A Historical Perspective on Uremia and Uremic Toxins.

Uremia, also known as uremic syndrome, refers to the clinical symptoms in the final stage of renal failure. The definition of the term has changed over time due to an improved comprehension of the kidney's function and the advancement of dialysis technology. Here, we aim to present an overview of the various concepts that have developed regarding uremia throughout the years. We provide a comprehensive review of the historical progression starting from the early days of Kolff and his predecessors, continuing with the initial research conducted by Niwa et al., and culminating in the remote sensing hypothesis of Nigam. Additionally, we explore the subsequent investigation into the function of these toxins as signaling molecules in various somatic cells.

Chronic kidney disease in inflammatory bowel disease, a systematic review and meta-analysis.

Inflammatory bowel disease (IBD) is associated with various immune mediated disorders including spondylarthritis, pyoderma gangrenosum, primary sclerosing cholangitis and uveitis. Chronic kidney disease (CKD) is defined by a reduction in kidney function (eGFR less than 60ml/min/1.73m2) and/ or damage markers that are present for at least three months, regardless of the aetiology. Case reports and cohort studies suggest that IBD is associated with CKD. The extent and magnitude of a potential association is unknown. A comprehensive search was conducted in EMBASE, MEDLINE, Web of Science, the Cochrane database, and SCOPUS. Two separate reviewers were involved in the process of article selection and evaluation. Odds ratios were calculated in those papers with a comparison between an IBD population and a non-IBD control population, the Mantel Haenszel test was employed, utilizing a random effect model. The systematic review was registered in PROSPERO (RD42023381927). Fifty-four articles were included in the systematic review. Of these, eight articles included data on prevalence of CKD in IBD patients (n = 102,230) vs. healthy populations (n = 762,430). Of these, diagnosis of CKD was based on ICD codes in five studies vs. on eGFR in three studies. The overall odds ratio of developing CKD in the IBD population is 1.59 (95%CI 1.31-1.93), without any difference between studies using diagnostic coding (OR 1.70 95%CI 1.33-2.19) vs. diagnosis based on eGFR (OR 1.36 95%CI 1.33-1.64). IBD is associated with a clinically meaningful increased CKD prevalence. We provide recommendations on diagnostic evaluation, as well as suggestions for future research.

Regional Citrate Anticoagulation: A Tale of More Than Two Stories.

Calcium is a key clotting factor, and several inorganic molecules that bind to calcium have been found to reduce the clotting propensity of blood. Citrate, a calcium chelator, is used as inhibitor of the coagulation cascade in blood transfusion. Also, it is used as an anaticoagulant during dialysis to maintain patency of the extracorporeal circuit, known as regional citrate anticoagulation (RCA). The amount of citrate should be chosen such that ionized calcium concentrations in the extracorporeal circuit are reduced enough to minimize propagation of the coagulation cascade. The dialytic removal of the calcium-citrate complexes combined with reduced ionized calcium concentrations makes necessary calcium supplementation of the blood returning to the patient. This can be achieved in different ways. In classical RCA, citrate and calcium are infused in the afferent and efferent tubing, respectively, whereas the dialysate does not contain calcium. This setup has been shown to be highly efficacious with a very low clotting propensity. Strict monitoring of blood electrolytes is required. Alternatively, the use of a high-calcium dialysate leads to calcium loading, obviating the need for a separate calcium infusion pump. The main advantages are simplified delivery of RCA and less fluctuation of systemic calcium concentrations. Currently, citric acid is sometimes added to the acid concentrate as a replacement for acetic acid. Differences and similarities between RCA and citrate-containing dialysate are discussed. RCA is an excellent alternative to heparin for patients at high risk of bleeding. Semin Nephrol 36:x-xx © 20XX Elsevier Inc. All rights reserved.

Avoiding Systemic Heparinization During Hemodialysis: How the Dialysis Setup Might Help.

Heparin is the most widely used anticoagulant for maintaining patency of the extracorporeal blood circuit during intermittent hemodialysis. Inadvertently, this leads to systemic heparinization of the patient. Repeated intermittent heparinization during hemodialysis has been associated with increased bleeding risks and metabolic and immunologic effects. Alternative strategies for minimizing systemic anticoagulation encompass dilution methods, regional citrate anticoagulation, priming of the extracorporeal circuit, and modifications to dialyzer membranes and dialysate composition. The effectiveness of these alternatives in maintaining patency of the extracorporeal circuit varies substantially. Although most studies have focused on particular changes in the hemodialysis setup, several combined interventions for adapting the hemodialysis setup are now being studied. This narrative review aims to present an overview of the current landscape of hemodialysis setup strategies aimed at limiting or avoiding systemic anticoagulation during treatment. Additionally, this review intends to shed light on the underlying pathophysiological mechanisms that contribute to variations observed in reported outcomes.

Extracorporeal Techniques in Kidney Failure.

During the last decades, various strategies have been optimized to enhance clearance of a variable spectrum of retained molecules to ensure hemodynamic tolerance to fluid removal and improve long-term survival in patients affected by kidney failure. Treatment effects are the result of the interaction of individual patient characteristics with device characteristics and treatment prescription. Historically, the nephrology community aimed to provide adequate treatment, along with the best possible quality of life and outcomes. In this article, we analyzed blood purification techniques that have been developed with their different characteristics.

Healthcare professional education in shared decision making in the context of chronic kidney disease: a scoping review.

RATIONALE & OBJECTIVE: Shared decision making (SDM) is a collaborative effort between healthcare professionals, individuals with CKD whereby clinical evidence, expected outcomes and potential side-effects are balanced with individual values and beliefs to provide the best mutually decided treatment option. Meaningful SDM is supported by effective training and education. We aimed to identify the available evidence on SDM training and education of healthcare professionals caring for people with chronic kidney disease. We aimed to identify existing training programs and to explore what means are used to evaluate the quality and effectiveness of these educational efforts. METHODOLOGY: We performed a scoping review to study the effectiveness of training or education about shared decision making of healthcare professionals treating patients with kidney disease. EMBASE, MEDLINE, CINAHL and APA PsycInfo were searched. RESULTS: After screening of 1190 articles, 24 articles were included for analysis, of which 20 were suitable for quality appraisal. These included 2 systematic reviews, 1 cohort study, 7 qualitative studies, and 10 studies using mixed methods. Study quality was varied with high quality (n = 5), medium quality (n = 12), and low quality (n = 3) studies. The majority of studies (n = 11) explored SDM education for nurses, and physicians (n = 11). Other HCP profiles included social workers (n = 6), dieticians (n = 4), and technicians (n = 2). Topics included education on SDM in withholding of dialysis, modality choice, patient engagement, and end-of-life decisions. LIMITATIONS: We observed significant heterogeneity in study design and varied quality of the data. As the literature search is restricted to evidence published between January 2000 and March 2021, relevant literature outside of this time window has not been taken into account. CONCLUSIONS: Evidence on training and education of SDM for healthcare professionals taking care of patients with CKD is limited. Curricula are not standardized, and educational and training materials do not belong to the public domain. The extent to which interventions have improved the process of shared-decision making is tested mostly by pre-post testing of healthcare professionals, whereas the impact from the patient perspective for the most part remains untested.

Strategies to prevent SARS-CoV-2 transmission in hemodialysis centres across Europe-lessons for the future.

Background: Early reports on the pandemic nature of coronavirus disease 2019 (COVID-19) directed the nephrology community to develop infection prevention and control (IPC) guidance. We aimed to make an inventory of strategies that dialysis centres followed to prevent infection with COVID-19 in the first pandemic wave. Methods: We analyzed IPC measures taken by hemodialysis centres treating patients presenting with COVID-19 between 1 March 2020 and 31 July 2020 and that completed the European Renal Association COVID-19 Database centre questionnaire. Additionally, we made an inventory of guidelines published in European countries to prevent spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in dialysis centres. Results: Data from 73 dialysis units located in and bordering Europe were analyzed. All participating centres implemented IPC measures to mitigate the impact of SARS-CoV-2 during the first pandemic wave. Measures mentioned most often included triage with questions before entering the dialysis ward, measuring body temperature, hand disinfection, masking for all patients and staff, and personal protective equipment for staff members. These measures were also recommended in most of the 14 guidelines that were identified in the inventory of national guidelines and were also scored as being among the most important measures by the authors of this paper. Heterogeneity existed between centres and national guidelines regarding the minimal distance between dialysis chairs and recommendations regarding isolation and cohorting. Conclusions: Although variation existed, measures to prevent transmission of SARS-CoV-2 were relatively similar across centres and national guidelines. Further research is needed to assess causal relationships between measures taken and spread of SARS-CoV-2.

Food-Derived Uremic Toxins in Chronic Kidney Disease.

Patients with chronic kidney disease (CKD) have a higher cardiovascular risk compared to the average population, and this is partially due to the plasma accumulation of solutes known as uremic toxins. The binding of some solutes to plasma proteins complicates their removal via conventional therapies, e.g., hemodialysis. Protein-bound uremic toxins originate either from endogenous production, diet, microbial metabolism, or the environment. Although the impact of diet on uremic toxicity in CKD is difficult to quantify, nutrient intake plays an important role. Indeed, most uremic toxins are gut-derived compounds. They include Maillard reaction products, hippurates, indoles, phenols, and polyamines, among others. In this review, we summarize the findings concerning foods and dietary components as sources of uremic toxins or their precursors. We then discuss their endogenous metabolism via human enzyme reactions or gut microbial fermentation. Lastly, we present potential dietary strategies found to be efficacious or promising in lowering uremic toxins plasma levels. Aligned with current nutritional guidelines for CKD, a low-protein diet with increased fiber consumption and limited processed foods seems to be an effective treatment against uremic toxins accumulation.

The Evolving View of Uremic Toxicity.

Indoxyl sulfate, closely related to indigo, a dye valued for it binding to cloth, has been recognized as a protein-bound solute bound to albumin, present in increased concentration in the serum of patients with impaired glomerular filtration (13). The early studies of Niwa identified indoxyl sulfate as a toxin capable of accelerating the rate of renal damage in subtotal nephrectomized rats (18). Over the past decade other protein-bound solutes have been identified in the plasma of patients with impaired glomerular filtration. Although the early studies, focused on the kidney, identified indoxyl sulfate as a toxic waste product dependent on the kidney for its removal, subsequent observations have identified organic anion transporters on many non-renal tissue, leading to the view that indoxyl sulfate is part of a systemic signaling system.

Effects of an SGLT Inhibitor on the Production, Toxicity, and Elimination of Gut-Derived Uremic Toxins: A Call for Additional Evidence.

Sodium-glucose cotransporter (SGLT) inhibitors are a class of oral hypoglycemic agents, which, in recent years, have been shown to improve renal and cardiovascular outcomes in patients with diabetic and non-diabetic chronic kidney disease. There remains considerable debate regarding the potential glucose-independent mechanisms by which these benefits are conferred. SGLT inhibitors, to a variable extent, impair small intestinal glucose absorption, facilitating the delivery of glucose into the colon. This suppresses protein fermentation, and thus the generation of uremic toxins such as phenols and indoles. It is acknowledged that such a shift in gut microbial metabolism yields health benefits for the host. SGLT inhibition, in addition, may be hypothesized to foster the renal clearance of protein-bound uremic toxins. Altered generation and elimination of uremic toxins may be in the causal pathway between SGLT inhibition and improved cardiometabolic health. Present review calls for additional research.

Natural History of Bone Disease following Kidney Transplantation.

BACKGROUND: Knowledge of the effect of kidney transplantation on bone is limited and fragmentary. The aim of this study was to characterize the evolution of bone disease in the first post-transplant year. METHODS: We performed a prospective, observational cohort study in patients referred for kidney transplantation under a steroid-sparing immunosuppressive protocol. Bone phenotyping was done before, or at the time of, kidney transplantation, and repeated at 12 months post-transplant. The phenotyping included bone histomorphometry, bone densitometry by dual-energy x-ray absorptiometry, and biochemical parameters of bone and mineral metabolism. RESULTS: Paired data were obtained for 97 patients (median age 55 years; 72% male; 21% of patients had diabetes). Bone turnover remained normal or improved in the majority of patients (65%). Bone histomorphometry revealed decreases in bone resorption (eroded perimeter, mean 4.6% pre- to 2.3% post-transplant; P<0.001) and disordered bone formation (fibrosis, 27% pre- versus 2% post-transplant; P<0.001). Whereas bone mineralization was normal in all but one patient pretransplant, delayed mineralization was seen in 15% of patients at 1 year post-transplant. Hypophosphatemia was associated with deterioration in histomorphometric parameters of bone mineralization. Changes in bone mineral density were highly variable, ranging from -18% to +17% per year. Cumulative steroid dose was related to bone loss at the hip, whereas resolution of hyperparathyroidism was related to bone gain at both spine and hip. CONCLUSIONS: Changes in bone turnover, mineralization, and volume post-transplant are related both to steroid exposure and ongoing disturbances of mineral metabolism. Optimal control of mineral metabolism may be key to improving bone quality in kidney transplant recipients. CLINICAL TRIAL REGISTRY NAME AND REGISTRATION NUMBER: Evolution of Bone Histomorphometry and Vascular Calcification Before and After Renal Transplantation, NCT01886950.

Diagnostic Accuracy of Noninvasive Bone Turnover Markers in Renal Osteodystrophy.

RATIONALE & OBJECTIVE: Bone biopsy remains the gold standard for diagnosing renal osteodystrophy as comparable noninvasive alternatives have yet to be established. This study investigated the diagnostic accuracy of biochemical markers of skeletal remodeling to predict bone turnover. STUDY DESIGN: Cross-sectional retrospective diagnostic test study. SETTING & PARTICIPANTS: Patients with chronic kidney disease glomerular filtration rate categories 4-5, including patients treated with dialysis (G4-G5D) and kidney transplant recipients with successful transiliac bone biopsies. TESTS COMPARED: Bone turnover as determined by bone histomorphometry was compared with the following biochemical markers: full-length (amino acids 1-84) "biointact" parathyroid hormone (PTH), bone-specific alkaline phosphatase (BsAP), intact procollagen type I N-terminal propeptide (PINP), and tartrate-resistant acid phosphatase isoform 5b (TRAP5b). OUTCOME: Diagnostic performance was evaluated by area under the receiver operator characteristics curve (AUC), sensitivity, specificity, and negative and positive predictive values. Optimal diagnostic cutoffs were determined in an exploration cohort (n = 100) and validated in a separate cohort (n = 99). RESULTS: All biomarkers differed across categories of low 33 (17%), normal 109 (55%), and high 57 (29%) bone turnover. AUC values were in the range of 0.75-0.85. High negative predictive values (≥90%) were found for both high and low bone turnover, indicating the ability to rule out both conditions using the suggested biomarker cutoffs. The highest diagnostic performances were seen with combinations of biomarkers, with overall diagnostic accuracies of 90% for high turnover, and 78% for low turnover. Results were comparable for kidney transplant candidates and recipients in a sensitivity analysis. LIMITATIONS: The single-center approach and heterogeneity of the study cohort are main limitations of this study. CONCLUSIONS: We conclude that the diagnostic performance of biochemical markers of bone turnover is acceptable, with clinical utility in ruling out both high and low turnover bone disease.

Strategies for asymmetrical triacetate dialyser heparin-free effective haemodialysis: the SAFE study.

BACKGROUND: In haemodialysis, maintaining patency of the extracorporeal circuit requires the use of anticoagulants. Although (low molecular weight) heparins are the mainstay, these are not well tolerated in all patients. Alternative approaches include saline infusion, citrate-containing dialysate, regional citrate anticoagulation or the use of heparin-coated membranes. Asymmetric cellulose triacetate (ATA) dialysers have a low degree of platelet contact activation and might be an alternative to heparin-coated dialysers. The aim of this study was to test the clotting propensity of ATA when used without systemic anticoagulation. METHODS: We performed a Phase II pilot study in maintenance dialysis patients. The 'Strategies for Asymmetrical Triacetate dialyzer heparin-Free Effective hemodialysis' (SAFE) study was a two-arm open-label crossover study. In Arm A, patients were dialysed using 1.9 m2 ATA membranes in combination with a citrate-containing dialysate (1 mM). In Arm B, the ATA membrane was combined with high-volume predilution haemodiafiltration (HDF) without any other anticoagulation. The primary endpoint was the success rate to complete 4 h of haemodialysis without preterm clotting. Secondary endpoints included time to clotting and measures of dialysis adequacy. RESULTS: We scheduled 240 dialysis sessions (120/arm) in 20 patients. Patients were randomized 1:1 to start with Arm A or B. All patients crossed to the other arm halfway through the study. A total of 232 (96.7%) study treatments were delivered. Overall, 23 clotting events occurred, 7 in Arm A and 16 in Arm B. The success rate in Arm A (ATA + citrate-containing dialysate) was 90.8/94.0% [intention to treat (ITT)/as treated]. The success rate in Arm B (ATA + predilution HDF) was 83.3/86.2% (ITT/as treated). Time to clotting was borderline significantly better in Arm A (Mantel-Cox log rank P = 0.05). CONCLUSION: ATA dialysers have a low clotting propensity and both predilution HDF and a citrate-containing dialysate resulted in high rates of completed dialysis sessions.

Effect of Vancomycin on the Gut Microbiome and Plasma Concentrations of Gut-Derived Uremic Solutes.

INTRODUCTION: Declining renal function results in the accumulation of solutes normally excreted by healthy kidneys. Data suggest that some of the protein-bound solutes mediate accelerated cardiovascular disease. Many of the poorly dialyzable protein-bound uremic retention solutes are products of gut bacterial metabolism. METHODS: We performed a blinded-randomized controlled trial comparing the changes in plasma concentrations of a panel of protein-bound solutes and microbiome structure in response to the once-weekly oral administration of 250 mg of vancomycin or placebo over a period of 12 weeks in a cohort of stable patients with end-stage kidney disease. We also examined the pattern of recovery of the solutes and gut microbiome over 12 weeks of placebo administration following vancomycin. RESULTS: We enrolled 15 subjects. Ten subjects provided sufficient plasma and stool samples to permit us to examine the effect of vancomycin on plasma solute levels. We showed that a weekly dose of vancomycin resulted in a reduction in the plasma concentration of 7 colon-derived solutes. We described a significant effect of vancomycin on the microbiome structure with a decrease in alpha diversity and change in beta diversity. Multiple taxa decreased with vancomycin including genera Clostridium and Bacteroides. We demonstrated microbiome recovery after stopping vancomycin. However, recovery in the solutes was highly variable between subjects. CONCLUSIONS: We demonstrated that microbiome suppression using vancomycin resulted in changes in multiple gut-derived uremic solutes. Future studies are needed to address whether reduction in those uremic solutes results in improvement of cardiovascular outcomes in ESKD patients.

Patterns of renal osteodystrophy 1 year after kidney transplantation.

BACKGROUND: Renal osteodystrophy is considered common, but is not well characterized in contemporary kidney transplant recipients. This study reports extensively on bone phenotype by bone histomorphometry, bone densitometry and novel bone biomarkers 1 year after kidney transplantation. METHODS: A transiliac bone biopsy and dual-energy X-ray absorptiometry scans were performed in 141 unselected kidney transplant recipients in this observational cohort study. Blood and 24-h urine samples were collected simultaneously. RESULTS: The median age was 57 ± 11 years, 71% were men and all were of Caucasian ethnicity. Bone turnover was normal in 71% of patients, low in 26% and high in just four cases (3%). Hyperparathyroidism with hypercalcaemia was present in 13% of patients, of which only one had high bone turnover. Delayed bone mineralization was detected in 16% of patients, who were characterized by hyperparathyroidism (137 versus 53 ρg/mL), a higher fractional excretion of phosphate (40 versus 32%) and lower levels of phosphate (2.68 versus 3.18 mg/dL) and calcidiol (29 versus 37 ng/mL) compared with patients with normal bone mineralization. Osteoporosis was present in 15-46% of patients, with the highest prevalence at the distal skeleton. The proportion of osteoporotic patients was comparable across categories of bone turnover and mineralization. CONCLUSIONS: The majority of kidney transplant recipients, including patients with osteoporosis, have normal bone turnover at 1-year post-transplant. Low bone turnover is seen in a substantial subset, while high bone turnover is rare. Vitamin D deficiency and hypophosphataemia represent potential interventional targets to improve bone health post-transplant.