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Long-term multilineage hematopoietic donor chimerism occurs sporadically in patients who receive a transplanted solid organ enriched in lymphoid tissues such as the intestine or liver. There is currently no evidence for the presence of kidney-resident hematopoietic stem cells in any mammal species. Graft-versus-host-reactive donor T cells promote engraftment of graft-derived hematopoietic stem cells by making space in the bone marrow. Here, we report full (over 99%) multilineage, donor-derived hematopoietic chimerism in a pediatric kidney transplant recipient with syndromic combined immune deficiency that leads to transplant tolerance. Interestingly, we found that the human kidney-derived hematopoietic stem cells took up long-term residence in the recipient's bone marrow and gradually replaced their host counterparts, leading to blood type conversion and full donor chimerism of both lymphoid and myeloid lineages. Thus, our findings highlight the existence of human kidney-derived hematopoietic stem cells with a self-renewal ability able to support multilineage hematopoiesis., (Copyright © 2022 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.)

Vascular calcification associated with chronic kidney disease (CKD) is an active, regulated process. Apoptosis of vascular smooth muscle cells has long been known to play a major role in its pathogenesis, with apoptotic bodies derived from these cells acting as nucleating structures for calcium crystal formation and deposition. Ye et al. now show in experimental models in vitro and in vivo that ferroptosis can also contribute to the development of vascular calcification in CKD., (Copyright © 2022 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.)

The most important contributors to the anemia of patients with chronic kidney disease are insufficient erythropoietin production and erythropoietin hyporesponsiveness, decreased red blood cell half-life, iron deficiency, and inflammation. However, in contrast to the role of kidney failure, that of proteinuria and nephrotic syndrome is less clear. Bissinger et al. now provide evidence in mouse models and patients with chronic kidney disease that heavy proteinuria alters erythrocyte metabolism and increases erythrocyte death., (Copyright © 2021 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.)

In chronic kidney disease (CKD), calcium-sensing receptor (CaSR) expression and function have been extensively studied in parathyroid tissue and vascular tissues. To examine whether similar changes occurred in other tissues, we measured total and surface CaSR expression in monocytes of patients with various stages of CKD and healthy volunteers respectively in cross-sectional studies. We further explored in vitro the impact of uremic serum on CaSR expression in monocytes (U937 and THP-1 cell lines), and whether human peripheral blood mononuclear cells or U937 and THP-1 monocytes might modify vascular calcium deposition in rat carotid arteries in vitro. CKD was associated with a decrease in peripheral blood mononuclear cell CaSR expression both in total and at the monocyte surface alone (43% and 34%, respectively in CKD stages 4-5). This decrease was associated with a reduction in the ability of monocytes to inhibit vascular calcification in vitro. Pretreatment with the calcimimetic NPSR568 of peripheral blood mononuclear cells isolated from patients with CKD significantly improved monocyte capacity to reduce carotid calcification in vitro. The fewer peripheral blood mononuclear cells expressing cell surface CaSR, the more calcimimetic treatment enhanced the decrease of carotid calcium content. Thus, we demonstrate that monocyte CaSR expression is decreased in patients with CKD and provide in vitro evidence for a potential role of this decrease in the promotion of vascular calcification. Hence, targeting this alteration or following monocyte CaSR expression as an accessible marker might represent a promising therapeutic strategy in CKD-associated arterial calcification., (Copyright © 2021 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.)

In chronic kidney disease, anemia and disordered iron homeostasis are prevalent and associated with significant adverse consequences. In 2012, Kidney Disease: Improving Global Outcomes (KDIGO) issued an anemia guideline for managing the diagnosis, evaluation, and treatment of anemia in chronic kidney disease. Since then, new data have accrued from basic research, epidemiological studies, and randomized trials that warrant a re-examination of previous recommendations. Therefore, in 2019, KDIGO decided to convene 2 Controversies Conferences to review the latest evidence, explore new and ongoing controversies, assess change implications for the current KDIGO anemia guideline, and propose a research agenda. The first conference, described here, focused mainly on iron-related issues, including the contribution of disordered iron homeostasis to the anemia of chronic kidney disease, diagnostic challenges, available and emerging iron therapies, treatment targets, and patient outcomes. The second conference will discuss issues more specifically related to erythropoiesis-stimulating agents, including epoetins, and hypoxia-inducible factor-prolyl hydroxylase inhibitors. Here we provide a concise overview of the consensus points and controversies resulting from the first conference and prioritize key questions that need to be answered by future research., (Copyright © 2021 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.)

In chronic kidney disease, parathyroid hormone (PTH), like all proteins, can undergo post-translational modifications, including oxidation. This can lead to structural and functional changes of the hormone. It has been hypothesized that currently used PTH measurement methods do not adequately reflect PTH-related bone and cardiovascular abnormalities in chronic kidney disease owing to the presence of oxidized, biologically inactive PTH in the circulation. Ursem et al. now report a strong correlation between serum non-oxidized and total PTH, and comparable associations with histomorphometric and circulating bone turnover markers, pleading against this hypothesis., (Copyright © 2021 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.)

Vascular calcification is common in patients with advanced kidney disease, and has been strongly linked to cardiovascular morbidity and mortality in the general population. Recent clinical and translational studies demonstrate that vascular calcification is also associated with cardiovascular morbidity in the setting of chronic kidney disease, and that once established, may persist even when kidney function is restored., (Copyright © 2017 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.)

The treatment of anemia with erythropoiesis-stimulating agents and iron supplementation has become the standard of care in patients with chronic kidney disease. Because of the risks associated with this approach, hypoxia inducible factor stabilizing prolyl hydroxylase inhibitors were developed as a potential treatment alternative. In recent phase 2 trials, these agents raised hemoglobin in a predictable and controlled manner and improved markers of iron metabolism. More experience is needed to establish long-term efficacy, tolerability, and safety, and to determine whether their use is associated with lower iron requirements., (Copyright © 2016 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.)

Vascular calcification and kidney fibrosis are 2 important features of chronic kidney disease. Bone morphogenetic proteins/growth differentiation factors and their receptors are implicated in the pathogenesis of both processes. Modulation of the bone morphogenetic protein/growth differentiation factor pathways by a soluble chimeric protein that contains the activin receptor IIA (ActRIIA) domain and acts as an ActRIIA ligand trap for activin and other ligands could become a new therapeutic strategy for vascular calcification and kidney fibrosis in chronic kidney disease., (Copyright © 2016 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.)

International clinical practice guidelines for the management of anemia in chronic kidney disease suggest target hemoglobin levels ≤ 11.5 g/dl (115 g/l), with individualized consideration of slightly higher hemoglobin targets to improve quality of life. An updated meta-analysis of randomized trials demonstrates no significant improvement in quality of life with erythropoietin-stimulating agent therapy targeting higher hemoglobin levels. Limitations of the available data suggest that individualized targets should nonetheless remain an option in future clinical practice guidelines., (Copyright © 2016 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.)

Chronic metabolic acidosis stimulates bone resorption, resulting in loss of calcium and bicarbonate from bone. Both osteoblasts and osteoclasts sense extracellular H(+) by the G-protein coupled receptor, OGR1, whose activation leads to increased bone resorption as well as decreased bone formation. Krieger et al. examined the effect of OGR1 knockout in mice. They found an unexpected increase in bone resorption, but nevertheless an increase in bone volume linked to enhanced bone formation. This discovery opens a window of opportunity to explore potential new anabolic treatments for patients with low bone mass., (Copyright © 2016 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.)

The relationship between salt and human health has been the subject of controversy over the past century. The largest study in the field demonstrates a J-curve relationship between sodium intake and adverse clinical outcomes, suggesting a need to reevaluate current recommendations to restrict sodium intake to less than 2 g/d in the general population., (Copyright © 2016 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.)

Serum phosphorus and the regulatory hormone fibroblast growth factor 23 have been strongly linked to cardiovascular morbidity and mortality in patients with chronic kidney disease. A recent study identified fibroblast growth factor receptor 4 as the primary receptor mediating the effect of fibroblast growth factor 23 on left ventricular hypertrophy, providing new mechanistic insights and a potential therapeutic target to reduce cardiovascular morbidity in chronic kidney disease., (Copyright © 2016 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.)

Iron deficiency in patients with chronic kidney disease (CKD) can be corrected by the oral or intravenous route. The natural intestinal barrier against iron overload is circumvented by intravenous iron. The balance between benefit and risk of high iron doses remains unclear. In a randomized controlled trial in CKD patients, Agarwal et al. find similar effects of oral and intravenous iron on hemoglobin levels and kidney function decline but more serious cardiovascular events and infections with intravenous iron.

In the majority of patients with chronic kidney disease (CKD) the total and low-density lipoprotein (LDL) cholesterol are usually normal, with the exception of patients with nephrotic-range proteinuria and in peritoneal dialysis patients. Moreover, epidemiological evidence shows that the link between serum total cholesterol or LDL cholesterol and cardiovascular disease (CVD) in CKD is not as straightforward as in the general population. In addition, atherosclerosis-related events are responsible for only ∼30% of CVD in these patients. Nevertheless, intervention trials, particularly the Study of Heart and Renal Protection, and meta-analyses showed a proportional reduction of cardiovascular risk associated with the absolute reduction in LDL cholesterol in patients with CKD similar to the general population, with apparent attenuation of this relationship in end-stage kidney disease. Therefore, the use of cholesterol-lowering agents appears to be indicated in early CKD stages to prevent atherosclerosis-related risk. However, uncertainty persists as to the optimal management of this risk in end-stage kidney disease patients. In the present review, we discuss these issues and end up with a practical plan aimed to help the nephrologist in managing atherosclerosis-related risk using cholesterol-lowering therapies in CKD patients.