Materiały źródłowe

• #1 Chronic Kidney Disease – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK535404/

  Chronic kidney disease (CKD) is characterized by the presence of kidney damage or an estimated glomerular filtration rate (eGFR) of less than 60 mL/min/1.73 m, persisting for 3 months or more. CKD involves a progressive loss of kidney function, often leading to the need for renal replacement therapy, such as dialysis or transplantation. […] CKD is a state of progressive loss of kidney function, ultimately resulting in the need for renal replacement therapy, such as dialysis or transplantation. Kidney damage refers to pathologic abnormalities suggested by imaging studies or renal biopsy, abnormalities in urinary sediment, or increased urinary albumin excretion rates. […] Unlike acute kidney injury (AKI), which often results in complete functional recovery, chronic and sustained insults from progressive nephropathies lead to ongoing kidney fibrosis and destruction of normal kidney architecture. This process affects all three compartments of the kidney: the glomeruli, tubules and interstitium, and vessels. Histologically, it manifests as glomerulosclerosis, tubulointerstitial fibrosis, and vascular sclerosis.

• #1 Chronic Kidney Disease – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK535404/

  The following events leading to scarring and fibrosis are complex, overlapping, and multistage phenomena: Infiltration of damaged kidneys with extrinsic inflammatory cells. Activation, proliferation, and loss of intrinsic renal cells (through apoptosis, necrosis, mesangiolysis, and podocytopenia). Activation and proliferation of extracellular matrix producing cells, including myofibroblasts and fibroblasts. Deposition of extracellular matrix, replacing the normal architecture. […] Clinical risk factors for the accelerated progression of CKD include proteinuria, hypertension, Black race, and hyperglycemia. Environmental exposures, such as lead, smoking, metabolic syndrome, certain analgesic agents, and obesity, have also been linked to the accelerated progression of CKD.

• #1 Chronic Kidney Disease (CKD): Practice Essentials, Pathophysiology, Etiology

  https://emedicine.medscape.com/article/238798-overview

  Chronic kidney disease (CKD) or chronic renal failure (CRF), as it was historically termed, is a term that encompasses all degrees of decreased kidney function, from damage at risk through mild, moderate, and severe chronic kidney failure. CKD is associated with an increased risk of cardiovascular disease and end-stage kidney disease (ESKD). The guidelines define CKD as either kidney damage or a decreased glomerular filtration rate (GFR) of less than 60 mL/min/1.73 m2 for at least 3 months. […] Once the loss of nephrons and reduction of functional renal mass reaches a certain point, the remaining nephrons begin a process of irreversible sclerosis that leads to a progressive decline in the GFR. […] The hyperfiltration and hypertrophy of residual nephrons, although beneficial for the reasons noted, has been hypothesized to represent a major cause of progressive kidney dysfunction. The increased glomerular capillary pressure may damage the capillaries, leading initially to secondary focal and segmental glomerulosclerosis (FSGS) and eventually to global glomerulosclerosis.

• #1

  https://www.vin.com/apputil/content/defaultadv1.aspx?id=8249827&pid=19840&

  The RAAS system is also a critical component in the pathophysiology of renal progression. Although normally protective in emergency situations such as shock or hypotension, the RAAS system becomes maladaptive in CKD. Combined with a loss of autoregulation in the diseased state, angiotensin II plays a major role in this pathologic process as it vasoconstricts the efferent arteriole to maintain GFR. Although GFR is maintained, the downsides of this mechanism are hypoperfusion of post-glomerular capillaries, including the interstitium, and glomerular capillary hypertension. Angiotensin II also has detrimental non-vascular effects including activating tubular cells, oxidative stress, stimulation of inflammatory cell accumulation and promotion of fibrosis. The importance of the RAAS system is further supported by clinical evidence in humans demonstrating a distinct clinical benefit from RAAS blockade. […]

• #1

  https://www.vin.com/apputil/content/defaultadv1.aspx?id=8249827&pid=19840&

  Oxidative damage to tubular cells is also an important factor in cell attrition and occurs from several sources. As previously discussed, it can occur as a result of direct harm from reabsorbed substances, some of which are attached to reabsorbed proteins. However, increased filtration of substances, such as glucose or protein, also greatly increases the metabolism of tubular cells and this leads to increased production of free radicals. It has been shown that antioxidant defense systems are decreased in CKD, and thus the kidney is little prepared to address this increase and oxidative stress results. In addition, increased metabolic demand of the remaining tubular epithelial cells results in relative hypoxia as cells receive the same amount of blood flow, but have a higher demand. The environment is further exacerbated if anemia is present. Hypoxia results from decreased oxygen presentation to the tissues and oxidative stress is increased as erythrocytes have a major antioxidant role. […]

• #1

  https://link.springer.com/article/10.1007/s00467-007-0524-0

  Podocytes are the primary target in many glomerular diseases, including FSGS and the experimental models of adriamycin and puromycin aminonucleoside-induced nephropathies. […] Loss of podocytes after injury is postulated to be a key factor resulting in progressive sclerosis. […] Podocyte loss is a key factor contributing to progressive kidney fibrosis. […] Proteinuria is a marker of renal injury, reflecting loss of normal permselecitvity. Further, proteinuria itself has been proposed to contribute to progressive renal injury inflammation. […] Increased proteinuria is associated with worse prognosis. […] Tubulointerstitial fibrosis classically was thought merely to reflect glomerular injury and resulting whole nephron ischemia in most CKD. […] Increased numbers of macrophages are closely correlated with both glomerulosclerosis and tubulointerstitial fibrosis and are usually decreased by interventions that decrease fibrosis.

• #1 New Insights into Molecular Mechanisms of Chronic Kidney Disease

  https://www.mdpi.com/2227-9059/10/11/2846

  Chronic, low-grade inflammation is a critical component of CKD and plays a crucial role in its pathophysiology. […] It is essential to understand molecular interactions between inflammation, oxidative stress, MMPs and other factors for a better understanding of the process of CKD and to find new targets for treatment.

• #1

  https://www.vin.com/apputil/content/defaultadv1.aspx?id=8249827&pid=19840&

  Tubulointerstitial inflammation is characterized by an inflammatory infiltrate in the interstitium that usually consists of mononuclear leucocytes including nephritogenic T-cells, monocytes and macrophages. These cells are thought to play a pivotal role in progression and fibrosis. In cats, tubulointerstitial inflammation is more strongly correlated with decreasing renal function than glomerular damage is, even though most renal diseases in humans and dogs are glomerular in origin. The presence of interstitial inflammation affects the ability of the kidney to autoregulate by directly affecting the afferent arteriole’s ability to respond to contractile stimuli. Impaired autoregulation exacerbates the already present hyperfiltration and intraglomerular hypertension leading to additional damage. Nephritogenic T-cells are thought to exacerbate the conditions present in the kidney through direct cytotoxic effects as well as non-cytotoxic mechanisms such as cytokine release, altered tubular function and proliferation of interstitial fibroblasts and fibrosis. Once fibrosis occurs, conditions become increasingly suboptimal as loss of peritubular capillaries and increased interstitial volume create resistance to oxygen diffusion and resultant hypoxia, which in turn stimulates more fibrosis. Loss of peritubular capillaries, increased interstitial volume and fibrosis are also strongly correlated with decreasing renal function as well as worse prognosis. […]

• #1

  https://www.vin.com/apputil/content/defaultadv1.aspx?id=8249827&pid=19840&

  One prevalent theme in the previous discussion that should be reiterated is the importance of hypoxia in the progression of CKD. In summary, tubulointerstitial inflammation leads to loss of peritubular capillaries which decreases blood flow to the tubules and creates a hypoxic environment. VEGF is integral to vascular health, and it appears that late-stage renal patients have compromised VEGF levels. Distortion and destruction of peritubular capillary blood supply by inflammatory infiltrate, extracellular matrix and fibrosis is a characteristic histologic feature of CKD in all species; this expansion of the interstitial area further impairs oxygen diffusion. Glomerular damage and vasoconstriction of afferent arterioles decrease postglomerular peritubular capillary blood flow. Angiotensin II also directly constricts efferent arterioles, as well as induces oxidative stress, which hampered efficient utilization of oxygen by tubular cells. Relative hypoxia occurs as a result of increased metabolic demand of tubular cells and anemia further exacerbates all by hindering oxygen delivery. Unfortunately, hypoxia is a strong stimulus for further formation of fibrosis, which sets in motion a vicious cycle of fibrosis and further hypoxia. Hypoxia also leads to apoptosis or epithelial-mesenchymal transdifferentiation of tubular cells into myofibroblasts. As a result of the multitude of factors involving hypoxia, researchers have recently argued that it is a critical component of CKD progression in other species and therefore a key therapeutic target. A better understanding of the pathogenesis of feline CKD will provide additional opportunities for therapeutic intervention.

• #1 An Overview of Chronic Kidney Disease Pathophysiology: The Impact of Gut Dysbiosis and Oral Disease

  https://pmc.ncbi.nlm.nih.gov/articles/PMC10669155/

  Chronic kidney disease (CKD) is a severe condition and a significant public health issue worldwide, carrying the burden of an increased risk of cardiovascular events and mortality. […] Moreover, gut dysbiosis, inflammation, and an impaired immune response are emerging as crucial mechanisms in the disease pathology. The gut microbiome and kidney disease exert a reciprocal influence commonly referred to as the gut-kidney axis through the induction of metabolic, immunological, and endocrine alterations. […] Growing evidence suggests that inflammatory and immune responses can be profoundly influenced by the bidirectional link between the kidneys and other organs, particularly the gut. […] CKD and the alteration (dysbiosis) of the gut microbiota are closely linked in a reciprocal way known as the gut-kidney axis, where metabolic and immune pathways are intertwined.

• #1 An Overview of Chronic Kidney Disease Pathophysiology: The Impact of Gut Dysbiosis and Oral Disease

  https://pmc.ncbi.nlm.nih.gov/articles/PMC10669155/

  Changes in the composition and/or metabolite production of the gut microbiota can influence inflammation, oxidative stress (OS), and fibrosis, thus, offering opportunities to positively manipulate the composition and/or functionality of gut microbiota as a complementary strategy to improve prognosis in renal diseases. […] The pathophysiology underlying elevated IL-18 levels in CKD may be related to monocyte chemoattractant protein-1 (MCP-1) levels since eGFR was independently associated with serum MCP-1 levels, thus, partially explaining the increased risk of cardiovascular complications in CKD. […] A CKD-specific risk factor is a group of gut-derived uremic toxins (GDUTs), such as indoxyl sulfate, p-cresol, p-cresol sulfate, and trimethylamine-N-oxide (TMAO). […] The accumulation of toxins and proinflammatory cytokines may constitute DAMPs to which endothelial cells are continuously exposed.

• #1 Signaling pathways of chronic kidney diseases, implications for therapeutics | Signal Transduction and Targeted Therapy

  https://www.nature.com/articles/s41392-022-01036-5

  The expression of components of TGF- signaling is upregulated in fibrotic kidneys of patients and animals with CKD. Classical and nonclassical pathways of TGF- are activated to promote the activation and proliferation of myofibroblasts, and the generation of ECM. […] Wnt/-catenin signaling is important signaling mediated renal fibrosis. Wnt/-catenin signaling is activated in AKI and CKD. The increased Wnt ligands and -catenin promoted renal repair in AKI. However, the sustained activation of Wnt/-catenin signaling aggravated renal fibrosis. […] The Notch pathway is a phylogenetically conserved pathway, which controls the signal communication between adjacent cells. […] RAAS is important for regulating blood pressure homeostasis, vascular injury, and repair responses.

• #1 Growth Differentiation Factor 15 in Chronic Kidney Disease | JIR

  https://www.dovepress.com/role-and-mechanism-of-growth-differentiation-factor-15-in-chronic-kidn-peer-reviewed-fulltext-article-JIR

  GDF-15 is involved in various signaling pathways, such as MAPK pathway, PI3K/AKT pathway, STAT3 pathway, RET pathway, and SMAD pathway. […] GDF-15 mainly improves the function of kidneys in CKD and plays an important role in the prediction of CKD progression and cardiovascular complications. […] The role of GDF-15 in the kidney may be related to the SMAD and MAPK pathways. […] GDF-15 is associated with cardiovascular diseases, cancer, and diabetes. […] It is demonstrated that levels of GDF-15 are closely related to CKD and risk of cardiovascular complications in CKD. […] Moreover, the increase of GDF-15 in CKD frequently causes inflammation, oxidative stress, fibrosis, and apoptosis, which suggest that GDF-15 play an important role in CKD. […] In CKD, GDF-15 are strongly associated with CKD survival rate, disease progression rate, cardiovascular complications risk, and complications such as renal fibrosis and anemia.

• #1 Role of ferroptosis in chronic kidney disease | Cell Communication and Signaling | Full Text

  https://biosignaling.biomedcentral.com/articles/10.1186/s12964-023-01422-8

  Chronic kidney disease (CKD) has historically been a significant global health concern, profoundly impacting both life and well-being. […] Ferroptosis has also been shown to play an important role in renal fibrosis, which is the most pivotal pathological change in CKD. […] Studies have indicated targeting ferroptosis with specific drugs promotes adaptive cell repair and ameliorates fibrosis, suggesting drug intervention in ferroptosis as a potential avenue for preventing kidney fibrosis. […] The pathology of CKD is characterized by progressive nephron loss, microvascular damage, metabolic alterations, oxidative stress, and inflammation, culminating in fibrosis. […] In conclusion, preventing and postponing the development of renal fibrosis is a critical step in the treatment and reversal of CKD.

• #1 Role of ferroptosis in chronic kidney disease | Cell Communication and Signaling | Full Text

  https://biosignaling.biomedcentral.com/articles/10.1186/s12964-023-01422-8

  The core process driving ferroptosis is the disruption of iron metabolism. […] Iron deposition in renal tissue leads to oxidative damage, fibrosis, and inflammatory responses. […] Therefore, mitigating tissue iron deposition seems to be more effective than ameliorating circulating iron deficiency in attenuating oxidative damage. […] The relationship between ferroptosis and CKD is currently not fully elucidated. […] Existing research suggests a bidirectional relationship between AKI and CKD, with AKI promoting CKD development, which, in turn, heightens susceptibility to AKI. […] CKD is a heterogeneous group of kidney diseases that includes several pathological types, such as diabetic nephropathy, hypertensive arteriolosclerosis, hereditary kidney disease, various glomerulonephritis and tubulointerstitial diseases.

• #1 Role of ferroptosis in chronic kidney disease | Cell Communication and Signaling | Full Text

  https://biosignaling.biomedcentral.com/articles/10.1186/s12964-023-01422-8

  Ferroptosis has been identified as one of the pathways contributing to renal fibrosis in vivo, and pharmacological targeting of ferroptosis shows promise in driving cells toward adaptive repair and ameliorating fibrosis. […] The existing studies on the connection between ferroptosis and disease have focused on specific indicators, such as GSH, GPX4, ROS, and Nrf2 levels. […] The complete pathway requires further exploration. […] As ferroptosis is a recently identified form of cell death, research has predominantly employed animal models, and clinical studies targeting ferroptosis in CKD are limited. […] Nevertheless, the undeniable potential of ferroptosis suggests it could offer a novel and efficacious therapeutic avenue for CKD treatment.

• #1 Metabolic acidosis and progression of chronic kidney disease: incidence, pathogenesis, and therapeutic options | Nefrología

  https://www.revistanefrologia.com/en-metabolic-acidosis-progression-chronic-kidney-disease-incidence-pathogenesis-therapeutic-options-articulo-X2013251412002346

  Hay una prevalencia importante de la acidosis metabólica en los pacientes que padecen enfermedad renal crónica, presentándose en niveles tempranos de pérdida de filtrado glomerular. La patogénesis se basa en la falta de síntesis de bicarbonato sérico con la acumulación de ácidos de naturaleza orgánica e inorgánica, ocasionando daño tubulointersticial a través de la retención de amoniaco y el depósito de complemento, aunque esta última hipótesis se ha cuestionado en el pasado. […] In the chronic kidney disease population metabolic acidosis is prevalent presenting already in the early stages of renal dysfunction. The pathogenesis associates the lack of bicarbonate production with the accumulation of organic/inorganic acids and the development of tubulointerstitial damage through ammonium retention and complement deposition.

• #1 Metabolic acidosis and progression of chronic kidney disease: incidence, pathogenesis, and therapeutic options | Nefrología

  https://www.revistanefrologia.com/en-metabolic-acidosis-progression-chronic-kidney-disease-incidence-pathogenesis-therapeutic-options-articulo-X2013251412002346

  Metabolic acidosis develops due to reduced renal mass and inability of the remaining nephrons to excrete the daily acid load through ammoniagenesis. The renal tubular production of NH3 is stimulated by intracellular acidosis. […] Several factors have been implicated in the progression of renal failure, in particular intraglomerular hypertension. […] Four mechanisms have been suggested to explain acidosis induced renal injury: 1) Increased in NH3- production and activation of the alternative complement pathway with generation of inflammatory mediators as well as alkalinization of the interstitium. […] 2) H+ retention induces endothelin and aldosterone mediated GFR decline even before metabolic acidosis, as demonstrated in 2/3 nephrectomized rat models. […] 3) Acidosis induced aminoacid degradation through ubiquitin-proteasome with increased renal excretion of NH3.

• #1 Chronic kidney disease – Knowledge @ AMBOSS

  https://www.amboss.com/us/knowledge/chronic-kidney-disease/

  CKD results in hypocalcemia via different mechanisms. […] Renal excretion of phosphate hyperphosphatemia calcium phosphate precipitation in tissues Ca2+. […] Renal hydroxylation of vitamin D 1,25-dihydroxyvitamin D intestinal Ca2+ absorption Ca2+. […] Chronically decreased calcium levels can cause secondary hyperparathyroidism, which can progress to tertiary hyperparathyroidism.

• #1 Chronic Kidney Disease – Genitourinary Disorders – Merck Manual Professional Edition

  https://www.merckmanuals.com/professional/genitourinary-disorders/chronic-kidney-disease/chronic-kidney-disease

  Abnormalities of calcium, phosphate, parathyroid hormone (PTH), and vitamin D metabolism can occur, as can renal osteodystrophy. […] Moderate metabolic acidosis (plasma bicarbonate content 15 to 20 mmol/L) is characteristic. Acidosis causes muscle wasting due to protein catabolism, bone loss due to bone buffering of acid, and accelerated progression of kidney disease. […] Anemia is characteristic of moderate to advanced CKD (stage 3). The anemia of CKD is normochromic-normocytic, with a hematocrit of 20 to 30% (35 to 40% in patients with polycystic kidney disease). […] Patients with mildly diminished renal reserve are asymptomatic. […] With more severe renal disease (eg, estimated glomerular filtration rate [eGFR] 15 mL/min/1.73 m2), neuromuscular symptoms may be present, including coarse muscular twitches, peripheral sensory and motor neuropathies, muscle cramps, hyperreflexia, restless legs syndrome, and seizures (usually the result of hypertensive or metabolic encephalopathy).

• #1 Anemia of Chronic Disease and Kidney Failure: Overview, Mechanism of Anemia of Chronic Disease, Prevalence of Anemia of Chronic Disease and CKD

  https://emedicine.medscape.com/article/1389854-overview

  Anemia of chronic illness traditionally encompassed any inflammatory, infectious, or malignant disease of a long-standing nature. The modern definition includes rheumatoid arthritis, severe trauma, heart disease, diabetes mellitus, and inflammatory bowel disease. Anemia of chronic disease is characterized primarily by the following: […] The severity of anemia of CKD is directly related to the degree of loss of kidney function, as the kidneys are responsible for approximately 90% of erythropoietin production. […] In individuals with advanced stages of CKD, the etiology of anemia tends to be multifactorial and include the following: decreased RBC production due to lack of erythropoietin and iron deficiency, increased RBC destruction due to hemolysis (intravascular or extravascular), and increased blood loss due to multiple venipunctures for an array of indications.

• #1 Role of Inflammation in the Pathogenesis of Anemia in Chronic Kidney Disease: Exploring the Impact of Inflammatory Biomarkers on Erythropoiesis and Erythropoietin Response | medRxiv

  https://www.medrxiv.org/content/10.1101/2025.01.01.25319873v1

  Anemia is one of the very common complications in Chronic Kidney Disease (CKD) and often included among patients who undergo hemodialysis. A very important aspect of anemia is that erythropoietin (EPO) resistance plays a very major role, whereas the role of inflammation to EPO resistance and impaired erythropoiesis is still poorly understood. […] The objective of this study research therefore was to measure the effects of inflammation assessed by C-reactive protein (CRP) on anemia and in response to EPO in CKD patients undergoing hemodialysis here. […] Inflammation as measured by CRP has an important effect on anemia management in CKD patients undergoing hemodialysis.

• #1 Chronic Kidney Disease (CKD): Practice Essentials, Pathophysiology, Etiology

  https://emedicine.medscape.com/article/238798-overview

  Factors other than the underlying disease process and glomerular hypertension that may cause progressive kidney injury include systemic hypertension, nephrotoxins, decreased perfusion, proteinuria, hyperlipidemia, hyperphosphatemia with calcium phosphate deposition, smoking, and uncontrolled diabetes. […] Thaker et al found a strong association between episodes of acute kidney injury (AKI) and cumulative risk for the development of advanced CKD in patients with diabetes mellitus who experienced AKI in multiple hospitalizations. […] The plasma creatinine value will approximately double with a 50% reduction in GFR. For example, a rise in plasma creatinine from a baseline value of 0.6 mg/dL to 1.2 mg/dL, although still within the adult reference range, actually represents a loss of 50% of functioning nephron mass.

• #1 Chronic Kidney Disease – Genitourinary Disorders – Merck Manual Professional Edition

  https://www.merckmanuals.com/professional/genitourinary-disorders/chronic-kidney-disease/chronic-kidney-disease

  Chronic kidney disease (CKD) is usually first suspected when serum creatinine rises. […] The etiology of acute kidney injury (AKI) and CKD is determined based on clinical context, personal and family history, social and environmental factors, medications (including over-the-counter) and supplements, physical examination, and possibly genetic testing. […] Progression of chronic kidney disease (CKD) is predicted in most cases by the degree of proteinuria. […] Common causes of CKD in the United States are diabetic nephropathy (the most common), hypertensive nephrosclerosis, glomerulopathies, and metabolic syndrome. […] Effects of CKD can include hypocalcemia, hyperphosphatemia, metabolic acidosis, anemia, secondary hyperparathyroidism, and renal osteodystrophy.

• #1 An Overview of Chronic Kidney Disease Pathophysiology: The Impact of Gut Dysbiosis and Oral Disease

  https://pmc.ncbi.nlm.nih.gov/articles/PMC10669155/

  In CKD, serum uric acid concentrations increase, contributing to renal tubular damage, endothelial dysfunction, OS, and intrarenal inflammation. […] The pathophysiological mechanisms underlying the inflammatory state in CKD are complex and involve a maladaptive cellular response to injury that leads to persistent activation of proinflammatory and profibrotic signaling. […] CKD is a devastating disease characterized by chronic inflammation and is associated with an increased risk of cardiovascular complications. […] Several factors contribute to chronic inflammatory status in CKD, including increased production and decreased clearance of pro-inflammatory cytokines, OS and acidosis, chronic and recurrent infections, altered adipose tissue metabolism, and gut dysbiosis. […] There has been a growing interest in studying the composition of the gut microbiota in patients with CKD and the mechanisms by which gut dysbiosis contributes to CKD progression to identify possible therapeutic targets to improve morbidity and survival in CKD. […] Thus, identifying bacteria associated with chronic systemic inflammation and elucidating the role and mechanisms by which the altered gut microbiota contributes to the inflammatory profile is urgently necessary to improve current CKD therapies.

• #1 An Overview of Chronic Kidney Disease Pathophysiology: The Impact of Gut Dysbiosis and Oral Disease

  https://www.mdpi.com/2227-9059/11/11/3033

  Changes in the composition and/or metabolite production of the gut microbiota can influence inflammation, oxidative stress (OS), and fibrosis, thus, offering opportunities to positively manipulate the composition and/or functionality of gut microbiota as a complementary strategy to improve prognosis in renal diseases. […] The pathophysiology underlying elevated IL-18 levels in CKD may be related to monocyte chemoattractant protein-1 (MCP-1) levels since eGFR was independently associated with serum MCP-1 levels, thus, partially explaining the increased risk of cardiovascular complications in CKD. […] In CKD, serum uric acid concentrations increase, contributing to renal tubular damage, endothelial dysfunction, OS, and intrarenal inflammation. […] The pathophysiological mechanisms underlying the inflammatory state in CKD are complex and involve a maladaptive cellular response to injury that leads to persistent activation of proinflammatory and profibrotic signaling.

• #1 New Insights into Molecular Mechanisms of Chronic Kidney Disease

  https://www.mdpi.com/2227-9059/10/11/2846

  The aim of our work is to describe the new insights into the molecular mechanism of chronic kidney disease. We focused on oxidative stress, the role of the inflammatory cells, neutrophil gelatinase-associated lipocalin, matrix metalloproteinases, the gut–kidney axis, and new treatment targets that have emerged as knowledge about these mechanisms has developed. […] The pathogenesis of CKD is complex and many molecular mechanisms play a significant role in the development and progression of the disease. […] Inflammation and oxidative stress are inseparable elements that promote kidney fibrosis and loss of function, as shown in the example of interaction between oxidative stress, cytokines, and cell growth factors, especially TGF-β1, which is the key molecule affecting the activation and conversion of fibroblasts to a myofibroblast phenotype.

• #1 Regulated cell death pathways in kidney disease | Nature Reviews Nephrology

  https://www.nature.com/articles/s41581-023-00694-0

  Disorders of cell number that result from an imbalance between the death of parenchymal cells and the proliferation or recruitment of maladaptive cells contributes to the pathogenesis of kidney disease. […] In chronic kidney disease, loss of kidney epithelial cells leads to glomerulosclerosis and tubular atrophy, whereas interstitial inflammation and fibrosis result from an excess of leukocytes and myofibroblasts. […] Indeed, pathways of regulated cell death including apoptosis and necrosis have emerged as central events in the pathogenesis of various kidney diseases that may be amenable to therapeutic intervention. […] Modes of regulated necrosis, such as ferroptosis, necroptosis and pyroptosis may cause kidney injury directly or through the recruitment of immune cells and stimulation of inflammatory responses.

• #1 Regulated cell death pathways in kidney disease | Nature Reviews Nephrology

  https://www.nature.com/articles/s41581-023-00694-0

  Regulated cell death through either apoptosis or necrosis contributes to parenchymal cell loss in acute and chronic kidney disease and may also modulate inflammation, fibrosis and the immune response. […] The diverse forms of regulated necrosis may be interrelated, share molecular pathways and cell defence mechanisms and coexist in the same kidney disease, affecting different cell types or the same cell type synchronously or sequentially. […] Regulated necrosis may release damage-associated molecular patterns, which induce an inflammatory response that amplifies tissue injury (necroinflammation or immunogenic cell death). […] Despite some promising preclinical data, no clinical studies have targeted regulated necrosis to prevent or treat human kidney disease.

• #1

  https://www.jci.org/articles/view/76825

  Kidney disease is one of the most prevalent chronic conditions and is a frequent complication of diabetes, cardiovascular disease, and obesity. […] The last decade has witnessed the emergence of novel technologies that will lead investigators to the next major breakthrough. […] For this series, we invited Reviews that encompass the breadth of nephrology research, avoiding focus on a single biological theme, in order to reflect the excitement engendered by discoveries in different areas of kidney biology and disease. […] CKD, like many complex disease phenotypes, reflects dynamic interactions between genetic susceptibilities and environmental factors. Unraveling the relative contributions and interactions of our genome and epigenome, diet and activity, and exposure to microorganisms and medications will be the major challenge in the near future.

• #1

  https://www.jci.org/articles/view/165654

  The genetic basis of DKD was first suggested by observation of the familial disease aggregation. […] Epigenomic changes are proposed to be responsible for the metabolic memory. […] Methylation of DNA cytosines is an important epigenetic modification that can cause transcriptional repression. […] Podocytes form the epithelial surface of the glomerulus, where filtration of molecules under 60 kDa takes place. […] Podocyte foot process effacement and enlargement are observed in early DKD, while podocyte loss is observed with more advanced disease. […] Recent genetic studies paradoxically indicated the role of proximal tubule (PT) cells, not glomerular cells, in determining glomerular filtration. […] PT cells play a key role in DKD development.

• #1

  https://link.springer.com/article/10.1007/s00467-007-0524-0

  The source of interstitial myofibroblasts is a topic of controversy. […] Epithelialmesenchymal transformation (EMT) is another possible mechanism for generation of interstitial myofibroblasts. […] Risk for development of CKD and its rate of progression varies in differing populations. […] Low birth weight is epidemiologically linked to increased risk for cardiovascular disease, hypertension and CKD in adulthood. […] These observations suggest that complex genetic traits can modulate the response of glomerular cells to pathogenic stimuli in experimental models.

• #1 Pathogenesis in Chronic Kidney Disease explored

  http://en.xjtu.edu.cn/2017-09/04/c_602844.htm

  Pathogenesis in Chronic Kidney Disease explored […] Recently, the research team led by Prof. Shi Yunzhong from the School of Basic Medical Sciences at XJTU announced new achievements in the study of the pathogenesis of chronic kidney disease. […] Renal arteriolosclerosis in hypertensive chronic kidney disease (CKD), is an independent risk factor for cardiovascular disease (CVD). Their research demonstrated that accumulated toxic substances in CKD will induce oxidative stress and endothelial dysfunction. Nephrotoxin damages endothelial cell function by stimulating miR-92a endothelial cellular expression, contributing to the development of cardiovascular disease. These findings provide a significant experimental evidence for understanding the pathogenesis of the renal complications of CVD and developing new therapeutic approaches.

• #1 Researchers uncover underlying mechanism driving membranous nephropathy, a chronic kidney disease in children

  https://medicalxpress.com/news/2024-04-uncover-underlying-mechanism-membranous-nephropathy.html

  Previously, researchers believed that the membrane-attack-complex (MAC) was the sole driver of podocyte injury and that inhibiting it was key to halting disease progression. The GOFARR research team discovered instead that signaling in the C3a/C3aR pathway plays a critical role in the progression of membranous nephropathy. […] „By probing what is actually happening at the molecular level, we found that an entirely different pathway than we initially thought was the main driver for primary membranous neuropathy,” says Dr. Da Sacco, Assistant Professor of Research Urology at the Keck School of Medicine of USC. […] „Finding what causes podocytes to fail is a step toward preventing—and eventually reversing—kidney deterioration. Our patients need better treatment options.”

• #1 A new mechanism may lead to new treatment options of chronic kidney diseases

  https://health.au.dk/en/display/artikel/ny-mekanisme-kan-faa-betydning-for-behandling-af-kroniske-nyresygdomme

  In the kidneys, the so-called megalin receptor is central to the reabsorption of filtered proteins, and thus to the amount of protein excreted in the urine. In patients where the receptor no longer functions optimally, the system becomes overloaded, leading to a condition called proteinuria, where there is an abnormally high level of protein in the patient’s urine. Proteinuria is an important indicator of kidney disease and a critical risk factor for developing chronic kidney disease. In the study, it is precisely the megalin receptor and thus the kidneys’ efficiency in reabsorbing filtered proteins that PCSK9 appears to negatively regulate. […] We demonstrate a new molecular mechanism by which PCSK9 affects the development of proteinuria. This mechanism has not been previously known. […] Our study provides a basis for further studies that will examine whether the use of PCSK9 inhibition is beneficial in kidney diseases. If it turns out that it actually enhances treatment, then within a relatively short period, a completely new form of therapy can be offered to kidney patients.

• #1 A new mechanism may lead to new treatment options for chronic kidney diseases

  https://medicalxpress.com/news/2023-07-mechanism-treatment-options-chronic-kidney.html

  Chronic kidney disease is a growing problem both in Denmark and internationally. Now, a new study from Aarhus University reveals that a protein known for treating cardiovascular diseases also counteracts a mechanism in the kidney that reabsorbs proteins. This could potentially lead to new treatment options. […] In the study, it is precisely the megalin receptor and thus the kidneys’ efficiency in reabsorbing filtered proteins that PCSK9 appears to negatively regulate. […] We demonstrate a new molecular mechanism by which PCSK9 affects the development of proteinuria. This mechanism has not been previously known. […] Our study provides a basis for further studies that will examine whether the use of PCSK9 inhibition is beneficial in kidney diseases. If it turns out that it actually enhances treatment, then within a relatively short period, a completely new form of therapy can be offered to kidney patients.

• #1 Mannose and glycine: Metabolites with potentially causal implications in chronic kidney disease pathogenesis | PLOS One

  https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0298729

  Chronic Kidney Disease (CKD) represents a global health challenge, with its etiology and underlying mechanisms yet to be fully elucidated. […] Our analysis identified four metabolites with a robust association with CKD risk, of which mannose and glycine showed the most reliable causal relationships. Pathway analysis spotlighted five significant metabolic pathways, notably including „Methionine Metabolism” and „Arginine and Proline Metabolism”, as key contributors to CKD pathogenesis. […] This study underscores the potential of certain serum metabolites as biomarkers for CKD and illuminates pivotal metabolic pathways in CKDs pathogenesis. […] In this study, the metabolic pathway analysis showed that Methionine Metabolism, Arginine and Proline Metabolism, Betaine Metabolism, Fatty Acid Biosynthesis and Glycine and Serine Metabolism pathways are mainly associated with CKD. […] Collectively, these findings suggest a potential relevance of these metabolites biosynthesis and metabolism to the biological mechanisms underpinning CKD.

• #2 Chronic Kidney Disease (CKD): Practice Essentials, Pathophysiology, Etiology

  https://emedicine.medscape.com/article/238798-overview

  Chronic kidney disease (CKD) or chronic renal failure (CRF), as it was historically termed, is a term that encompasses all degrees of decreased kidney function, from damage at risk through mild, moderate, and severe chronic kidney failure. CKD is associated with an increased risk of cardiovascular disease and end-stage kidney disease (ESKD). The guidelines define CKD as either kidney damage or a decreased glomerular filtration rate (GFR) of less than 60 mL/min/1.73 m2 for at least 3 months. […] Once the loss of nephrons and reduction of functional renal mass reaches a certain point, the remaining nephrons begin a process of irreversible sclerosis that leads to a progressive decline in the GFR. […] The hyperfiltration and hypertrophy of residual nephrons, although beneficial for the reasons noted, has been hypothesized to represent a major cause of progressive kidney dysfunction. The increased glomerular capillary pressure may damage the capillaries, leading initially to secondary focal and segmental glomerulosclerosis (FSGS) and eventually to global glomerulosclerosis.

• #2

  https://link.springer.com/article/10.1007/s00467-007-0524-0

  Chronic kidney disease (CKD) occurs in all age groups, including children. Regardless of the underlying cause, CKD is characterized by progressive scarring that ultimately affects all structures of the kidney. The relentless progression of CKD is postulated to result from a self-perpetuating vicious cycle of fibrosis activated after initial injury. […] We will review possible mechanisms of progressive renal damage, including systemic and glomerular hypertension, various cytokines and growth factors, with special emphasis on the reninangiotensinaldosterone system (RAAS), podocyte loss, dyslipidemia and proteinuria. […] CKD shares a common appearance of glomerulosclerosis, vascular sclerosis and tubulointerstitial fibrosis, suggesting a common final pathway of progressive injury. […] Adaptive changes in nephrons after initial injury are postulated ultimately to be maladaptive, eventually causing scarring and further nephron loss, thus perpetuating a vicious cycle that results in the end-stage kidney.

• #2 Overview of the management of chronic kidney disease in adults – UpToDate

  https://www.uptodate.com/contents/overview-of-the-management-of-chronic-kidney-disease-in-adults

  An overview of the general issues involved in the management of the patient with chronic kidney disease (CKD), including modalities to slow the rate of progression, will be presented here. […] Adaptive hyperfiltration, although initially beneficial, eventually causes damage to the glomeruli of the remaining nephrons, which is manifest by albuminuria and progressive kidney failure. This process appears to be responsible for the development of kidney failure among those in whom the original illness is either inactive or cured. […] The institution of measures to help prevent this process, such as treatment with an angiotensin-converting enzyme (ACE) inhibitor or an angiotensin II receptor blocker (ARB), and sodium-glucose cotransporter-2 (SGLT2) inhibitors, may slow progressive disease and even preserve kidney function.

• #2

  https://www.vin.com/apputil/content/defaultadv1.aspx?id=8249827&pid=19840&

  Impairment of renal function is correlated with the degree of tubulointerstitial injury, including inflammation, tubular atrophy, and tubulointerstitial fibrosis. In a recent retrospective study that assessed the correlation between CKD and histopathology in cats, fibrosis was found to be significantly correlated with the stage of CKD. Hyperfiltration, proteinuria, tubulointerstitial inflammation, oxidative damage, hypoxia and induction of the renin- angiotensin-aldosterone system (RAAS) are major factors that are thought to contribute to the process of tubulointerstitial injury. […] […] Loss of functional nephrons results in hyperfiltration due to an increase in remaining single nephron GFR. Combined with a loss of the ability to autoregulate blood flow to the kidney, hyperfiltration results in intraglomerular hypertension, which can be further exacerbated by systemic hypertension. […]

• #2

  https://link.springer.com/article/10.1007/s00467-007-0524-0

  We will review possible mechanisms of progressive renal damage, which include, but are not limited to, hemodynamic factors, the reninangiotensinaldosterone system (RAAS), various cytokines and growth factors, podocyte loss, dyslipidemia, proteinuria, specific mechanisms of tubulointerstitial fibrosis, and possible underlying predispositions for CKD, such as genetic factors and low nephron number. […] The RAAS has been the focus of investigation of progression in CKD because of the efficacy of inhibition of its components in CKD. […] Many profibrotic actions of the RAAS are mediated directly by AngII. […] Importantly, new data indicate that aldosterone has both genomic and non-genomic actions to promote fibrosis, independent of its actions to increase blood pressure by mediating salt retention.

• #2 New Insights into Molecular Mechanisms of Chronic Kidney Disease

  https://www.mdpi.com/2227-9059/10/11/2846

  The aim of our work is to describe the new insights into the molecular mechanism of chronic kidney disease. We focused on oxidative stress, the role of the inflammatory cells, neutrophil gelatinase-associated lipocalin, matrix metalloproteinases, the gut–kidney axis, and new treatment targets that have emerged as knowledge about these mechanisms has developed. […] The pathogenesis of CKD is complex and many molecular mechanisms play a significant role in the development and progression of the disease. […] Inflammation and oxidative stress are inseparable elements that promote kidney fibrosis and loss of function, as shown in the example of interaction between oxidative stress, cytokines, and cell growth factors, especially TGF-β1, which is the key molecule affecting the activation and conversion of fibroblasts to a myofibroblast phenotype.

• #2

  https://www.vin.com/apputil/content/defaultadv1.aspx?id=8249827&pid=19840&

  Tubulointerstitial inflammation is characterized by an inflammatory infiltrate in the interstitium that usually consists of mononuclear leucocytes including nephritogenic T-cells, monocytes and macrophages. These cells are thought to play a pivotal role in progression and fibrosis. In cats, tubulointerstitial inflammation is more strongly correlated with decreasing renal function than glomerular damage is, even though most renal diseases in humans and dogs are glomerular in origin. The presence of interstitial inflammation affects the ability of the kidney to autoregulate by directly affecting the afferent arteriole’s ability to respond to contractile stimuli. Impaired autoregulation exacerbates the already present hyperfiltration and intraglomerular hypertension leading to additional damage. Nephritogenic T-cells are thought to exacerbate the conditions present in the kidney through direct cytotoxic effects as well as non-cytotoxic mechanisms such as cytokine release, altered tubular function and proliferation of interstitial fibroblasts and fibrosis. Once fibrosis occurs, conditions become increasingly suboptimal as loss of peritubular capillaries and increased interstitial volume create resistance to oxygen diffusion and resultant hypoxia, which in turn stimulates more fibrosis. Loss of peritubular capillaries, increased interstitial volume and fibrosis are also strongly correlated with decreasing renal function as well as worse prognosis. […]

• #2 An Overview of Chronic Kidney Disease Pathophysiology: The Impact of Gut Dysbiosis and Oral Disease

  https://www.mdpi.com/2227-9059/11/11/3033

  Chronic kidney disease (CKD) is a severe condition and a significant public health issue worldwide, carrying the burden of an increased risk of cardiovascular events and mortality. […] Moreover, gut dysbiosis, inflammation, and an impaired immune response are emerging as crucial mechanisms in the disease pathology. […] The gut microbiome and kidney disease exert a reciprocal influence commonly referred to as “the gut-kidney axis” through the induction of metabolic, immunological, and endocrine alterations. […] Growing evidence suggests that inflammatory and immune responses can be profoundly influenced by the bidirectional link between the kidneys and other organs, particularly the gut. […] CKD and the alteration (dysbiosis) of the gut microbiota are closely linked in a reciprocal way known as “the gut-kidney axis”, where metabolic and immune pathways are intertwined.

• #2 An Overview of Chronic Kidney Disease Pathophysiology: The Impact of Gut Dysbiosis and Oral Disease

  https://www.mdpi.com/2227-9059/11/11/3033

  Changes in the composition and/or metabolite production of the gut microbiota can influence inflammation, oxidative stress (OS), and fibrosis, thus, offering opportunities to positively manipulate the composition and/or functionality of gut microbiota as a complementary strategy to improve prognosis in renal diseases. […] The pathophysiology underlying elevated IL-18 levels in CKD may be related to monocyte chemoattractant protein-1 (MCP-1) levels since eGFR was independently associated with serum MCP-1 levels, thus, partially explaining the increased risk of cardiovascular complications in CKD. […] In CKD, serum uric acid concentrations increase, contributing to renal tubular damage, endothelial dysfunction, OS, and intrarenal inflammation. […] The pathophysiological mechanisms underlying the inflammatory state in CKD are complex and involve a maladaptive cellular response to injury that leads to persistent activation of proinflammatory and profibrotic signaling.

• #2 An Overview of Chronic Kidney Disease Pathophysiology: The Impact of Gut Dysbiosis and Oral Disease

  https://www.mdpi.com/2227-9059/11/11/3033

  Systemic and chronic proinflammatory states due to CKD contribute to vascular and myocardial remodeling processes resulting in atherosclerotic lesions, vascular calcification, and vascular senescence, as well as myocardial fibrosis and calcification of cardiac valves. […] CKD and the gut microbiota influence each other. Just as gut dysbiosis can affect kidney function, CKD has a substantial impact on the gut microbial profile, which is highly sensitive to the level of UTs. […] The vicious circle worsens CKD and leads to several conditions, including insulin resistance, protein malnutrition, immune dysregulation, and atherosclerosis. […] The protein-bound uremic toxins, such as indoxyl sulfate and p-cresol sulfate, are derived from the byproducts of aromatic amino acid breakdown by the gut microbiota. […] CKD impairs barrier function and alters microbial flora of the intestine: A major link to inflammation and uremic toxicity. […] The gut microbiota can manipulate the processes leading to CKD onset and progression through inflammatory, toxic, and neuroendocrine pathways.

• #2 Signaling pathways of chronic kidney diseases, implications for therapeutics | Signal Transduction and Targeted Therapy

  https://www.nature.com/articles/s41392-022-01036-5

  The expression of components of TGF- signaling is upregulated in fibrotic kidneys of patients and animals with CKD. Classical and nonclassical pathways of TGF- are activated to promote the activation and proliferation of myofibroblasts, and the generation of ECM. […] Wnt/-catenin signaling is important signaling mediated renal fibrosis. Wnt/-catenin signaling is activated in AKI and CKD. The increased Wnt ligands and -catenin promoted renal repair in AKI. However, the sustained activation of Wnt/-catenin signaling aggravated renal fibrosis. […] The Notch pathway is a phylogenetically conserved pathway, which controls the signal communication between adjacent cells. […] RAAS is important for regulating blood pressure homeostasis, vascular injury, and repair responses.

• #2 Growth Differentiation Factor 15 in Chronic Kidney Disease | JIR

  https://www.dovepress.com/role-and-mechanism-of-growth-differentiation-factor-15-in-chronic-kidn-peer-reviewed-fulltext-article-JIR

  Particularly, GDF-15 are linked to both decreased kidney function and higher risk for cardiovascular diseases in diabetic nephropathy patients. […] GDF-15 can suppress CKD cellular apoptosis via the PI3K/AKT signaling pathway, exerting renal protective effects. […] GDF-15 is also involved in the occurrence of complications in CKD. […] GDF-15 is independently associated with cardiovascular risk in patients with diabetic nephropathy. […] GDF-15 is related with the complications such as renal fibrosis. […] In conclusion, GDF-15 may be a therapeutic target for kidney disease.

• #2 Metabolic acidosis and progression of chronic kidney disease: incidence, pathogenesis, and therapeutic options | Nefrología

  https://www.revistanefrologia.com/en-metabolic-acidosis-progression-chronic-kidney-disease-incidence-pathogenesis-therapeutic-options-articulo-X2013251412002346

  Metabolic acidosis develops due to reduced renal mass and inability of the remaining nephrons to excrete the daily acid load through ammoniagenesis. The renal tubular production of NH3 is stimulated by intracellular acidosis. […] Several factors have been implicated in the progression of renal failure, in particular intraglomerular hypertension. […] Four mechanisms have been suggested to explain acidosis induced renal injury: 1) Increased in NH3- production and activation of the alternative complement pathway with generation of inflammatory mediators as well as alkalinization of the interstitium. […] 2) H+ retention induces endothelin and aldosterone mediated GFR decline even before metabolic acidosis, as demonstrated in 2/3 nephrectomized rat models. […] 3) Acidosis induced aminoacid degradation through ubiquitin-proteasome with increased renal excretion of NH3.

• #2 Chronic kidney disease – Knowledge @ AMBOSS

  https://www.amboss.com/us/knowledge/chronic-kidney-disease/

  CKD results in hypocalcemia via different mechanisms. […] Renal excretion of phosphate hyperphosphatemia calcium phosphate precipitation in tissues Ca2+. […] Renal hydroxylation of vitamin D 1,25-dihydroxyvitamin D intestinal Ca2+ absorption Ca2+. […] Chronically decreased calcium levels can cause secondary hyperparathyroidism, which can progress to tertiary hyperparathyroidism.

• #2 Anemia of Chronic Disease and Kidney Failure: Overview, Mechanism of Anemia of Chronic Disease, Prevalence of Anemia of Chronic Disease and CKD

  https://emedicine.medscape.com/article/1389854-overview

  The importance of these tests lies in the fact that the diagnosis of iron deficiency anemia is not truly straightforward, as the possible etiologies include both insufficient iron stores (absolute iron deficiency) and insufficient release of stored iron by the reticuloendothelial tissues, so that too little iron is available for erythropoiesis (functional iron deficiency). […] Anemia of CKD tends to primarily involve functional iron deficiency. Traditionally, this is characterized by a TSAT less than 20% and a ferritin level less than 100 ng/mL; however, there is evidence that those cutoffs may not be sensitive to detect iron deficiency. […] The possible central role of hepcidin in the pathogenesis of anemia of chronic disease has been the subject of numerous publications.

• #2 Chronic Kidney Disease (CKD): Practice Essentials, Pathophysiology, Etiology

  https://emedicine.medscape.com/article/238798-overview

  Factors other than the underlying disease process and glomerular hypertension that may cause progressive kidney injury include systemic hypertension, nephrotoxins, decreased perfusion, proteinuria, hyperlipidemia, hyperphosphatemia with calcium phosphate deposition, smoking, and uncontrolled diabetes. […] Thaker et al found a strong association between episodes of acute kidney injury (AKI) and cumulative risk for the development of advanced CKD in patients with diabetes mellitus who experienced AKI in multiple hospitalizations. […] The plasma creatinine value will approximately double with a 50% reduction in GFR. For example, a rise in plasma creatinine from a baseline value of 0.6 mg/dL to 1.2 mg/dL, although still within the adult reference range, actually represents a loss of 50% of functioning nephron mass.

• #2 An Overview of Chronic Kidney Disease Pathophysiology: The Impact of Gut Dysbiosis and Oral Disease

  https://pmc.ncbi.nlm.nih.gov/articles/PMC10669155/

  In CKD, serum uric acid concentrations increase, contributing to renal tubular damage, endothelial dysfunction, OS, and intrarenal inflammation. […] The pathophysiological mechanisms underlying the inflammatory state in CKD are complex and involve a maladaptive cellular response to injury that leads to persistent activation of proinflammatory and profibrotic signaling. […] CKD is a devastating disease characterized by chronic inflammation and is associated with an increased risk of cardiovascular complications. […] Several factors contribute to chronic inflammatory status in CKD, including increased production and decreased clearance of pro-inflammatory cytokines, OS and acidosis, chronic and recurrent infections, altered adipose tissue metabolism, and gut dysbiosis. […] There has been a growing interest in studying the composition of the gut microbiota in patients with CKD and the mechanisms by which gut dysbiosis contributes to CKD progression to identify possible therapeutic targets to improve morbidity and survival in CKD. […] Thus, identifying bacteria associated with chronic systemic inflammation and elucidating the role and mechanisms by which the altered gut microbiota contributes to the inflammatory profile is urgently necessary to improve current CKD therapies.

• #2 New Insights into Molecular Mechanisms of Chronic Kidney Disease

  https://www.mdpi.com/2227-9059/10/11/2846

  Chronic, low-grade inflammation is a critical component of CKD and plays a crucial role in its pathophysiology. […] It is essential to understand molecular interactions between inflammation, oxidative stress, MMPs and other factors for a better understanding of the process of CKD and to find new targets for treatment.

• #2 Regulated cell death pathways in kidney disease | Nature Reviews Nephrology

  https://www.nature.com/articles/s41581-023-00694-0

  Regulated cell death through either apoptosis or necrosis contributes to parenchymal cell loss in acute and chronic kidney disease and may also modulate inflammation, fibrosis and the immune response. […] The diverse forms of regulated necrosis may be interrelated, share molecular pathways and cell defence mechanisms and coexist in the same kidney disease, affecting different cell types or the same cell type synchronously or sequentially. […] Regulated necrosis may release damage-associated molecular patterns, which induce an inflammatory response that amplifies tissue injury (necroinflammation or immunogenic cell death). […] Despite some promising preclinical data, no clinical studies have targeted regulated necrosis to prevent or treat human kidney disease.

• #3 Signaling pathways of chronic kidney diseases, implications for therapeutics | Signal Transduction and Targeted Therapy

  https://www.nature.com/articles/s41392-022-01036-5

  The expression of components of TGF- signaling is upregulated in fibrotic kidneys of patients and animals with CKD. Classical and nonclassical pathways of TGF- are activated to promote the activation and proliferation of myofibroblasts, and the generation of ECM. […] Wnt/-catenin signaling is important signaling mediated renal fibrosis. Wnt/-catenin signaling is activated in AKI and CKD. The increased Wnt ligands and -catenin promoted renal repair in AKI. However, the sustained activation of Wnt/-catenin signaling aggravated renal fibrosis. […] The Notch pathway is a phylogenetically conserved pathway, which controls the signal communication between adjacent cells. […] RAAS is important for regulating blood pressure homeostasis, vascular injury, and repair responses.

• #3 Metabolic acidosis and progression of chronic kidney disease: incidence, pathogenesis, and therapeutic options | Nefrología

  https://www.revistanefrologia.com/en-metabolic-acidosis-progression-chronic-kidney-disease-incidence-pathogenesis-therapeutic-options-articulo-X2013251412002346

  4) Ammoniagenesis may cause renal injury by stimulating the hypertrophy of renal tubular cells. […] The trials mentioned above are the only human studies to date in patients with pre-ESRD that showed oral HCO3 as a therapeutic option with minimal side effects, inexpensive and with potential benefit in delaying progression of CKD.

• #3 Chronic Kidney Disease (CKD): Practice Essentials, Pathophysiology, Etiology

  https://emedicine.medscape.com/article/238798-overview

  Factors other than the underlying disease process and glomerular hypertension that may cause progressive kidney injury include systemic hypertension, nephrotoxins, decreased perfusion, proteinuria, hyperlipidemia, hyperphosphatemia with calcium phosphate deposition, smoking, and uncontrolled diabetes. […] Thaker et al found a strong association between episodes of acute kidney injury (AKI) and cumulative risk for the development of advanced CKD in patients with diabetes mellitus who experienced AKI in multiple hospitalizations. […] The plasma creatinine value will approximately double with a 50% reduction in GFR. For example, a rise in plasma creatinine from a baseline value of 0.6 mg/dL to 1.2 mg/dL, although still within the adult reference range, actually represents a loss of 50% of functioning nephron mass.

• #3 An Overview of Chronic Kidney Disease Pathophysiology: The Impact of Gut Dysbiosis and Oral Disease

  https://pmc.ncbi.nlm.nih.gov/articles/PMC10669155/

  In CKD, serum uric acid concentrations increase, contributing to renal tubular damage, endothelial dysfunction, OS, and intrarenal inflammation. […] The pathophysiological mechanisms underlying the inflammatory state in CKD are complex and involve a maladaptive cellular response to injury that leads to persistent activation of proinflammatory and profibrotic signaling. […] CKD is a devastating disease characterized by chronic inflammation and is associated with an increased risk of cardiovascular complications. […] Several factors contribute to chronic inflammatory status in CKD, including increased production and decreased clearance of pro-inflammatory cytokines, OS and acidosis, chronic and recurrent infections, altered adipose tissue metabolism, and gut dysbiosis. […] There has been a growing interest in studying the composition of the gut microbiota in patients with CKD and the mechanisms by which gut dysbiosis contributes to CKD progression to identify possible therapeutic targets to improve morbidity and survival in CKD. […] Thus, identifying bacteria associated with chronic systemic inflammation and elucidating the role and mechanisms by which the altered gut microbiota contributes to the inflammatory profile is urgently necessary to improve current CKD therapies.

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