Kidney Failure Risk Equations. The former provides a reasonable estimate of short-term mortality risk, the latter provides the risk of chronic kidney disease progression. In conclusion, the elderly individual with advanced chronic kidney disease is often comorbid and frail with peculiarities in terms of disease grading, clinical assessment and monitoring. The time has come to reshape the care of this growing number of patients by focusing on multidisciplinary teams both in the hospital and in the community.

Validation of formulas calculating normalized protein catabolic rate in patients undergoing home hemodialysis.

Depner and Daugirdas developed a simplified formula to estimate the normalized protein catabolic rate in patients on twice- or thrice-weekly hemodialysis (JASN, 1996). The aim of our work was to establish formulas in more frequent schedules and validate them in home-based hemodialysis patients. We realized that the structure of Depner and Daugirdas' normalized protein catabolic rate formulas has a general meaning and can be expressed as PCRn = C0/[a + b*(Kt/V) + c/(Kt/V)] + d, where C0 is pre-dialysis blood urea nitrogen, Kt/V is dialysis dose, a, b, c, d are the specific coefficients for each combination of home-based hemodialysis schedules and the day of blood sampling. The same applies to the formula that adjusts C0 (C'0) for residual kidney clearance of blood water urea (Kru) and urea distribution volume (V): C'0 = C0*[1 + (a1 + b1/(Kt/V))*Kru/V]. On this basis, we computed the six coefficients (a, b, c, d, a1, b1) for each of the 50 possible combinations and simulated a total of 24,000 weekly dialysis cycles using the Daugirdas Solute Solver software recommended by the KDOQI 2015 guidelines. From the associated statistical analyses we obtained 50 sets of coefficient values, which were validated comparing the paired normalized protein catabolic rate values (i.e., those estimated with our formulas with those modeled with Solute Solver) in 210 datasets of 27 patients on home-based hemodialysis. The mean values ± SD were 1.06 ± 0.262 and 1.07 ± 0.283 g/kg/day, respectively, with a mean difference of 0.004 ± 0.034 g/kg/day (p = 0.11). The paired values were highly correlated (R2 = 0.99). In conclusion, even if the coefficient values were validated in a relatively small sample of patients, they allow an accurate estimation of normalized protein catabolic rate in home-based hemodialysis patients.

Home-based exercise in patients on maintenance dialysis: a systematic review and meta-analysis of randomized clinical trials.

BACKGROUND: The impact of home-based exercise on physical performance and quality of life (QoL) in patients on maintenance dialysis has not yet been fully established. METHODS: We searched four large electronic databases to identify randomized controlled trials (RCTs) reporting the impact of home-based exercise interventions vs. usual care or intradialytic exercise interventions, on physical performance and QoL in patients on dialysis. The meta-analysis was performed using fixed effects modeling. RESULTS: We included 12 unique RCTs involving 791 patients of various ages on maintenance dialysis. Home-based exercise interventions were associated with an improvement of walking speed at the 6 Minutes Walking Test [6MWT; nine RCTs; pooled weighted mean differences (WMD): 33.7 m, 95% confidence interval (CI) 22.8-44.5; P < 0.001; I2 = 0%) and in aerobic capacity as assessed by the peak oxygen consumption (VO2 peak; 3 RCTs; pooled WMD: 2.04 ml/kg/min, 95% CI 0.25-3.83; P = 0.03; I2 = 0%). They were also associated with improved QoL, as assessed by the Short Form (36) Health (SF-36) score. Stratifying the RCTs by control groups, no significant difference was found between home-based exercise and intradialytic exercise interventions. Funnel plots did not reveal any significant publication bias. CONCLUSIONS: Our systematic review and meta-analysis showed that home-based exercise interventions for 3-6 months were associated with significant improvements in physical performance in patients on maintenance dialysis. However, further RCTs with a longer follow-up should be conducted to assess the safety, adherence, feasibility, and effects on QoL of home-based exercise programs in dialysis patients.

Endocrinological disorders in acute kidney injury: an often overlooked field of clinical research.

Acute kidney injury (AKI) is a common comorbidity, affecting approximately one in five hospitalized adults. The kidney is the site for the production, metabolism or excretion of most hormones, including the production of erythropoietin (EPO), the active form of vitamin D, renin, thrombopoietin, and the excretion of insulin, catecholamines, gastrin and many other hormones. Therefore, it is reasonable to say that AKI can have a considerable impact on the endocrine system. Although the effects of AKI on various parameters, including cardiovascular parameters, serum electrolytes and acid-base disorders, neuro-humoral mechanisms and neurological outcomes have been extensively studied, the endocrinological consequences of AKI are understudied. Thyroid dysfunction, mainly euthyroid sick syndrome, hypo/hyperglycemia, bone mineral disorders, changes in EPO and atrial natriuretic peptide (ANP) levels are commonly found in AKI. EPO, thyroxine and ANP administration have been evaluated as potential tools to prevent or treat AKI with varying success, while the effects of AKI on some key hormones, including cortisol and insulin, have never been studied. Aim of this narrative review is to illustrate what is known and what is not known about the endocrinological outcomes of AKI. Few clinical trials are ongoing: however, there is a clear need for large-scale randomized controlled trials investigating the endocrinological consequences of AKI.

Outcomes of COVID-19 in peritoneal dialysis patients: A report by the European Renal Association COVID-19 Database.

BACKGROUND: The clinical course of COVID-19 in peritoneal dialysis (PD) patients has so far only been analysed in relatively small, often single-centre case series. Therefore, we studied patient- and disease-related characteristics and outcomes of COVID-19 in a larger European cohort of PD patients. METHODS: We used data from the European Renal Association COVID-19 Database (ERACODA) on PD and haemodialysis (HD) patients with COVID-19 (presentation between February 2020 and April 2021). Hazard ratios (HR) for mortality at 3 months were calculated using Cox proportional-hazards regression. In addition, we examined functional and mental health status among survivors at this time point as determined by their treating physician. RESULTS: Of 216 PD patients with COVID-19, 80 (37%) were not hospitalised and 136 (63%) were hospitalised, of whom 19 (8.8%) were admitted to an intensive care unit. Mortality at 3 months for these subgroups was 18%, 40%, and 37%, respectively (p = 0.0031). Compared with HD patients, PD patients had higher mortality (crude HR: 1.49; 95% CI: 1.33-1.66), even when adjusted for patient characteristics and disease severity (adjusted HR: 1.56; 95% CI: 1.39-1.75). Follow-up data on 67 of 146 patients who survived COVID-19 showed functional recovery to pre-COVID-19 levels in 52 (78%) and mental recovery in 58 patients (87%) at 3 months after the COVID-19 diagnosis. CONCLUSION: The mortality rate in the first 3 months after presentation with COVID-19 is high, especially among PD patients who were hospitalised. PD patients with COVID-19 had a higher mortality risk than HD patients. The majority of surviving patients recovered both functionally and mentally from COVID-19 within 3 months.

Is there any robust evidence showing that SGLT2 inhibitor use predisposes to acute kidney injury?

A novel class of oral glucose lowering drugs, sodium-glucose co-transporter type 2 inhibitors (SGLT2is), has shown additional beneficial effects on body weight, serum uric acid levels, blood pressure, and cardiac and renal function. Conflicting data have been published regarding the potential risk of acute kidney injury (AKI) when using SGLT2is. Aim of this manuscript was to review the current literature on this issue. SGLT2is induce a mild acute decline in estimated glomerular filtration rate, attributed to the effect of proximal tubular natriuresis on tubuloglomerular feedback through increased macula densa sodium delivery, leading to afferent arteriole vasoconstriction and reduced intraglomerular pressure. This functional effect with a subsequent rise in serum creatinine fulfills the creatinine-based criteria for AKI, as defined in clinical practice and trial settings. Other proposed potential mechanisms as to how SGLT2is lead to AKI include osmotic diuresis leading to volume depletion, increased urinary uric acid levels, intratubular oxidative stress, local inflammation and tubular injury. Despite the warning published by the US Food and Drug Administration in 2016 about a potential risk of AKI and the report of some clinical cases of AKI after treatment with SGLT2is, large observational real-life retrospective studies, randomized controlled trials and propensity-matched analyses of data from clinical practice unambiguously demonstrate that SGLT2is are safe for the kidney and do not predispose to AKI. In conclusion, while we can probably stop worrying about AKI risk when using SGLT2is, the question whether these agents should be withheld in the presence of clinical situations at high risk for AKI remains unaddressed.

The conundrum of the complex relationship between acute kidney injury and cardiac arrhythmias.

Acute kidney injury (AKI) is defined by a rapid increase in serum creatinine levels, reduced urine output or both. Death may occur in 16-49% of patients admitted to an intensive care unit with severe AKI. Complex arrhythmias are a potentially serious complication in AKI patients with pre-existing or AKI-induced heart damage and myocardial dysfunction, with fluid overload, especially electrolyte and acid-base disorders, representing the pathogenetic mechanisms of arrhythmogenesis. Cardiac arrhythmias, in turn, increase the risk of poor renal outcomes, including AKI. Arrhythmic risk in AKI patients receiving kidney replacement treatment may be reduced by modifying dialysis/replacement fluid composition. The most common arrhythmia observed in AKI patients is atrial fibrillation. Severe hyperkalaemia, sometimes combined with hypocalcaemia, causes severe bradyarrhythmias in this clinical setting. Although the likelihood of life-threatening ventricular arrhythmias is reportedly low, the combination of cardiac ischaemia and specific electrolyte or acid-base abnormalities may increase this risk, particularly in AKI patients who require kidney replacement treatment. The purpose of this review is to summarize the available epidemiological, pathophysiological and prognostic evidence aiming to clarify the complex relationships between AKI and cardiac arrhythmias.

Preparing European Nephrology for the next pandemic: lessons from the ERACODA collaboration.

Owing to the vulnerability of patients with chronic kidney disease to infectious diseases, the coronavirus disease 2019 (COVID-19) pandemic has been particularly devastating for the nephrology community. Unfortunately, the possibility of future COVID-19 waves or outbreaks of other infectious diseases with pandemic potential cannot be ruled out. The nephrology community made tremendous efforts to contain the consequences of the COVID-19 pandemic. Despite this, the COVID-19 pandemic has highlighted several shortcomings in our response to the pandemic and has taught us important lessons that can be utilized to improve our preparedness for any future health crises of a similar nature. In this article we draw lessons from the European Renal Association COVID-19 Database (ERACODA) project, a pan-European collaboration initiated in March 2020 to understand the prognosis of COVID-19 in patients on kidney function replacement therapy. We discuss the challenges faced in generating timely and robust evidence for informed management of patients with kidney disease and give recommendations for our preparedness for the next pandemic in Europe. Limited collaboration, the absence of common data architecture and the sub-optimal quality of available data posed challenges in our response to COVID-19. Aligning different research initiatives, strengthening electronic health records, and involving experts in study design and data analysis will be important in our response to the next pandemic. The European Renal Association may take a leading role in aligning research initiatives via its engagement with other scientific societies, national registries, administrators and researchers.

On the importance of the interplay of residual renal function with clinical outcomes in end-stage kidney disease.

Chronic kidney disease (CKD) is one of the most important public health concerns of the century, and is associated with high rates of morbidity, mortality and social costs. CKD evolving towards end-stage kidney disease (ESKD) is on the rise resulting in a greater number of patients requiring peritoneal dialysis (PD) and hemodialysis (HD). The aim of this manuscript is to review the current literature on the interplay of residual renal function (RRF) with clinical outcomes in ESKD. The persistence of RRF is one of the most important predictors of decreased morbidity, mortality, and better quality of life in both PD and HD patients. RRF contributes to the well-being of ESKD patients through various mechanisms including higher clearance of solutes, maintenance of fluid balance, removal of uremic toxins and control of electrolytes. Furthermore, RRF has beneficial effects on inflammation, anemia, malnutrition, diabetes mellitus, obesity, changes in the microbiota, and cardiac diseases. Several strategies have been proposed to preserve RRF, such as blockade of the renin-angiotensin-aldosterone system, better blood pressure control, incremental PD and HD. Several clinical trials investigating the issue of preservation of RRF are ongoing. They are needed to broaden our understanding of the interplay of RRF with clinical outcomes in ESKD.