Despite recent advances in chronic kidney disease (CKD) and end-stage renal disease (ESRD) management, morbidity and mortality in this population remain exceptionally high. Persistent, low-grade ...inflammation has been recognized as an important component of CKD, playing a unique role in its pathophysiology and being accountable in part for cardiovascular and all-cause mortality, as well as contributing to the development of protein-energy wasting.
The variety of factors contribute to chronic inflammatory status in CKD, including increased production and decreased clearance of pro-inflammatory cytokines, oxidative stress and acidosis, chronic and recurrent infections, including those related to dialysis access, altered metabolism of adipose tissue, and intestinal dysbiosis. Inflammation directly correlates with the glomerular filtration rate (GFR) in CKD and culminates in dialysis patients, where extracorporeal factors, such as impurities in dialysis water, microbiological quality of the dialysate, and bioincompatible factors in the dialysis circuit play an additional role. Genetic and epigenetic influences contributing to inflammatory activation in CKD are currently being intensively investigated. A number of interventions have been proposed to target inflammation in CKD, including lifestyle modifications, pharmacological agents, and optimization of dialysis. Importantly, some of these therapies have been recently tested in randomized controlled trials.
Chronic inflammation should be regarded as a common comorbid condition in CKD and especially in dialysis patients. A number of interventions have been proven to be safe and effective in well-designed clinical studies. This includes such inexpensive approaches as modification of physical activity and dietary supplementation. Further investigations are needed to evaluate the effects of these interventions on hard outcomes, as well as to better understand the role of inflammation in selected CKD populations (e.g., in children).
Chronic kidney disease is an ongoing deterioration of renal function that often progresses to end-stage renal disease. Management goals in children include slowing disease progression, prevention and ...treatment of complications, and optimizing growth, development, and quality of life. Nutritional management is critically important to achieve these goals. Control of blood pressure, proteinuria, and metabolic acidosis with dietary and pharmacologic measures may slow progression of chronic kidney disease. Although significant progress in management has been made, further research is required to resolve many outstanding controversies. We review recent developments in pediatric chronic kidney disease, focusing on dietary measures to improve outcomes.
Chronic kidney disease (CKD) leads to alterations of iron metabolism, which contribute to the development of anemia and necessitates iron supplementation in patients with CKD. Elevated hepcidin ...accounts for a significant iron redistribution in CKD. Recent data indicate that these alterations in iron homeostasis coupled with therapeutic iron supplementation have pleiotropic effects on many organ systems in patients with CKD, far beyond the traditional hematologic effects of iron; these include effects of iron on inflammation, oxidative stress, kidney fibrosis, cardiovascular disease, CKD-mineral and bone disorder, and skeletal growth in children. The effects of iron supplementation appear to be largely dependent on the route of administration and on the specific iron preparation. Iron-based phosphate binders exemplify the opportunity for using iron for both traditional (anemia) and novel (hyperphosphatemia) indications. Further optimization of iron therapy in patients with CKD may inform new approaches to the treatment of CKD complications and potentially allow modification of disease progression.
Background
Mineral and bone disorder (MBD) and growth impairment are common complications of pediatric chronic kidney disease (CKD). Chronic inflammation detrimentally affects bone health and ...statural growth in non-CKD settings, but the impact of inflammation on CKD-MBD and growth in pediatric CKD remains poorly understood. This study assessed associations between inflammatory cytokines with biomarkers of CKD-MBD and statural growth in pediatric CKD.
Methods
This is a cross-sectional study of children with predialysis CKD stages II–V. Cytokines (IL-1b, IL-4, IL-6, IL-8, IL-10, IL-12, IL-13, TNF-α, interferon-γ), bone alkaline phosphatase (BAP), and procollagen type 1 N-terminal propeptide (P1NP) were measured at the same time as standard CKD-MBD biomarkers. Associations between cytokines, CKD-MBD biomarkers, and height
z
-score were assessed using linear regression analysis.
Results
Among 63 children, 52.4% had stage 3 CKD, 76.2% non-glomerular CKD etiology, and 21% short stature. TNF-α was the only cytokine associated with parathyroid hormone (PTH) independent of glomerular filtration rate. After stratification by low, medium, and high TNF-α tertiles, significant differences in PTH, serum phosphorus, alkaline phosphatase, BAP, P1NP, and height
z
-score were found. In a multivariate analysis, TNF-α positively associated with phosphorus, PTH, and alkaline phosphatase and inversely associated with height
z
-score, independent of kidney function, age, sex, and active vitamin D analogue use.
Conclusions
TNF-α is positively associated with biomarkers of CKD-MBD and inversely associated with height
z
-score, indicating that inflammation likely contributes to the development of CKD-MBD and growth impairment in pediatric CKD. Prospective studies to definitively assess causative effects of inflammation on bone health and growth in children with CKD are warranted.
In the past 20 years, multiple genetic mutations have been identified in patients with congenital nephrotic syndrome (CNS) and both familial and sporadic focal segmental glomerulosclerosis (FSGS). ...Characterization of the genetic basis of CNS and FSGS has led to the recognition of the importance of podocyte injury to the development of glomerulosclerosis. Genetic mutations induce injury due to effects on the podocyte’s structure, actin cytoskeleton, calcium signaling, and lysosomal and mitochondrial function. Transgenic animal studies have contributed to our understanding of podocyte pathobiology. Podocyte endoplasmic reticulum stress response, cell polarity, and autophagy play a role in maintenance of podocyte health. Further investigations related to the effects of genetic mutations on podocytes may identify new pathways for targeting therapeutics for nephrotic syndrome.
Mitophagy, by maintaining mitochondrial quality control, plays a key role in maintaining kidney function and is impaired in pathologic states. Macrophages are well known for their pathogenic role in ...kidney fibrosis. Here, we report that PINK1/Parkin-mediated mitophagy in macrophages is compromised in experimental and human kidney fibrosis. We demonstrate downregulation of mitophagy regulators mitofusin-2 (MFN2) and Parkin downstream of PINK1 in kidney fibrosis. Loss of either Pink1 or Prkn promoted renal extracellular matrix accumulation and frequency of profibrotic/M2 macrophages. Pink1-/- or Prkn-/- BM-derived macrophages (BMDMs) showed enhanced expression of rictor. Mitochondria from TGF-β1-treated Pink1-/- BMDMs exhibited increased superoxide levels, along with reduced respiration and ATP production. In addition, mitophagy in macrophages involves PINK1-mediated phosphorylation of downstream MFN2, MFN2-facilitated recruitment of Parkin to damaged mitochondria, and macrophage-specific deletion of Mfn2 aggravates kidney fibrosis. Moreover, mitophagy regulators were downregulated in human CKD kidney and TGF-β1-treated human renal macrophages, whereas Mdivi1 treatment suppressed mitophagy mediators and promoted fibrotic response. Taken together, our study is the first to our knowledge to demonstrate that macrophage mitophagy plays a protective role against kidney fibrosis via regulating the PINK1/MFN2/Parkin-mediated pathway.
Acute respiratory distress syndrome (ARDS), a life-threatening condition during critical illness, is a common complication of COVID-19. It can originate from various disease etiologies, including ...severe infections, major injury, or inhalation of irritants. ARDS poses substantial clinical challenges due to a lack of etiology-specific therapies, multisystem involvement, and heterogeneous, poor patient outcomes. A molecular comparison of ARDS groups holds the potential to reveal common and distinct mechanisms underlying ARDS pathogenesis.
We performed a comparative analysis of urine-based metabolomics and proteomics profiles from COVID-19 ARDS patients (n = 42) and bacterial sepsis-induced ARDS patients (n = 17). To this end, we used two different approaches, first we compared the molecular omics profiles between ARDS groups, and second, we correlated clinical manifestations within each group with the omics profiles.
The comparison of the two ARDS etiologies identified 150 metabolites and 70 proteins that were differentially abundant between the two groups. Based on these findings, we interrogated the interplay of cell adhesion/extracellular matrix molecules, inflammation, and mitochondrial dysfunction in ARDS pathogenesis through a multi-omic network approach. Moreover, we identified a proteomic signature associated with mortality in COVID-19 ARDS patients, which contained several proteins that had previously been implicated in clinical manifestations frequently linked with ARDS pathogenesis.
In summary, our results provide evidence for significant molecular differences in ARDS patients from different etiologies and a potential synergy of extracellular matrix molecules, inflammation, and mitochondrial dysfunction in ARDS pathogenesis. The proteomic mortality signature should be further investigated in future studies to develop prediction models for COVID-19 patient outcomes.
Sepsis causes acute kidney injury (AKI) in critically ill patients, although the pathophysiology remains unclear. The receptor-interacting protein kinase-3 (RIPK3), a cardinal regulator of ...necroptosis, has recently been implicated in the pathogenesis of human disease. In mice subjected to polymicrobial sepsis, we demonstrate that RIPK3 promotes sepsis-induced AKI. Utilizing genetic deletion and biochemical approaches in vitro and in vivo, we identify a potentially novel pathway by which RIPK3 aggravates kidney tubular injury independently of the classical mixed lineage kinase domain-like protein-dependent (MLKL-dependent) necroptosis pathway. In kidney tubular epithelial cells, we show that RIPK3 promotes oxidative stress and mitochondrial dysfunction involving upregulation of NADPH oxidase-4 (NOX4) and inhibition of mitochondrial complex I and -III, and that RIPK3 and NOX4 are critical for kidney tubular injury in vivo. Furthermore, we demonstrate that RIPK3 is required for increased mitochondrial translocation of NOX4 in response to proinflammatory stimuli, by a mechanism involving protein-protein interactions. Finally, we observed elevated urinary and plasma RIPK3 levels in human patients with sepsis-induced AKI, representing potential markers of this condition. In conclusion, we identify a pathway by which RIPK3 promotes kidney tubular injury via mitochondrial dysfunction, independently of MLKL, which may represent a promising therapeutic target in sepsis-induced AKI.
Children with chronic kidney disease (CKD) frequently exhibit delayed physical development and reduced physical performance, presumably due to skeletal muscle dysfunction. However, the cellular and ...molecular basis of skeletal muscle impairment in juvenile CKD remains poorly understood. Cellular (single fiber) and molecular (myosin‐actin interactions and myofilament properties) function was examined ex vivo in slow (soleus) and fast (extensor digitorum longus) contracting muscles of juvenile male (6 weeks old) CKD and control mice. CKD was induced by 0.2% adenine diet for 3 weeks starting at 3 weeks of age. Specific tension (maximal isometric force divided by cross‐sectional area) was reduced in larger myosin heavy chain (MHC) I and IIA fibers and in all IIB fibers in juvenile male mice with CKD due to fewer strongly bound myosin‐actin cross‐bridges. Fiber cross‐sectional area in juvenile CKD mice was unchanged in MHC I and IIB fibers and increased in MHC IIA fibers, compared to controls. CKD slowed cross‐bridge kinetics (slower rate of myosin force production and longer myosin attachment time, ton) in MHC IIA fibers, and accelerated kinetics (shorter ton) in MHC IIB fibers, which may indicate fiber type dependent shifts in contractile velocity in juvenile CKD. Overall, our findings show that single fiber myopathy is an early event during juvenile CKD, manifesting prior to the development of cellular atrophy as reduced force generation due to fewer strongly bound myosin heads. These results warrant clinical translation and call for early interventions to preserve physical function in children with CKD.
Juvenile mice with early‐stage CKD display reduced single fiber contractile function. Cellular force production is lower primarily due to less strongly bound myosin‐actin cross‐bridges. Additionally, myosin‐actin cross‐bridge kinetics slow in myosin heavy chain IIA fibers.
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