Materiały źródłowe

• #1 Nephrogenic Systemic Fibrosis, Moh’d sharshir | PPT

  https://www.slideshare.net/slideshow/nephrogenic-systemic-fibrosis/101723380

  Nephrogenic systemic fibrosis (NSF) is a fibrosing disorder seen only in patients with kidney failure. It is characterized by two primary features: Thickening and hardening of the skin overlying the extremities and trunk. Marked expansion and fibrosis of the dermis in association with CD34- positive fibrocytes. […] NSF occurs exclusively in patients with kidney failure. The first cases were noted between 1997 and 2000 in hemodialysis patients or patients with failed renal allografts who developed severe skin induration that was histologically thought to be scleromyxedema. […] The number of cases has declined dramatically since initial reports, most certainly due to the avoidance of gadolinium-containing agents among at-risk patients. As of January 2013, over 400 cases of NSF had been reported to the International NSF Registry at Yale University. Almost all cases were in adults, but children were also affected.

• #2 Nephrogenic systemic fibrosis/nephrogenic fibrosing dermopathy in advanced kidney disease – UpToDate

  https://www.uptodate.com/contents/nephrogenic-systemic-fibrosis-nephrogenic-fibrosing-dermopathy-in-advanced-kidney-disease

  Nephrogenic systemic fibrosis (NSF) is a disorder seen only in patients with advanced kidney disease and is characterized by two primary features: […] Marked expansion and fibrosis of the dermis in association with CD34+ fibrocytes. […] NSF was originally named nephrogenic fibrosing dermopathy (NFD) because of the characteristic skin findings. However, subsequent studies showed that some patients had fibrosis of deeper structures, including muscle, fascia, lungs, and heart. […] Because of the systemic findings, NSF is preferred to NFD. […] While NSF is only seen among patients with kidney disease, retention of gadolinium (Gd) has been demonstrated in other organs (eg, brain) in patients without and with kidney disease.

• #3 Nephrogenic systemic fibrosis following hair-dye ingestion induced acute renal failure – Indian Journal of Dermatology, Venereology and Leprology

  https://ijdvl.com/nephrogenic-systemic-fibrosis-following-hair-dye-ingestion-induced-acute-renal-failure/

  Nephrogenic systemic fibrosis is a recently described, acquired, idiopathic fibrosing disorder exclusively seen in patients with renal dysfunction. Cowper et al. in 2000, described this condition as „scleroderma-like cutaneous disease” in patients who were on hemodialysis or after renal transplant. […] The systemic nature of the disease was subsequently reported with involvement of diaphragm, lungs, liver, muscle, heart and it was re-designated as „nephrogenic systemic fibrosis.” […] Though NSF has typical clinical and histopathological features, the exact etiology and pathogenesis are not known. […] Endothelial damage, triggered by events such as a major surgery (renal transplant), placement of dialysis fistulas, central venous lines, hypercoagulable states and thrombotic events may play a role in the pathogenesis.

• #4 Nephrogenic Systemic Fibrosis, Moh’d sharshir | PPT

  https://www.slideshare.net/slideshow/nephrogenic-systemic-fibrosis/101723380

  Nephrogenic systemic fibrosis (NSF) is a fibrosing disorder seen only in patients with kidney failure. It is characterized by two primary features: Thickening and hardening of the skin overlying the extremities and trunk. Marked expansion and fibrosis of the dermis in association with CD34- positive fibrocytes. […] NSF occurs exclusively in patients with kidney failure. The first cases were noted between 1997 and 2000 in hemodialysis patients or patients with failed renal allografts who developed severe skin induration that was histologically thought to be scleromyxedema. […] The number of cases has declined dramatically since initial reports, most certainly due to the avoidance of gadolinium-containing agents among at-risk patients. As of January 2013, over 400 cases of NSF had been reported to the International NSF Registry at Yale University. Almost all cases were in adults, but children were also affected.

• #5 Nephrogenic Systemic Fibrosis – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK567754/

  Nephrogenic systemic fibrosis (NSF) is a progressive multiorgan fibrosing condition caused by exposure to gadolinium-based contrast agents (GBCAs) used for magnetic resonance imaging (MRI) in the setting of low glomerular filtration rate (GFR). This condition is characterized by thickening of the skin and subcutaneous tissue in addition to systemic manifestations. The clinical features may also involve skeletal muscle and any fibrous tissue in the body, including the internal organs such as the liver, heart, and lungs. NSF is a clinically highly variable condition. Some patients may have only mild effects on the skin, but many patients develop significant debility. In some patients, the disease may be lethal. […] The prevailing theory is that Gd exposure is prolonged in patients with renal disease, allowing the Gd to dissociate from its organic chelators and bind with calcium, phosphate, and other endogenous compounds to deposit in the skin and tissues. This sets off a fibrotic reaction involving the proliferation of fibroblasts in the dermis and the replacement of normal tissue with thickened collagen and extracellular matrix hyaluronan. Deposition also occurs in other tissues and leads to multi-organ involvement.

• #6 Nephrogenic Systemic Fibrosis – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK567754/

  Nephrogenic systemic fibrosis (NSF) is a progressive multiorgan fibrosing condition caused by exposure to gadolinium-based contrast agents (GBCAs) used for magnetic resonance imaging (MRI) in the setting of low glomerular filtration rate (GFR). This condition is characterized by thickening of the skin and subcutaneous tissue in addition to systemic manifestations. The clinical features may also involve skeletal muscle and any fibrous tissue in the body, including the internal organs such as the liver, heart, and lungs. NSF is a clinically highly variable condition. Some patients may have only mild effects on the skin, but many patients develop significant debility. In some patients, the disease may be lethal. […] The prevailing theory is that Gd exposure is prolonged in patients with renal disease, allowing the Gd to dissociate from its organic chelators and bind with calcium, phosphate, and other endogenous compounds to deposit in the skin and tissues. This sets off a fibrotic reaction involving the proliferation of fibroblasts in the dermis and the replacement of normal tissue with thickened collagen and extracellular matrix hyaluronan. Deposition also occurs in other tissues and leads to multi-organ involvement.

• #7 Nephrogenic systemic fibrosis (NSF) – Questions and Answers ​in MRI

  https://mriquestions.com/what-is-nsf.html

  Nephrogenic systemic fibrosis (NSF) is a rare, progressive, often fatal disease characterized by skin thickening, painful joint contractures, and fibrosis of multiple organs including the lungs, liver, muscles, and heart. Nearly all documented cases have occurred in patients with chronic severe renal insufficiency who have received gadolinium contrast. The association between gadolinium and NSF was first reported by Danish nephrologists in 2006. Between 2006 and 2010 several hundred cases were diagnosed worldwide. […] NSF usually develops clinically within days to months following gadolinium exposure, although rare cases have been reported years later. Nearly all patients have been in various degrees of renal failure and many were on dialysis. Only exceedingly rare cases have been reported in patients with eGFRs 30 mL/min/1.73m. High and/or multiple doses of contrast are frequently reported, as are the use of linear contrast agents (ACR Group I). Other risk factors include liver disease and acidosis.

• #8 Nephrogenic Systemic Fibrosis – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK567754/

  Nephrogenic systemic fibrosis (NSF) is a progressive multiorgan fibrosing condition caused by exposure to gadolinium-based contrast agents (GBCAs) used for magnetic resonance imaging (MRI) in the setting of low glomerular filtration rate (GFR). This condition is characterized by thickening of the skin and subcutaneous tissue in addition to systemic manifestations. The clinical features may also involve skeletal muscle and any fibrous tissue in the body, including the internal organs such as the liver, heart, and lungs. NSF is a clinically highly variable condition. Some patients may have only mild effects on the skin, but many patients develop significant debility. In some patients, the disease may be lethal. […] The prevailing theory is that Gd exposure is prolonged in patients with renal disease, allowing the Gd to dissociate from its organic chelators and bind with calcium, phosphate, and other endogenous compounds to deposit in the skin and tissues. This sets off a fibrotic reaction involving the proliferation of fibroblasts in the dermis and the replacement of normal tissue with thickened collagen and extracellular matrix hyaluronan. Deposition also occurs in other tissues and leads to multi-organ involvement.

• #9

  https://link.springer.com/article/10.1007/s00467-013-2636-z

  Nephrogenic systemic fibrosis (NSF) is a multisystem disease seen exclusively in patients with renal impairment. […] There is a strong association with gadolinium-based contrast agents used in magnetic resonance imaging (MRI). […] The occurrence of NSF following gadolinium (Gd)-based contrast-agent administration was first reported in 2006. […] We will discuss the emergence of NSF as a clinical entity and consider the evidence for Gd as a causative agent. […] In 2006, Groebner reported a series of five patients with end-stage kidney disease who developed NSF 24 weeks following Gd-enhanced MRA. […] This association with Gd sparked immediate research into its possible role in NSF, and case series and retrospective case-control analyses have subsequently reported Gd-based contrast administration prior to NSF onset in nearly all cases.

• #10

  https://link.springer.com/article/10.1007/s00467-013-2636-z

  Nephrogenic systemic fibrosis (NSF) is a multisystem disease seen exclusively in patients with renal impairment. […] There is a strong association with gadolinium-based contrast agents used in magnetic resonance imaging (MRI). […] The occurrence of NSF following gadolinium (Gd)-based contrast-agent administration was first reported in 2006. […] We will discuss the emergence of NSF as a clinical entity and consider the evidence for Gd as a causative agent. […] In 2006, Groebner reported a series of five patients with end-stage kidney disease who developed NSF 24 weeks following Gd-enhanced MRA. […] This association with Gd sparked immediate research into its possible role in NSF, and case series and retrospective case-control analyses have subsequently reported Gd-based contrast administration prior to NSF onset in nearly all cases.

• #11

  https://link.springer.com/article/10.1007/s00467-013-2636-z

  The reported delay between Gd exposure and NSF presentation varies greatly for individual patients, ranging from a few days to 3 years, with a median of 62 days. […] In summary, for approximately 90 % of cases, there is a clear temporal sequence between Gd administration and NSF development. […] Data show a strong association between Gd exposure and NSF, and there is a likely dose-response relationship. […] It is postulated that Gd dissociation leads to insoluble Gd salt deposition in the interstitium, providing a nidus for fibrosis. […] Free Gd has indeed been shown to stimulate human fibroblast proliferation in vitro, with hyaluronan and collagen synthesis, as seen in biopsies from patients with NSF. […] Although the majority of the in vitro studies relate to nonchelated Gd as a trigger for NSF, human macrophages and monocytes also express pro-fibrotic cytokines and growth factors capable of stimulating NSF-like fibrosis in response to chelated gadodiamide and gadopentetate dimeglumine.

• #12 Nephrogenic Systemic Fibrosis: Background, Pathophysiology, Etiology

  https://emedicine.medscape.com/article/1097889-overview

  The mechanism by which this occurs in not known, but it seems to involve a cell termed a circulating fibrocyte that is stimulated by gadolinium. Endothelin-1/endothelin receptor signaling plays a role in the calcification and fibrosis of nephrogenic systemic fibrosis. […] Toll-like receptors (TLR), in particular TLR4 and TLR7, play a role in the development of nephrogenic systemic fibrosis. […] Thomsen et al noted that more than 90% of proven nephrogenic systemic fibrosis cases are related to gadodiamide (Omniscan) and some to gadopentetate (Magnevist). As such, gadoversetamide (OptiMARK) and gadopentetate dimeglumine (Magnevist) should not be used for imaging in patients with renal impairment. […] The amount of gadolinium needed to induce aberrant production of hyaluronic acid seems to be minimal. According to an abstract presented by Dr. Susie Mukherjee reported at the 2007 annual meeting of the British Association of Dermatologists, only tiny concentrations of gadolinium are needed to stimulate hyaluronan synthesis by fibroblasts.

• #13 Nephrogenic systemic fibrosis | Radiology Reference Article | Radiopaedia.org

  https://radiopaedia.org/articles/nephrogenic-systemic-fibrosis?lang=us

  Low-stability gadolinium contrast media show the strongest association with nephrogenic systemic fibrosis. A literature review has shown that ~78% of all unconfounded, single-agent cases of nephrogenic systemic fibrosis have been associated with Omniscan (gadodiamide), while ~20% have been associated with Magnevist (gadopentetate dimeglumine), and less than 2% with OptiMARK (gadoversetamide), all of which are group I GBCAs.

• #14 Nephrogenic Systemic Fibrosis – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK567754/

  Nephrogenic systemic fibrosis (NSF) is a progressive multiorgan fibrosing condition caused by exposure to gadolinium-based contrast agents (GBCAs) used for magnetic resonance imaging (MRI) in the setting of low glomerular filtration rate (GFR). This condition is characterized by thickening of the skin and subcutaneous tissue in addition to systemic manifestations. The clinical features may also involve skeletal muscle and any fibrous tissue in the body, including the internal organs such as the liver, heart, and lungs. NSF is a clinically highly variable condition. Some patients may have only mild effects on the skin, but many patients develop significant debility. In some patients, the disease may be lethal. […] The prevailing theory is that Gd exposure is prolonged in patients with renal disease, allowing the Gd to dissociate from its organic chelators and bind with calcium, phosphate, and other endogenous compounds to deposit in the skin and tissues. This sets off a fibrotic reaction involving the proliferation of fibroblasts in the dermis and the replacement of normal tissue with thickened collagen and extracellular matrix hyaluronan. Deposition also occurs in other tissues and leads to multi-organ involvement.

• #15 Nephrogenic systemic fibrosis: A frivolous entity

  https://www.wjgnet.com/2220-6124/full/v10/i3/29.htm

  Reduced kidney function results in a substantial increase in its half-life from 1.5 h (normal kidney function) to 5.61 h and 9.18 h at CKD stage 4 and 5, respectively. […] Vascular injury and endothelial dysfunction enhance free Gd invasion into tissues, where Gd is phagocytosed by macrophages to release local profibrotic cytokines and sends signals to attract circulating fibrocytes into the tissues. […] These circulating fibrocytes are cardinal cells that play the interlinking role between Gd deposition and the initiation of fibrosis. […] This hypothesis is held up by the presence of excess Gd in the affected tissues of NSF patients when compared to unaffected tissues.

• #16 Nephrogenic systemic fibrosis (NSF) – Questions and Answers ​in MRI

  https://mriquestions.com/what-is-nsf.html

  The strong association with renal insufficiency most likely relates to the prolonged biological half-life due to prolonged excretion of gadolinium. However, other factors have been imputed, including metabolic acidosis; elevated iron and phosphate levels; erythropoietin therapy; vasculopathy; and infectious/inflammatory mediators. […] The pathogenesis of NSF is believed to begin with the displacement of the Gd ion from its chelate by another metallic cation (Fe+3, Zn+2, or Ca+2) through a so-called transmetalation reaction: (Metal ion) + Gd-Chelate Metal-Chelate + Gd+3. The free Gd ion is then deposited in the skin and other soft tissues. There it is engulfed by CD163+ iron-recycling and other macrophages creating an inflammatory response and cytokine release. Circulating fibrocytes (immunologically unique CD-34 positive cells derived from bone marrow) deposit in tissue, transforming into spindle cells that proliferate and become the hallmark of the disease. Following recognition of this disorder and its association with gadolinium in patients with renal insufficiency, the worldwide radiology community responded immediately to put an end to this iatrogenic disease. Today, NSF has been nearly completely eliminated due to these measures. In more recent times, however, gadolinium-induced plaques have been reported in the extremities not meeting the full criteria for NSF. The story of NSF is sad one that we radiologists created. It should serve as a lesson that even drugs which appear to be extraordinarily safe may not be infinitely safe for all patients. Sometimes adverse effects may be subtle, disguised, or appear at long time intervals following administration. NSF is thus a call and reminder to be forever vigilant.

• #17 Nephrogenic systemic fibrosis (NSF) – Questions and Answers ​in MRI

  https://mriquestions.com/what-is-nsf.html

  The strong association with renal insufficiency most likely relates to the prolonged biological half-life due to prolonged excretion of gadolinium. However, other factors have been imputed, including metabolic acidosis; elevated iron and phosphate levels; erythropoietin therapy; vasculopathy; and infectious/inflammatory mediators. […] The pathogenesis of NSF is believed to begin with the displacement of the Gd ion from its chelate by another metallic cation (Fe+3, Zn+2, or Ca+2) through a so-called transmetalation reaction: (Metal ion) + Gd-Chelate Metal-Chelate + Gd+3. The free Gd ion is then deposited in the skin and other soft tissues. There it is engulfed by CD163+ iron-recycling and other macrophages creating an inflammatory response and cytokine release. Circulating fibrocytes (immunologically unique CD-34 positive cells derived from bone marrow) deposit in tissue, transforming into spindle cells that proliferate and become the hallmark of the disease. Following recognition of this disorder and its association with gadolinium in patients with renal insufficiency, the worldwide radiology community responded immediately to put an end to this iatrogenic disease. Today, NSF has been nearly completely eliminated due to these measures. In more recent times, however, gadolinium-induced plaques have been reported in the extremities not meeting the full criteria for NSF. The story of NSF is sad one that we radiologists created. It should serve as a lesson that even drugs which appear to be extraordinarily safe may not be infinitely safe for all patients. Sometimes adverse effects may be subtle, disguised, or appear at long time intervals following administration. NSF is thus a call and reminder to be forever vigilant.

• #18 Nephrogenic Systemic Fibrosis – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK567754/

  Nephrogenic systemic fibrosis (NSF) is a progressive multiorgan fibrosing condition caused by exposure to gadolinium-based contrast agents (GBCAs) used for magnetic resonance imaging (MRI) in the setting of low glomerular filtration rate (GFR). This condition is characterized by thickening of the skin and subcutaneous tissue in addition to systemic manifestations. The clinical features may also involve skeletal muscle and any fibrous tissue in the body, including the internal organs such as the liver, heart, and lungs. NSF is a clinically highly variable condition. Some patients may have only mild effects on the skin, but many patients develop significant debility. In some patients, the disease may be lethal. […] The prevailing theory is that Gd exposure is prolonged in patients with renal disease, allowing the Gd to dissociate from its organic chelators and bind with calcium, phosphate, and other endogenous compounds to deposit in the skin and tissues. This sets off a fibrotic reaction involving the proliferation of fibroblasts in the dermis and the replacement of normal tissue with thickened collagen and extracellular matrix hyaluronan. Deposition also occurs in other tissues and leads to multi-organ involvement.

• #19 SciELO Brazil – Nephrogenic systemic fibrosis: concepts and perspectives Nephrogenic systemic fibrosis: concepts and perspectives

  https://www.scielo.br/j/abd/a/YRrkNwbg8vdYmP5SR85wmcG/?lang=en

  Direct toxic effects are suggested by the presence of Gd deposits in the skin of individuals who develop NSF. […] An increase in serum iron (Fe) concentration can induce in vivo transmetallation of Gd, a phenomenon whereby free Gd is released from the chelate and subsequent binds to endogenous ions. […] Increased expression and activation of transglutaminases in NSF were documented, but with no exact role in the pathogenesis of the disease. […] Procoagulant states, recent surgery (especially vascular), deep vein thrombosis, newly transplanted-kidney failure and sudden-onset kidney disease with significant swelling of the extremities may be associated with NSF. […] The injured vessels allow the dissociated Gd prompt penetration in the interstitial space and tissues. […] The presence of Gd deposits can be seen via spectrometry, but their intensity does not correlate with the extent of clinical involvement.

• #20 Nephrogenic Systemic Fibrosis as a Complication after Gadolinium-Containing Contrast Agents: A Rapid Review

  https://www.mdpi.com/1660-4601/18/6/3000

  Nephrogenic systemic fibrosis (NFS) is a generalized disorder occurring in people with kidney failure. This new disease entity can lead to significant disability or even death. Gadolinium-associated systemic fibrosis is related to exposure to contrast agents used for magnetic resonance imaging. The first to hypothesize that gadolinium-based contrast agents are involved in the pathogenesis of NSF was Grobner. The most commonly used magnetic contrast agents for magnetic resonance imaging (MRI) are gadolinium chelates. Their excretion from the body takes place through the kidneys. The prolonged exposure time results in the dissociation of ions from the paramagnetic particles and their accumulation as deposits in the lymph nodes, bones, brain and liver. In addition, the presence of Gd3+ causes the activation of dendritic cells. These cells, producing transforming growth factor beta 1, initiate fibrosis and mobilize other dendritic cells. This may lead to an intensification of the fibrosis process. Another mechanism that may initiate fibrosis is related to the phagocytosis of Gd3+ by macrophages. By releasing proinflammatory cytokines, these cells attract circulating fibrocytes, which then transform in the dermis into fibroblasts and initiate fibrosis. An additional causative factor, especially in patients with renal failure, may be the transmetalation process. This process releases gadolinium by replacing Gd3+ in chelate molecules with systemic cations such as iron, zinc and copper. The process of the release of free Gd3+ ions varies depending on the structure of the compound, which is part of the contrast agents. There are two structural forms of chelates: linear and cyclic. A higher probability of the release of Gd3+ ions from chelate compounds is with linear contrast media, as opposed to cyclic chelate compounds, in which gadolinium is trapped inside. Since 2006, data have been collected on the basis of studies that confirm the relationship between NSF occurrence after exposure to contrast mediums containing gadodiamide and gadopentetate dimeglumine. Most of the described cases were exposed to linear gadolinium chelates during magnetic resonance imaging. These were gadodiamide (Omniscan) and gadopentetate dimeglumine (Magnevist). The authors of five studies have pointed out other variables that occurred in patients with NSF, which may also be a factor increasing the development of the disease. In one study, all patients who developed NSF had metabolic acidosis, while healthy patients showed normal pH values. Others noted elevated inflammatory values during contrast administration in patients who developed NSF. Marckmann et al., suggest that the risk of NSF increases during therapy with higher doses of erythropoietin and higher serum concentrations of calcium and phosphorus in patients at the time of exposure to contrast agents. The hypothesis that gadolinium contrast agents are related to the development of NSF was put forward for the first time by Grobner et al., in 2006. The common feature of all patients with NSF is renal failure. Many authors emphasized that the highest risk of NSF exists in patients with a GFR < 15 mL/min/1.73 m² (i.e., chronic kidney disease at stage 5). In patients with kidney failure, the period of the elimination of the contrast medium from the body can be extended up to over 30 h. The role of dialysis in preventing NSF is unclear. Currently, it is assumed that the risk of developing NSF may decrease when patients undergo immediate dialysis (<24 h) after contrast medium administration. However, Saitoh et al., pointed out that one dialysis treatment is not sufficient to remove all gadolinium. In a study by Perez-Rodrigue et al., seven patients underwent dialysis within 24 h of contrast medium exposure and continued to develop NSF. Some authors suggest that it might be acceptable to give some additional dialysis sessions to patients already undergoing renal replacement therapy. It would, at least, limit the potential Gd3+ toxicities. Metabolic acidosis, ongoing inflammatory process, treatment with erythropoietin and high serum concentrations of calcium and phosphorus have been reported as factors contributing to the development of NSF. In the Grobner et al. study, all patients affected by NSF had metabolic acidosis. Their mean pH was 7.29 ± 0.04 (mean actual bicarbonate value 19.5 ± 1.7 mmol/L), while the mean pH of healthy individuals was 7.39 ± 0.01 (mean actual bicarbonate value: 22.95 ± 0.58 mmol/L). Marckmann et al., did not confirm this hypothesis. In their clinical–control study, no significant difference in serum bicarbonate concentration between patients with NSF and the control group was found. However, the researchers pointed out the difference in treatment with erythropoietin. Ultimately, the hypothesis that NSF may be induced by analogs of erythropoietin was rejected because three of their subjects have never been treated with such drugs. However, there was a tendency to use higher doses of erythropoietin in people with NSF than in the control group. Higher doses of erythropoietin were used in people with a severe course of NSF. Of note, a series of cases described by Othersen et al., did not support this hypothesis—two patients received a small dose of erythropoietin, and two did not take it while exposed to gadolinium. The researchers suggest that in the case of erythropoietin treatment, the relationship with NSF is unlikely to be causative. In a study by Marckmann et al., it was noted that all NSF cases had significantly higher concentrations of phosphate and ionized calcium in serum during exposure to contrast media. This confirms the chemical theory that higher levels of ionized calcium and phosphates lead to a process of transmetallation and a greater risk of Gd3+ ion retention outside the contrast agent complex. This leads to the retention of Gd3+ ion, which is toxic to the body, and its penetration through membranes to other cells. A significant relationship between NSF and infection was confirmed by Golding et al. Precisely 6.7% of NSF cases were with an infection. It has been estimated that infection in patients with renal failure increases the risk of NSF 25-fold.

• #21 Nephrogenic systemic fibrosis (NSF) – Questions and Answers ​in MRI

  https://mriquestions.com/what-is-nsf.html

  The strong association with renal insufficiency most likely relates to the prolonged biological half-life due to prolonged excretion of gadolinium. However, other factors have been imputed, including metabolic acidosis; elevated iron and phosphate levels; erythropoietin therapy; vasculopathy; and infectious/inflammatory mediators. […] The pathogenesis of NSF is believed to begin with the displacement of the Gd ion from its chelate by another metallic cation (Fe+3, Zn+2, or Ca+2) through a so-called transmetalation reaction: (Metal ion) + Gd-Chelate Metal-Chelate + Gd+3. The free Gd ion is then deposited in the skin and other soft tissues. There it is engulfed by CD163+ iron-recycling and other macrophages creating an inflammatory response and cytokine release. Circulating fibrocytes (immunologically unique CD-34 positive cells derived from bone marrow) deposit in tissue, transforming into spindle cells that proliferate and become the hallmark of the disease. Following recognition of this disorder and its association with gadolinium in patients with renal insufficiency, the worldwide radiology community responded immediately to put an end to this iatrogenic disease. Today, NSF has been nearly completely eliminated due to these measures. In more recent times, however, gadolinium-induced plaques have been reported in the extremities not meeting the full criteria for NSF. The story of NSF is sad one that we radiologists created. It should serve as a lesson that even drugs which appear to be extraordinarily safe may not be infinitely safe for all patients. Sometimes adverse effects may be subtle, disguised, or appear at long time intervals following administration. NSF is thus a call and reminder to be forever vigilant.

• #22 Nephrogenic systemic fibrosis (NSF) – Questions and Answers ​in MRI

  https://mriquestions.com/what-is-nsf.html

  The strong association with renal insufficiency most likely relates to the prolonged biological half-life due to prolonged excretion of gadolinium. However, other factors have been imputed, including metabolic acidosis; elevated iron and phosphate levels; erythropoietin therapy; vasculopathy; and infectious/inflammatory mediators. […] The pathogenesis of NSF is believed to begin with the displacement of the Gd ion from its chelate by another metallic cation (Fe+3, Zn+2, or Ca+2) through a so-called transmetalation reaction: (Metal ion) + Gd-Chelate Metal-Chelate + Gd+3. The free Gd ion is then deposited in the skin and other soft tissues. There it is engulfed by CD163+ iron-recycling and other macrophages creating an inflammatory response and cytokine release. Circulating fibrocytes (immunologically unique CD-34 positive cells derived from bone marrow) deposit in tissue, transforming into spindle cells that proliferate and become the hallmark of the disease. Following recognition of this disorder and its association with gadolinium in patients with renal insufficiency, the worldwide radiology community responded immediately to put an end to this iatrogenic disease. Today, NSF has been nearly completely eliminated due to these measures. In more recent times, however, gadolinium-induced plaques have been reported in the extremities not meeting the full criteria for NSF. The story of NSF is sad one that we radiologists created. It should serve as a lesson that even drugs which appear to be extraordinarily safe may not be infinitely safe for all patients. Sometimes adverse effects may be subtle, disguised, or appear at long time intervals following administration. NSF is thus a call and reminder to be forever vigilant.

• #23 Nephrogenic systemic fibrosis : (nephrogenic fibrosing dermopathy) – Creative Med Doses

  https://creativemeddoses.com/?post_type=topic&p=1048

  Nephrogenic systemic fibrosis (NSF), as the name implies, is a systemic fibrosis involving multiple organs and tissues due to nephrogenic pathology (chronic/acute renal failure). […] The exact cause and pathogenesis of NSF is unknown. The precise pathogenesis of NSF remains unknown but is believed to be multifactorial. […] Gadolinium-based contrast agents are frequently used for MRI. In cases with impaired renal function, the administration of GBCAs may trigger fibrosis. […] The vascular and endothelial injury associated with chronic kidney disease facilitates the gadolinium invasion into the tissues. The accumulated gadolinium chelates with iron and phosphate gets deposited in various tissues/organs. The tissue macrophages phagocytose the foreign gadolinium in order to eliminate it. The activated macrophages release cytokines and chemokines, some of which stimulate increased production of CD 34 positive fibroblasts in bone marrow. The newly produced fibrocytes come into the circulation and trigger fibrosis of various organs.

• #24 SciELO Brazil – Nephrogenic systemic fibrosis: concepts and perspectives Nephrogenic systemic fibrosis: concepts and perspectives

  https://www.scielo.br/j/abd/a/YRrkNwbg8vdYmP5SR85wmcG/?lang=en

  Nephrogenic systemic fibrosis is a chronic, progressive condition that develops in some patients with renal impairment after exposure to gadolinium-based contrast agents used in magnetic resonance imaging. […] The mechanisms through which injury is caused in the skin and other organs are not well understood. […] The discovery of Gd deposits in the skin of affected patients led to the recommendation of cautious use of these contrast agents in patients with CRI by the Food and Drug Administration (FDA) and the European Medicines Agency (EMA). […] The sequence of physiopathological events in NSF is not yet clear. Theories postulate that NSF results from activation of circulating fibrocytes, a population of bone marrow-derived circulating mesenchymal stem cells, that are induced by Gd to differentiate in the dermis into cells that functionally and histologically resemble dermal fibroblasts.

• #25 Nephrogenic systemic fibrosis (NSF) – Questions and Answers ​in MRI

  https://mriquestions.com/what-is-nsf.html

  The strong association with renal insufficiency most likely relates to the prolonged biological half-life due to prolonged excretion of gadolinium. However, other factors have been imputed, including metabolic acidosis; elevated iron and phosphate levels; erythropoietin therapy; vasculopathy; and infectious/inflammatory mediators. […] The pathogenesis of NSF is believed to begin with the displacement of the Gd ion from its chelate by another metallic cation (Fe+3, Zn+2, or Ca+2) through a so-called transmetalation reaction: (Metal ion) + Gd-Chelate Metal-Chelate + Gd+3. The free Gd ion is then deposited in the skin and other soft tissues. There it is engulfed by CD163+ iron-recycling and other macrophages creating an inflammatory response and cytokine release. Circulating fibrocytes (immunologically unique CD-34 positive cells derived from bone marrow) deposit in tissue, transforming into spindle cells that proliferate and become the hallmark of the disease. Following recognition of this disorder and its association with gadolinium in patients with renal insufficiency, the worldwide radiology community responded immediately to put an end to this iatrogenic disease. Today, NSF has been nearly completely eliminated due to these measures. In more recent times, however, gadolinium-induced plaques have been reported in the extremities not meeting the full criteria for NSF. The story of NSF is sad one that we radiologists created. It should serve as a lesson that even drugs which appear to be extraordinarily safe may not be infinitely safe for all patients. Sometimes adverse effects may be subtle, disguised, or appear at long time intervals following administration. NSF is thus a call and reminder to be forever vigilant.

• #26 Nephrogenic Systemic Fibrosis | Treatment & Management | Point of Care

  https://www.statpearls.com/point-of-care/25703

  Activation of dermal fibroblasts is a key component in the pathogenesis of NSF. The dermal fibroblasts synthesize excess glycosaminoglycans, particularly hyaluronan, which is partially responsible for the characteristic skin thickening. […] Gd has also been shown to be immunogenic in vitro, activating toll-like receptors, macrophages, and dendritic cells. This initiates a vicious fibrotic cycle of transforming growth factor-beta 1 production and dendritic cell maturation, resulting in excessive collagen deposition in the extracellular matrix and soft tissues. […] Abnormal calcium and phosphorus metabolism has also been found in patients who develop NSF compared to patients with a similar estimated glomerular filtration rate who did not develop NSF, and calcium and phosphorus deposits have also been found in the gadolinium-containing deposits of NSF.

• #27 Nephrogenic Systemic Fibrosis | Treatment & Management | Point of Care

  https://www.statpearls.com/point-of-care/25703

  Activation of dermal fibroblasts is a key component in the pathogenesis of NSF. The dermal fibroblasts synthesize excess glycosaminoglycans, particularly hyaluronan, which is partially responsible for the characteristic skin thickening. […] Gd has also been shown to be immunogenic in vitro, activating toll-like receptors, macrophages, and dendritic cells. This initiates a vicious fibrotic cycle of transforming growth factor-beta 1 production and dendritic cell maturation, resulting in excessive collagen deposition in the extracellular matrix and soft tissues. […] Abnormal calcium and phosphorus metabolism has also been found in patients who develop NSF compared to patients with a similar estimated glomerular filtration rate who did not develop NSF, and calcium and phosphorus deposits have also been found in the gadolinium-containing deposits of NSF.

• #28 Nephrogenic Systemic Fibrosis: Background, Pathophysiology, Etiology

  https://emedicine.medscape.com/article/1097889-overview

  The mechanism by which this occurs in not known, but it seems to involve a cell termed a circulating fibrocyte that is stimulated by gadolinium. Endothelin-1/endothelin receptor signaling plays a role in the calcification and fibrosis of nephrogenic systemic fibrosis. […] Toll-like receptors (TLR), in particular TLR4 and TLR7, play a role in the development of nephrogenic systemic fibrosis. […] Thomsen et al noted that more than 90% of proven nephrogenic systemic fibrosis cases are related to gadodiamide (Omniscan) and some to gadopentetate (Magnevist). As such, gadoversetamide (OptiMARK) and gadopentetate dimeglumine (Magnevist) should not be used for imaging in patients with renal impairment. […] The amount of gadolinium needed to induce aberrant production of hyaluronic acid seems to be minimal. According to an abstract presented by Dr. Susie Mukherjee reported at the 2007 annual meeting of the British Association of Dermatologists, only tiny concentrations of gadolinium are needed to stimulate hyaluronan synthesis by fibroblasts.

• #29 Nephrogenic Systemic Fibrosis | Treatment & Management | Point of Care

  https://www.statpearls.com/point-of-care/25703

  Activation of dermal fibroblasts is a key component in the pathogenesis of NSF. The dermal fibroblasts synthesize excess glycosaminoglycans, particularly hyaluronan, which is partially responsible for the characteristic skin thickening. […] Gd has also been shown to be immunogenic in vitro, activating toll-like receptors, macrophages, and dendritic cells. This initiates a vicious fibrotic cycle of transforming growth factor-beta 1 production and dendritic cell maturation, resulting in excessive collagen deposition in the extracellular matrix and soft tissues. […] Abnormal calcium and phosphorus metabolism has also been found in patients who develop NSF compared to patients with a similar estimated glomerular filtration rate who did not develop NSF, and calcium and phosphorus deposits have also been found in the gadolinium-containing deposits of NSF.

• #30

  https://journals.lww.com/idoj/fulltext/2011/02020/nephrogenic_systemic_fibrosis.1.aspx

  The pathogenic mechanism involves CD45RO+ / CD34+ / collagen I positive circulatory fibrocytes that are recruited by the skin, yielding fibrosis. […] These circulating fibrocytes are aberrantly targeted to the dermis, which causes a local release of a profibrotic cytokine-like transforming growth factor (TGF)-1. […] Skin biopsy specimen of patients with NSF shows increased expression of the transforming growth factor (TGF)-1 messenger RNA and decorin messenger RNA, which plays an important role in collagen metabolism. […] Renal insufficiency leads to abnormal accumulation of ions in the body fluids and tissues; these ions can combine with gadolinium and form insoluble conjugates. […] Deposition of such complexes can lead to the activation of resident dermal fibroblastic cells, ultimately leading to excess accumulation of collagen and extracellular ground matrix (mucin).

• #31

  https://journals.lww.com/idoj/fulltext/2011/02020/nephrogenic_systemic_fibrosis.1.aspx

  The pathogenic mechanism involves CD45RO+ / CD34+ / collagen I positive circulatory fibrocytes that are recruited by the skin, yielding fibrosis. […] These circulating fibrocytes are aberrantly targeted to the dermis, which causes a local release of a profibrotic cytokine-like transforming growth factor (TGF)-1. […] Skin biopsy specimen of patients with NSF shows increased expression of the transforming growth factor (TGF)-1 messenger RNA and decorin messenger RNA, which plays an important role in collagen metabolism. […] Renal insufficiency leads to abnormal accumulation of ions in the body fluids and tissues; these ions can combine with gadolinium and form insoluble conjugates. […] Deposition of such complexes can lead to the activation of resident dermal fibroblastic cells, ultimately leading to excess accumulation of collagen and extracellular ground matrix (mucin).

• #32 Nephrogenic Systemic Fibrosis: Background, Pathophysiology, Etiology

  https://emedicine.medscape.com/article/1097889-overview

  Parsons et al performed immunohistochemical studies using antibodies to transglutaminase-2, factor XIIIa, transglutaminase isopeptide, and the histiocyte marker CD68 on 5 archived skin biopsy specimens of nephrogenic systemic fibrosis. Parsons et al found that dermal fibroblasts and histiocytes of nephrogenic systemic fibrosis expressed transglutaminase-2, CD68, factor XIIIa, and transglutaminase isopeptide. They posited that this represented increased expression, activation, or concomitant activation and expression of transglutaminases in nephrogenic systemic fibrosis. […] The cause of nephrogenic systemic fibrosis is the connexation of renal insufficiency and gadolinium exposure from imaging studies. The exact degree of renal insufficiency that sets up the development of nephrogenic systemic fibrosis is not known. Risk factors include advanced chronic kidney disease (stages 4 and 5) and acute or chronic inflammatory insults. […] Nephrogenic systemic fibrosis is a debilitating and sometimes fatal disease. Characteristics include red or dark patches on the skin; burning, itching, swelling, hardening, and tightening of the skin; yellow spots on the whites of the eyes; joint stiffness with trouble moving or straightening the arms, hands, legs, or feet; pain deep in the hip bones or ribs; and muscle weakness.

• #33 SciELO Brazil – Nephrogenic systemic fibrosis: concepts and perspectives Nephrogenic systemic fibrosis: concepts and perspectives

  https://www.scielo.br/j/abd/a/YRrkNwbg8vdYmP5SR85wmcG/?lang=en

  Direct toxic effects are suggested by the presence of Gd deposits in the skin of individuals who develop NSF. […] An increase in serum iron (Fe) concentration can induce in vivo transmetallation of Gd, a phenomenon whereby free Gd is released from the chelate and subsequent binds to endogenous ions. […] Increased expression and activation of transglutaminases in NSF were documented, but with no exact role in the pathogenesis of the disease. […] Procoagulant states, recent surgery (especially vascular), deep vein thrombosis, newly transplanted-kidney failure and sudden-onset kidney disease with significant swelling of the extremities may be associated with NSF. […] The injured vessels allow the dissociated Gd prompt penetration in the interstitial space and tissues. […] The presence of Gd deposits can be seen via spectrometry, but their intensity does not correlate with the extent of clinical involvement.

• #34 Nephrogenic Systemic Fibrosis as a Complication after Gadolinium-Containing Contrast Agents: A Rapid Review

  https://www.mdpi.com/1660-4601/18/6/3000

  Nephrogenic systemic fibrosis (NFS) is a generalized disorder occurring in people with kidney failure. This new disease entity can lead to significant disability or even death. Gadolinium-associated systemic fibrosis is related to exposure to contrast agents used for magnetic resonance imaging. The first to hypothesize that gadolinium-based contrast agents are involved in the pathogenesis of NSF was Grobner. The most commonly used magnetic contrast agents for magnetic resonance imaging (MRI) are gadolinium chelates. Their excretion from the body takes place through the kidneys. The prolonged exposure time results in the dissociation of ions from the paramagnetic particles and their accumulation as deposits in the lymph nodes, bones, brain and liver. In addition, the presence of Gd3+ causes the activation of dendritic cells. These cells, producing transforming growth factor beta 1, initiate fibrosis and mobilize other dendritic cells. This may lead to an intensification of the fibrosis process. Another mechanism that may initiate fibrosis is related to the phagocytosis of Gd3+ by macrophages. By releasing proinflammatory cytokines, these cells attract circulating fibrocytes, which then transform in the dermis into fibroblasts and initiate fibrosis. An additional causative factor, especially in patients with renal failure, may be the transmetalation process. This process releases gadolinium by replacing Gd3+ in chelate molecules with systemic cations such as iron, zinc and copper. The process of the release of free Gd3+ ions varies depending on the structure of the compound, which is part of the contrast agents. There are two structural forms of chelates: linear and cyclic. A higher probability of the release of Gd3+ ions from chelate compounds is with linear contrast media, as opposed to cyclic chelate compounds, in which gadolinium is trapped inside. Since 2006, data have been collected on the basis of studies that confirm the relationship between NSF occurrence after exposure to contrast mediums containing gadodiamide and gadopentetate dimeglumine. Most of the described cases were exposed to linear gadolinium chelates during magnetic resonance imaging. These were gadodiamide (Omniscan) and gadopentetate dimeglumine (Magnevist). The authors of five studies have pointed out other variables that occurred in patients with NSF, which may also be a factor increasing the development of the disease. In one study, all patients who developed NSF had metabolic acidosis, while healthy patients showed normal pH values. Others noted elevated inflammatory values during contrast administration in patients who developed NSF. Marckmann et al., suggest that the risk of NSF increases during therapy with higher doses of erythropoietin and higher serum concentrations of calcium and phosphorus in patients at the time of exposure to contrast agents. The hypothesis that gadolinium contrast agents are related to the development of NSF was put forward for the first time by Grobner et al., in 2006. The common feature of all patients with NSF is renal failure. Many authors emphasized that the highest risk of NSF exists in patients with a GFR < 15 mL/min/1.73 m² (i.e., chronic kidney disease at stage 5). In patients with kidney failure, the period of the elimination of the contrast medium from the body can be extended up to over 30 h. The role of dialysis in preventing NSF is unclear. Currently, it is assumed that the risk of developing NSF may decrease when patients undergo immediate dialysis (<24 h) after contrast medium administration. However, Saitoh et al., pointed out that one dialysis treatment is not sufficient to remove all gadolinium. In a study by Perez-Rodrigue et al., seven patients underwent dialysis within 24 h of contrast medium exposure and continued to develop NSF. Some authors suggest that it might be acceptable to give some additional dialysis sessions to patients already undergoing renal replacement therapy. It would, at least, limit the potential Gd3+ toxicities. Metabolic acidosis, ongoing inflammatory process, treatment with erythropoietin and high serum concentrations of calcium and phosphorus have been reported as factors contributing to the development of NSF. In the Grobner et al. study, all patients affected by NSF had metabolic acidosis. Their mean pH was 7.29 ± 0.04 (mean actual bicarbonate value 19.5 ± 1.7 mmol/L), while the mean pH of healthy individuals was 7.39 ± 0.01 (mean actual bicarbonate value: 22.95 ± 0.58 mmol/L). Marckmann et al., did not confirm this hypothesis. In their clinical–control study, no significant difference in serum bicarbonate concentration between patients with NSF and the control group was found. However, the researchers pointed out the difference in treatment with erythropoietin. Ultimately, the hypothesis that NSF may be induced by analogs of erythropoietin was rejected because three of their subjects have never been treated with such drugs. However, there was a tendency to use higher doses of erythropoietin in people with NSF than in the control group. Higher doses of erythropoietin were used in people with a severe course of NSF. Of note, a series of cases described by Othersen et al., did not support this hypothesis—two patients received a small dose of erythropoietin, and two did not take it while exposed to gadolinium. The researchers suggest that in the case of erythropoietin treatment, the relationship with NSF is unlikely to be causative. In a study by Marckmann et al., it was noted that all NSF cases had significantly higher concentrations of phosphate and ionized calcium in serum during exposure to contrast media. This confirms the chemical theory that higher levels of ionized calcium and phosphates lead to a process of transmetallation and a greater risk of Gd3+ ion retention outside the contrast agent complex. This leads to the retention of Gd3+ ion, which is toxic to the body, and its penetration through membranes to other cells. A significant relationship between NSF and infection was confirmed by Golding et al. Precisely 6.7% of NSF cases were with an infection. It has been estimated that infection in patients with renal failure increases the risk of NSF 25-fold.

• #35 Gadolinium-Induced Nephrogenic Systemic Fibrosis: Classification, Risk and Guidelines

  https://consultqd.clevelandclinic.org/gadolinium-induced-nephrogenic-systemic-fibrosis-classification-risk-and-guidelines

  Gadolinium-based contrast agents share a common structure, with a central heavy metal ion (gadolinium) bound tightly by an organic ligand to form a stable complex, thus minimizing the potential natural toxicity of the free metal ion. To avoid gadolinium toxicity, these agents should be highly stable so the gadolinium does not dissociate. Their stability is conferred by their chemical structure, namely whether they are linear or cyclic and whether they are charged (ionic) or electrically neutral (nonionic). It is generally recognized that macrocyclic and ionic structures are more stable than linear and nonionic ones. Thus, in highly stable agents, gadolinium dissociation is minimized and so is the risk of NSF. […] Although NSF has been basically eradicated since the guidelines were implemented, several cases of NSF have been reported in patients who never were exposed to gadolinium. This suggests that gadolinium-based contrast agents are a major trigger for NSF, but they may not be the only one. Time will tell if indeed other triggers have yet to be discovered. Additionally, in recent years, there have been data suggesting that gadolinium can deposit in the brain after repeated exposure to gadolinium-based contrast agents, even in patients with healthy kidneys. This finding was confirmed histologically and has led to the birth of a new term to describe it: gadolinium deposition disease. The significance of this brain deposition remains unknown, and to date, no adverse health effects have been uncovered. However, the FDA published a safety alert in 2015 indicating the active investigation of the risk and clinical significance of these gadolinium deposits.

• #36 Nephrogenic systemic fibrosis – Symptoms and causes – Mayo Clinic

  https://www.mayoclinic.org/diseases-conditions/nephrogenic-systemic-fibrosis/symptoms-causes/syc-20352299

  Nephrogenic systemic fibrosis is a rare disease that occurs mainly in people with advanced kidney failure with or without dialysis. […] For some people with advanced kidney disease, being exposed to older gadolinium-based contrast agents (group 1) during magnetic resonance imaging (MRI) and other imaging studies has been identified as a trigger for development of this disease. […] The exact cause of nephrogenic systemic fibrosis isn’t fully understood. Fibrous connective tissue forms in the skin and connective tissues, resulting in scarring of tissue throughout the body, most commonly the skin and subcutaneous tissues. […] Exposure to older gadolinium-based contrast agents (group 1) during magnetic resonance imaging (MRI) has been identified as a trigger for development of this disease in people with kidney disease. This increased risk is thought to be related to the kidneys’ reduced ability to remove the contrast agent from the bloodstream. […] Avoidance of older gadolinium-based contrast agents (group 1) is key to preventing nephrogenic systemic fibrosis, as newer gadolinium-based contrast agents (group 2) are safer and are not associated with increased risk.

• #37 Nephrogenic systemic fibrosis (NSF) and gadolinium-based contrast media | Ngoya | South African Journal of Radiology

  https://sajr.org.za/index.php/sajr/article/view/277/354

  Nephrogenic systemic fibrosis (NSF), unknown before March 1997 and first described in 2000, is a systemic disorder characterised by widespread tissue fibrosis. […] The link between nephrogenic systemic fibrosis (NSF) and GBCAs was recognised in 2006. […] Typical is the unique histopathology of NSF that includes thickened collagen bundles with surrounding clefts, increased dermal mucin deposition, proliferation of dendritic cells and increased elastic fibers. […] NSF is only observed in patients with severe renal dysfunction, primarily patients undergoing or approaching dialysis, hence the use of nephrogenic in its name. […] Possible side-effects occur owing to dissociation of the Gd-ligand complex into the metal ion and ligand. […] In renal failure, the combination of metabolic acidosis and the absence of adequate clearance of Gd-containing agent results in precipitation of salts with anions which are then deposited in the interstitium of muscle, bone, liver and skin.

• #38 Nephrogenic Systemic Fibrosis as a Complication after Gadolinium-Containing Contrast Agents: A Rapid Review

  https://www.mdpi.com/1660-4601/18/6/3000

  Nephrogenic systemic fibrosis (NFS) is a generalized disorder occurring in people with kidney failure. This new disease entity can lead to significant disability or even death. Gadolinium-associated systemic fibrosis is related to exposure to contrast agents used for magnetic resonance imaging. The first to hypothesize that gadolinium-based contrast agents are involved in the pathogenesis of NSF was Grobner. The most commonly used magnetic contrast agents for magnetic resonance imaging (MRI) are gadolinium chelates. Their excretion from the body takes place through the kidneys. The prolonged exposure time results in the dissociation of ions from the paramagnetic particles and their accumulation as deposits in the lymph nodes, bones, brain and liver. In addition, the presence of Gd3+ causes the activation of dendritic cells. These cells, producing transforming growth factor beta 1, initiate fibrosis and mobilize other dendritic cells. This may lead to an intensification of the fibrosis process. Another mechanism that may initiate fibrosis is related to the phagocytosis of Gd3+ by macrophages. By releasing proinflammatory cytokines, these cells attract circulating fibrocytes, which then transform in the dermis into fibroblasts and initiate fibrosis. An additional causative factor, especially in patients with renal failure, may be the transmetalation process. This process releases gadolinium by replacing Gd3+ in chelate molecules with systemic cations such as iron, zinc and copper. The process of the release of free Gd3+ ions varies depending on the structure of the compound, which is part of the contrast agents. There are two structural forms of chelates: linear and cyclic. A higher probability of the release of Gd3+ ions from chelate compounds is with linear contrast media, as opposed to cyclic chelate compounds, in which gadolinium is trapped inside. Since 2006, data have been collected on the basis of studies that confirm the relationship between NSF occurrence after exposure to contrast mediums containing gadodiamide and gadopentetate dimeglumine. Most of the described cases were exposed to linear gadolinium chelates during magnetic resonance imaging. These were gadodiamide (Omniscan) and gadopentetate dimeglumine (Magnevist). The authors of five studies have pointed out other variables that occurred in patients with NSF, which may also be a factor increasing the development of the disease. In one study, all patients who developed NSF had metabolic acidosis, while healthy patients showed normal pH values. Others noted elevated inflammatory values during contrast administration in patients who developed NSF. Marckmann et al., suggest that the risk of NSF increases during therapy with higher doses of erythropoietin and higher serum concentrations of calcium and phosphorus in patients at the time of exposure to contrast agents. The hypothesis that gadolinium contrast agents are related to the development of NSF was put forward for the first time by Grobner et al., in 2006. The common feature of all patients with NSF is renal failure. Many authors emphasized that the highest risk of NSF exists in patients with a GFR < 15 mL/min/1.73 m² (i.e., chronic kidney disease at stage 5). In patients with kidney failure, the period of the elimination of the contrast medium from the body can be extended up to over 30 h. The role of dialysis in preventing NSF is unclear. Currently, it is assumed that the risk of developing NSF may decrease when patients undergo immediate dialysis (<24 h) after contrast medium administration. However, Saitoh et al., pointed out that one dialysis treatment is not sufficient to remove all gadolinium. In a study by Perez-Rodrigue et al., seven patients underwent dialysis within 24 h of contrast medium exposure and continued to develop NSF. Some authors suggest that it might be acceptable to give some additional dialysis sessions to patients already undergoing renal replacement therapy. It would, at least, limit the potential Gd3+ toxicities. Metabolic acidosis, ongoing inflammatory process, treatment with erythropoietin and high serum concentrations of calcium and phosphorus have been reported as factors contributing to the development of NSF. In the Grobner et al. study, all patients affected by NSF had metabolic acidosis. Their mean pH was 7.29 ± 0.04 (mean actual bicarbonate value 19.5 ± 1.7 mmol/L), while the mean pH of healthy individuals was 7.39 ± 0.01 (mean actual bicarbonate value: 22.95 ± 0.58 mmol/L). Marckmann et al., did not confirm this hypothesis. In their clinical–control study, no significant difference in serum bicarbonate concentration between patients with NSF and the control group was found. However, the researchers pointed out the difference in treatment with erythropoietin. Ultimately, the hypothesis that NSF may be induced by analogs of erythropoietin was rejected because three of their subjects have never been treated with such drugs. However, there was a tendency to use higher doses of erythropoietin in people with NSF than in the control group. Higher doses of erythropoietin were used in people with a severe course of NSF. Of note, a series of cases described by Othersen et al., did not support this hypothesis—two patients received a small dose of erythropoietin, and two did not take it while exposed to gadolinium. The researchers suggest that in the case of erythropoietin treatment, the relationship with NSF is unlikely to be causative. In a study by Marckmann et al., it was noted that all NSF cases had significantly higher concentrations of phosphate and ionized calcium in serum during exposure to contrast media. This confirms the chemical theory that higher levels of ionized calcium and phosphates lead to a process of transmetallation and a greater risk of Gd3+ ion retention outside the contrast agent complex. This leads to the retention of Gd3+ ion, which is toxic to the body, and its penetration through membranes to other cells. A significant relationship between NSF and infection was confirmed by Golding et al. Precisely 6.7% of NSF cases were with an infection. It has been estimated that infection in patients with renal failure increases the risk of NSF 25-fold.

• #39 Nephrogenic Systemic Fibrosis | Treatment & Management | Point of Care

  https://www.statpearls.com/point-of-care/25703

  Nephrogenic systemic fibrosis (NSF) is a progressive multiorgan fibrosing condition caused by exposure to gadolinium-based contrast agents (GBCAs) used for magnetic resonance imaging (MRI) in the setting of low glomerular filtration rate (GFR). […] The condition was first described in 2000 when several physicians across the United States (US) noted patients with a scleroderma-type illness, and the association with GBCA administration in the setting of renal failure was solidified as more cases were presented. […] NSF occurs in patients with acute or severe chronic renal failure, usually stage 4 or 5 chronic kidney disease (CKD), but it has also been described in patients with stage 3 CKD. […] The prevailing theory is that Gd exposure is prolonged in patients with renal disease, allowing the Gd to dissociate from its organic chelators and bind with calcium, phosphate, and other endogenous compounds to deposit in the skin and tissues. This sets off a fibrotic reaction involving the proliferation of fibroblasts in the dermis and the replacement of normal tissue with thickened collagen and extracellular matrix hyaluronan.

• #40 Nephrogenic Systemic Fibrosis – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK567754/

  Activation of dermal fibroblasts is a key component in the pathogenesis of NSF. The dermal fibroblasts synthesize excess glycosaminoglycans, particularly hyaluronan, which is partially responsible for the characteristic skin thickening. Factors contributing to NSF include total gadolinium exposure, hypercalcemia, hyperphosphatemia, high-dose erythropoietin therapy, hepatorenal syndrome, immunosuppression, and vasculopathy. Results from one notable study showed that the risk of NSF was increased by 25 times when infection was present. […] Abnormal calcium and phosphorus metabolism has also been found in patients who develop NSF compared to patients with a similar estimated glomerular filtration rate who did not develop NSF, and calcium and phosphorus deposits have also been found in the gadolinium-containing deposits of NSF. Traumatic calcinosis cutis, osseous metaplasia, calciphylaxis, and metastatic calcification have also been observed in dialysis patients with NSF.

• #41 Nephrogenic systemic fibrosis (NSF) – Questions and Answers ​in MRI

  https://mriquestions.com/what-is-nsf.html

  Nephrogenic systemic fibrosis (NSF) is a rare, progressive, often fatal disease characterized by skin thickening, painful joint contractures, and fibrosis of multiple organs including the lungs, liver, muscles, and heart. Nearly all documented cases have occurred in patients with chronic severe renal insufficiency who have received gadolinium contrast. The association between gadolinium and NSF was first reported by Danish nephrologists in 2006. Between 2006 and 2010 several hundred cases were diagnosed worldwide. […] NSF usually develops clinically within days to months following gadolinium exposure, although rare cases have been reported years later. Nearly all patients have been in various degrees of renal failure and many were on dialysis. Only exceedingly rare cases have been reported in patients with eGFRs 30 mL/min/1.73m. High and/or multiple doses of contrast are frequently reported, as are the use of linear contrast agents (ACR Group I). Other risk factors include liver disease and acidosis.

• #42 Nephrogenic Systemic Fibrosis as a Complication after Gadolinium-Containing Contrast Agents: A Rapid Review

  https://www.mdpi.com/1660-4601/18/6/3000

  Nephrogenic systemic fibrosis (NFS) is a generalized disorder occurring in people with kidney failure. This new disease entity can lead to significant disability or even death. Gadolinium-associated systemic fibrosis is related to exposure to contrast agents used for magnetic resonance imaging. The first to hypothesize that gadolinium-based contrast agents are involved in the pathogenesis of NSF was Grobner. The most commonly used magnetic contrast agents for magnetic resonance imaging (MRI) are gadolinium chelates. Their excretion from the body takes place through the kidneys. The prolonged exposure time results in the dissociation of ions from the paramagnetic particles and their accumulation as deposits in the lymph nodes, bones, brain and liver. In addition, the presence of Gd3+ causes the activation of dendritic cells. These cells, producing transforming growth factor beta 1, initiate fibrosis and mobilize other dendritic cells. This may lead to an intensification of the fibrosis process. Another mechanism that may initiate fibrosis is related to the phagocytosis of Gd3+ by macrophages. By releasing proinflammatory cytokines, these cells attract circulating fibrocytes, which then transform in the dermis into fibroblasts and initiate fibrosis. An additional causative factor, especially in patients with renal failure, may be the transmetalation process. This process releases gadolinium by replacing Gd3+ in chelate molecules with systemic cations such as iron, zinc and copper. The process of the release of free Gd3+ ions varies depending on the structure of the compound, which is part of the contrast agents. There are two structural forms of chelates: linear and cyclic. A higher probability of the release of Gd3+ ions from chelate compounds is with linear contrast media, as opposed to cyclic chelate compounds, in which gadolinium is trapped inside. Since 2006, data have been collected on the basis of studies that confirm the relationship between NSF occurrence after exposure to contrast mediums containing gadodiamide and gadopentetate dimeglumine. Most of the described cases were exposed to linear gadolinium chelates during magnetic resonance imaging. These were gadodiamide (Omniscan) and gadopentetate dimeglumine (Magnevist). The authors of five studies have pointed out other variables that occurred in patients with NSF, which may also be a factor increasing the development of the disease. In one study, all patients who developed NSF had metabolic acidosis, while healthy patients showed normal pH values. Others noted elevated inflammatory values during contrast administration in patients who developed NSF. Marckmann et al., suggest that the risk of NSF increases during therapy with higher doses of erythropoietin and higher serum concentrations of calcium and phosphorus in patients at the time of exposure to contrast agents. The hypothesis that gadolinium contrast agents are related to the development of NSF was put forward for the first time by Grobner et al., in 2006. The common feature of all patients with NSF is renal failure. Many authors emphasized that the highest risk of NSF exists in patients with a GFR < 15 mL/min/1.73 m² (i.e., chronic kidney disease at stage 5). In patients with kidney failure, the period of the elimination of the contrast medium from the body can be extended up to over 30 h. The role of dialysis in preventing NSF is unclear. Currently, it is assumed that the risk of developing NSF may decrease when patients undergo immediate dialysis (<24 h) after contrast medium administration. However, Saitoh et al., pointed out that one dialysis treatment is not sufficient to remove all gadolinium. In a study by Perez-Rodrigue et al., seven patients underwent dialysis within 24 h of contrast medium exposure and continued to develop NSF. Some authors suggest that it might be acceptable to give some additional dialysis sessions to patients already undergoing renal replacement therapy. It would, at least, limit the potential Gd3+ toxicities. Metabolic acidosis, ongoing inflammatory process, treatment with erythropoietin and high serum concentrations of calcium and phosphorus have been reported as factors contributing to the development of NSF. In the Grobner et al. study, all patients affected by NSF had metabolic acidosis. Their mean pH was 7.29 ± 0.04 (mean actual bicarbonate value 19.5 ± 1.7 mmol/L), while the mean pH of healthy individuals was 7.39 ± 0.01 (mean actual bicarbonate value: 22.95 ± 0.58 mmol/L). Marckmann et al., did not confirm this hypothesis. In their clinical–control study, no significant difference in serum bicarbonate concentration between patients with NSF and the control group was found. However, the researchers pointed out the difference in treatment with erythropoietin. Ultimately, the hypothesis that NSF may be induced by analogs of erythropoietin was rejected because three of their subjects have never been treated with such drugs. However, there was a tendency to use higher doses of erythropoietin in people with NSF than in the control group. Higher doses of erythropoietin were used in people with a severe course of NSF. Of note, a series of cases described by Othersen et al., did not support this hypothesis—two patients received a small dose of erythropoietin, and two did not take it while exposed to gadolinium. The researchers suggest that in the case of erythropoietin treatment, the relationship with NSF is unlikely to be causative. In a study by Marckmann et al., it was noted that all NSF cases had significantly higher concentrations of phosphate and ionized calcium in serum during exposure to contrast media. This confirms the chemical theory that higher levels of ionized calcium and phosphates lead to a process of transmetallation and a greater risk of Gd3+ ion retention outside the contrast agent complex. This leads to the retention of Gd3+ ion, which is toxic to the body, and its penetration through membranes to other cells. A significant relationship between NSF and infection was confirmed by Golding et al. Precisely 6.7% of NSF cases were with an infection. It has been estimated that infection in patients with renal failure increases the risk of NSF 25-fold.

• #43 Nephrogenic Systemic Fibrosis as a Complication after Gadolinium-Containing Contrast Agents: A Rapid Review

  https://www.mdpi.com/1660-4601/18/6/3000

  Nephrogenic systemic fibrosis (NFS) is a generalized disorder occurring in people with kidney failure. This new disease entity can lead to significant disability or even death. Gadolinium-associated systemic fibrosis is related to exposure to contrast agents used for magnetic resonance imaging. The first to hypothesize that gadolinium-based contrast agents are involved in the pathogenesis of NSF was Grobner. The most commonly used magnetic contrast agents for magnetic resonance imaging (MRI) are gadolinium chelates. Their excretion from the body takes place through the kidneys. The prolonged exposure time results in the dissociation of ions from the paramagnetic particles and their accumulation as deposits in the lymph nodes, bones, brain and liver. In addition, the presence of Gd3+ causes the activation of dendritic cells. These cells, producing transforming growth factor beta 1, initiate fibrosis and mobilize other dendritic cells. This may lead to an intensification of the fibrosis process. Another mechanism that may initiate fibrosis is related to the phagocytosis of Gd3+ by macrophages. By releasing proinflammatory cytokines, these cells attract circulating fibrocytes, which then transform in the dermis into fibroblasts and initiate fibrosis. An additional causative factor, especially in patients with renal failure, may be the transmetalation process. This process releases gadolinium by replacing Gd3+ in chelate molecules with systemic cations such as iron, zinc and copper. The process of the release of free Gd3+ ions varies depending on the structure of the compound, which is part of the contrast agents. There are two structural forms of chelates: linear and cyclic. A higher probability of the release of Gd3+ ions from chelate compounds is with linear contrast media, as opposed to cyclic chelate compounds, in which gadolinium is trapped inside. Since 2006, data have been collected on the basis of studies that confirm the relationship between NSF occurrence after exposure to contrast mediums containing gadodiamide and gadopentetate dimeglumine. Most of the described cases were exposed to linear gadolinium chelates during magnetic resonance imaging. These were gadodiamide (Omniscan) and gadopentetate dimeglumine (Magnevist). The authors of five studies have pointed out other variables that occurred in patients with NSF, which may also be a factor increasing the development of the disease. In one study, all patients who developed NSF had metabolic acidosis, while healthy patients showed normal pH values. Others noted elevated inflammatory values during contrast administration in patients who developed NSF. Marckmann et al., suggest that the risk of NSF increases during therapy with higher doses of erythropoietin and higher serum concentrations of calcium and phosphorus in patients at the time of exposure to contrast agents. The hypothesis that gadolinium contrast agents are related to the development of NSF was put forward for the first time by Grobner et al., in 2006. The common feature of all patients with NSF is renal failure. Many authors emphasized that the highest risk of NSF exists in patients with a GFR < 15 mL/min/1.73 m² (i.e., chronic kidney disease at stage 5). In patients with kidney failure, the period of the elimination of the contrast medium from the body can be extended up to over 30 h. The role of dialysis in preventing NSF is unclear. Currently, it is assumed that the risk of developing NSF may decrease when patients undergo immediate dialysis (<24 h) after contrast medium administration. However, Saitoh et al., pointed out that one dialysis treatment is not sufficient to remove all gadolinium. In a study by Perez-Rodrigue et al., seven patients underwent dialysis within 24 h of contrast medium exposure and continued to develop NSF. Some authors suggest that it might be acceptable to give some additional dialysis sessions to patients already undergoing renal replacement therapy. It would, at least, limit the potential Gd3+ toxicities. Metabolic acidosis, ongoing inflammatory process, treatment with erythropoietin and high serum concentrations of calcium and phosphorus have been reported as factors contributing to the development of NSF. In the Grobner et al. study, all patients affected by NSF had metabolic acidosis. Their mean pH was 7.29 ± 0.04 (mean actual bicarbonate value 19.5 ± 1.7 mmol/L), while the mean pH of healthy individuals was 7.39 ± 0.01 (mean actual bicarbonate value: 22.95 ± 0.58 mmol/L). Marckmann et al., did not confirm this hypothesis. In their clinical–control study, no significant difference in serum bicarbonate concentration between patients with NSF and the control group was found. However, the researchers pointed out the difference in treatment with erythropoietin. Ultimately, the hypothesis that NSF may be induced by analogs of erythropoietin was rejected because three of their subjects have never been treated with such drugs. However, there was a tendency to use higher doses of erythropoietin in people with NSF than in the control group. Higher doses of erythropoietin were used in people with a severe course of NSF. Of note, a series of cases described by Othersen et al., did not support this hypothesis—two patients received a small dose of erythropoietin, and two did not take it while exposed to gadolinium. The researchers suggest that in the case of erythropoietin treatment, the relationship with NSF is unlikely to be causative. In a study by Marckmann et al., it was noted that all NSF cases had significantly higher concentrations of phosphate and ionized calcium in serum during exposure to contrast media. This confirms the chemical theory that higher levels of ionized calcium and phosphates lead to a process of transmetallation and a greater risk of Gd3+ ion retention outside the contrast agent complex. This leads to the retention of Gd3+ ion, which is toxic to the body, and its penetration through membranes to other cells. A significant relationship between NSF and infection was confirmed by Golding et al. Precisely 6.7% of NSF cases were with an infection. It has been estimated that infection in patients with renal failure increases the risk of NSF 25-fold.

• #44 Nephrogenic Systemic Fibrosis as a Complication after Gadolinium-Containing Contrast Agents: A Rapid Review

  https://www.mdpi.com/1660-4601/18/6/3000

  Nephrogenic systemic fibrosis (NFS) is a generalized disorder occurring in people with kidney failure. This new disease entity can lead to significant disability or even death. Gadolinium-associated systemic fibrosis is related to exposure to contrast agents used for magnetic resonance imaging. The first to hypothesize that gadolinium-based contrast agents are involved in the pathogenesis of NSF was Grobner. The most commonly used magnetic contrast agents for magnetic resonance imaging (MRI) are gadolinium chelates. Their excretion from the body takes place through the kidneys. The prolonged exposure time results in the dissociation of ions from the paramagnetic particles and their accumulation as deposits in the lymph nodes, bones, brain and liver. In addition, the presence of Gd3+ causes the activation of dendritic cells. These cells, producing transforming growth factor beta 1, initiate fibrosis and mobilize other dendritic cells. This may lead to an intensification of the fibrosis process. Another mechanism that may initiate fibrosis is related to the phagocytosis of Gd3+ by macrophages. By releasing proinflammatory cytokines, these cells attract circulating fibrocytes, which then transform in the dermis into fibroblasts and initiate fibrosis. An additional causative factor, especially in patients with renal failure, may be the transmetalation process. This process releases gadolinium by replacing Gd3+ in chelate molecules with systemic cations such as iron, zinc and copper. The process of the release of free Gd3+ ions varies depending on the structure of the compound, which is part of the contrast agents. There are two structural forms of chelates: linear and cyclic. A higher probability of the release of Gd3+ ions from chelate compounds is with linear contrast media, as opposed to cyclic chelate compounds, in which gadolinium is trapped inside. Since 2006, data have been collected on the basis of studies that confirm the relationship between NSF occurrence after exposure to contrast mediums containing gadodiamide and gadopentetate dimeglumine. Most of the described cases were exposed to linear gadolinium chelates during magnetic resonance imaging. These were gadodiamide (Omniscan) and gadopentetate dimeglumine (Magnevist). The authors of five studies have pointed out other variables that occurred in patients with NSF, which may also be a factor increasing the development of the disease. In one study, all patients who developed NSF had metabolic acidosis, while healthy patients showed normal pH values. Others noted elevated inflammatory values during contrast administration in patients who developed NSF. Marckmann et al., suggest that the risk of NSF increases during therapy with higher doses of erythropoietin and higher serum concentrations of calcium and phosphorus in patients at the time of exposure to contrast agents. The hypothesis that gadolinium contrast agents are related to the development of NSF was put forward for the first time by Grobner et al., in 2006. The common feature of all patients with NSF is renal failure. Many authors emphasized that the highest risk of NSF exists in patients with a GFR < 15 mL/min/1.73 m² (i.e., chronic kidney disease at stage 5). In patients with kidney failure, the period of the elimination of the contrast medium from the body can be extended up to over 30 h. The role of dialysis in preventing NSF is unclear. Currently, it is assumed that the risk of developing NSF may decrease when patients undergo immediate dialysis (<24 h) after contrast medium administration. However, Saitoh et al., pointed out that one dialysis treatment is not sufficient to remove all gadolinium. In a study by Perez-Rodrigue et al., seven patients underwent dialysis within 24 h of contrast medium exposure and continued to develop NSF. Some authors suggest that it might be acceptable to give some additional dialysis sessions to patients already undergoing renal replacement therapy. It would, at least, limit the potential Gd3+ toxicities. Metabolic acidosis, ongoing inflammatory process, treatment with erythropoietin and high serum concentrations of calcium and phosphorus have been reported as factors contributing to the development of NSF. In the Grobner et al. study, all patients affected by NSF had metabolic acidosis. Their mean pH was 7.29 ± 0.04 (mean actual bicarbonate value 19.5 ± 1.7 mmol/L), while the mean pH of healthy individuals was 7.39 ± 0.01 (mean actual bicarbonate value: 22.95 ± 0.58 mmol/L). Marckmann et al., did not confirm this hypothesis. In their clinical–control study, no significant difference in serum bicarbonate concentration between patients with NSF and the control group was found. However, the researchers pointed out the difference in treatment with erythropoietin. Ultimately, the hypothesis that NSF may be induced by analogs of erythropoietin was rejected because three of their subjects have never been treated with such drugs. However, there was a tendency to use higher doses of erythropoietin in people with NSF than in the control group. Higher doses of erythropoietin were used in people with a severe course of NSF. Of note, a series of cases described by Othersen et al., did not support this hypothesis—two patients received a small dose of erythropoietin, and two did not take it while exposed to gadolinium. The researchers suggest that in the case of erythropoietin treatment, the relationship with NSF is unlikely to be causative. In a study by Marckmann et al., it was noted that all NSF cases had significantly higher concentrations of phosphate and ionized calcium in serum during exposure to contrast media. This confirms the chemical theory that higher levels of ionized calcium and phosphates lead to a process of transmetallation and a greater risk of Gd3+ ion retention outside the contrast agent complex. This leads to the retention of Gd3+ ion, which is toxic to the body, and its penetration through membranes to other cells. A significant relationship between NSF and infection was confirmed by Golding et al. Precisely 6.7% of NSF cases were with an infection. It has been estimated that infection in patients with renal failure increases the risk of NSF 25-fold.

• #45 Nephrogenic Systemic Fibrosis as a Complication after Gadolinium-Containing Contrast Agents: A Rapid Review

  https://www.mdpi.com/1660-4601/18/6/3000

  Nephrogenic systemic fibrosis (NFS) is a generalized disorder occurring in people with kidney failure. This new disease entity can lead to significant disability or even death. Gadolinium-associated systemic fibrosis is related to exposure to contrast agents used for magnetic resonance imaging. The first to hypothesize that gadolinium-based contrast agents are involved in the pathogenesis of NSF was Grobner. The most commonly used magnetic contrast agents for magnetic resonance imaging (MRI) are gadolinium chelates. Their excretion from the body takes place through the kidneys. The prolonged exposure time results in the dissociation of ions from the paramagnetic particles and their accumulation as deposits in the lymph nodes, bones, brain and liver. In addition, the presence of Gd3+ causes the activation of dendritic cells. These cells, producing transforming growth factor beta 1, initiate fibrosis and mobilize other dendritic cells. This may lead to an intensification of the fibrosis process. Another mechanism that may initiate fibrosis is related to the phagocytosis of Gd3+ by macrophages. By releasing proinflammatory cytokines, these cells attract circulating fibrocytes, which then transform in the dermis into fibroblasts and initiate fibrosis. An additional causative factor, especially in patients with renal failure, may be the transmetalation process. This process releases gadolinium by replacing Gd3+ in chelate molecules with systemic cations such as iron, zinc and copper. The process of the release of free Gd3+ ions varies depending on the structure of the compound, which is part of the contrast agents. There are two structural forms of chelates: linear and cyclic. A higher probability of the release of Gd3+ ions from chelate compounds is with linear contrast media, as opposed to cyclic chelate compounds, in which gadolinium is trapped inside. Since 2006, data have been collected on the basis of studies that confirm the relationship between NSF occurrence after exposure to contrast mediums containing gadodiamide and gadopentetate dimeglumine. Most of the described cases were exposed to linear gadolinium chelates during magnetic resonance imaging. These were gadodiamide (Omniscan) and gadopentetate dimeglumine (Magnevist). The authors of five studies have pointed out other variables that occurred in patients with NSF, which may also be a factor increasing the development of the disease. In one study, all patients who developed NSF had metabolic acidosis, while healthy patients showed normal pH values. Others noted elevated inflammatory values during contrast administration in patients who developed NSF. Marckmann et al., suggest that the risk of NSF increases during therapy with higher doses of erythropoietin and higher serum concentrations of calcium and phosphorus in patients at the time of exposure to contrast agents. The hypothesis that gadolinium contrast agents are related to the development of NSF was put forward for the first time by Grobner et al., in 2006. The common feature of all patients with NSF is renal failure. Many authors emphasized that the highest risk of NSF exists in patients with a GFR < 15 mL/min/1.73 m² (i.e., chronic kidney disease at stage 5). In patients with kidney failure, the period of the elimination of the contrast medium from the body can be extended up to over 30 h. The role of dialysis in preventing NSF is unclear. Currently, it is assumed that the risk of developing NSF may decrease when patients undergo immediate dialysis (<24 h) after contrast medium administration. However, Saitoh et al., pointed out that one dialysis treatment is not sufficient to remove all gadolinium. In a study by Perez-Rodrigue et al., seven patients underwent dialysis within 24 h of contrast medium exposure and continued to develop NSF. Some authors suggest that it might be acceptable to give some additional dialysis sessions to patients already undergoing renal replacement therapy. It would, at least, limit the potential Gd3+ toxicities. Metabolic acidosis, ongoing inflammatory process, treatment with erythropoietin and high serum concentrations of calcium and phosphorus have been reported as factors contributing to the development of NSF. In the Grobner et al. study, all patients affected by NSF had metabolic acidosis. Their mean pH was 7.29 ± 0.04 (mean actual bicarbonate value 19.5 ± 1.7 mmol/L), while the mean pH of healthy individuals was 7.39 ± 0.01 (mean actual bicarbonate value: 22.95 ± 0.58 mmol/L). Marckmann et al., did not confirm this hypothesis. In their clinical–control study, no significant difference in serum bicarbonate concentration between patients with NSF and the control group was found. However, the researchers pointed out the difference in treatment with erythropoietin. Ultimately, the hypothesis that NSF may be induced by analogs of erythropoietin was rejected because three of their subjects have never been treated with such drugs. However, there was a tendency to use higher doses of erythropoietin in people with NSF than in the control group. Higher doses of erythropoietin were used in people with a severe course of NSF. Of note, a series of cases described by Othersen et al., did not support this hypothesis—two patients received a small dose of erythropoietin, and two did not take it while exposed to gadolinium. The researchers suggest that in the case of erythropoietin treatment, the relationship with NSF is unlikely to be causative. In a study by Marckmann et al., it was noted that all NSF cases had significantly higher concentrations of phosphate and ionized calcium in serum during exposure to contrast media. This confirms the chemical theory that higher levels of ionized calcium and phosphates lead to a process of transmetallation and a greater risk of Gd3+ ion retention outside the contrast agent complex. This leads to the retention of Gd3+ ion, which is toxic to the body, and its penetration through membranes to other cells. A significant relationship between NSF and infection was confirmed by Golding et al. Precisely 6.7% of NSF cases were with an infection. It has been estimated that infection in patients with renal failure increases the risk of NSF 25-fold.

• #46 Nephrogenic systemic fibrosis: A frivolous entity

  https://www.wjgnet.com/2220-6124/full/v10/i3/29.htm

  Reduced kidney function results in a substantial increase in its half-life from 1.5 h (normal kidney function) to 5.61 h and 9.18 h at CKD stage 4 and 5, respectively. […] Vascular injury and endothelial dysfunction enhance free Gd invasion into tissues, where Gd is phagocytosed by macrophages to release local profibrotic cytokines and sends signals to attract circulating fibrocytes into the tissues. […] These circulating fibrocytes are cardinal cells that play the interlinking role between Gd deposition and the initiation of fibrosis. […] This hypothesis is held up by the presence of excess Gd in the affected tissues of NSF patients when compared to unaffected tissues.

• #47 SciELO Brazil – Nephrogenic systemic fibrosis: concepts and perspectives Nephrogenic systemic fibrosis: concepts and perspectives

  https://www.scielo.br/j/abd/a/YRrkNwbg8vdYmP5SR85wmcG/?lang=en

  Direct toxic effects are suggested by the presence of Gd deposits in the skin of individuals who develop NSF. […] An increase in serum iron (Fe) concentration can induce in vivo transmetallation of Gd, a phenomenon whereby free Gd is released from the chelate and subsequent binds to endogenous ions. […] Increased expression and activation of transglutaminases in NSF were documented, but with no exact role in the pathogenesis of the disease. […] Procoagulant states, recent surgery (especially vascular), deep vein thrombosis, newly transplanted-kidney failure and sudden-onset kidney disease with significant swelling of the extremities may be associated with NSF. […] The injured vessels allow the dissociated Gd prompt penetration in the interstitial space and tissues. […] The presence of Gd deposits can be seen via spectrometry, but their intensity does not correlate with the extent of clinical involvement.

• #48 Nephrogenic Systemic Fibrosis: Background, Pathophysiology, Etiology

  https://emedicine.medscape.com/article/1097889-overview

  Parsons et al performed immunohistochemical studies using antibodies to transglutaminase-2, factor XIIIa, transglutaminase isopeptide, and the histiocyte marker CD68 on 5 archived skin biopsy specimens of nephrogenic systemic fibrosis. Parsons et al found that dermal fibroblasts and histiocytes of nephrogenic systemic fibrosis expressed transglutaminase-2, CD68, factor XIIIa, and transglutaminase isopeptide. They posited that this represented increased expression, activation, or concomitant activation and expression of transglutaminases in nephrogenic systemic fibrosis. […] The cause of nephrogenic systemic fibrosis is the connexation of renal insufficiency and gadolinium exposure from imaging studies. The exact degree of renal insufficiency that sets up the development of nephrogenic systemic fibrosis is not known. Risk factors include advanced chronic kidney disease (stages 4 and 5) and acute or chronic inflammatory insults. […] Nephrogenic systemic fibrosis is a debilitating and sometimes fatal disease. Characteristics include red or dark patches on the skin; burning, itching, swelling, hardening, and tightening of the skin; yellow spots on the whites of the eyes; joint stiffness with trouble moving or straightening the arms, hands, legs, or feet; pain deep in the hip bones or ribs; and muscle weakness.

• #49 Nephrogenic Systemic Fibrosis – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK567754/

  Activation of dermal fibroblasts is a key component in the pathogenesis of NSF. The dermal fibroblasts synthesize excess glycosaminoglycans, particularly hyaluronan, which is partially responsible for the characteristic skin thickening. Factors contributing to NSF include total gadolinium exposure, hypercalcemia, hyperphosphatemia, high-dose erythropoietin therapy, hepatorenal syndrome, immunosuppression, and vasculopathy. Results from one notable study showed that the risk of NSF was increased by 25 times when infection was present. […] Abnormal calcium and phosphorus metabolism has also been found in patients who develop NSF compared to patients with a similar estimated glomerular filtration rate who did not develop NSF, and calcium and phosphorus deposits have also been found in the gadolinium-containing deposits of NSF. Traumatic calcinosis cutis, osseous metaplasia, calciphylaxis, and metastatic calcification have also been observed in dialysis patients with NSF.

• #50 Nephrogenic systemic fibrosis (NSF) – Questions and Answers ​in MRI

  https://mriquestions.com/what-is-nsf.html

  Nephrogenic systemic fibrosis (NSF) is a rare, progressive, often fatal disease characterized by skin thickening, painful joint contractures, and fibrosis of multiple organs including the lungs, liver, muscles, and heart. Nearly all documented cases have occurred in patients with chronic severe renal insufficiency who have received gadolinium contrast. The association between gadolinium and NSF was first reported by Danish nephrologists in 2006. Between 2006 and 2010 several hundred cases were diagnosed worldwide. […] NSF usually develops clinically within days to months following gadolinium exposure, although rare cases have been reported years later. Nearly all patients have been in various degrees of renal failure and many were on dialysis. Only exceedingly rare cases have been reported in patients with eGFRs 30 mL/min/1.73m. High and/or multiple doses of contrast are frequently reported, as are the use of linear contrast agents (ACR Group I). Other risk factors include liver disease and acidosis.

• #51 What Causes Nephrogenic Systemic Fibrosis? – The Rheumatologist

  https://www.the-rheumatologist.org/article/what-causes-nephrogenic-systemic-fibrosis/?singlepage=1

  Although NSF most notably involves the skin, tissue obtained during surgery and at autopsy has revealed systemic involvement. Examination of striated and cardiac muscles has demonstrated muscle fiber atrophy, perimysial and endomysial fibrosis, calcium deposition, scattered interstitial chronic inflammation, and endomysial deposition of collagen fibrils. In the lungs, mild interstitial fibrosis, thickening of the adventitia of small- and medium-size arterioles, and fibrosis of the pleura and diaphragm have been observed. Cardiac involvement also occurs, with fibrosis of the pericardium, great vessels, left ventricle, and interventricular septum. Fibrotic changes of the genitourinary tract and of the dura mater also have been observed. […] The strong association between NSF and prior exposure to gadolinium-containing contrast agents suggests that this condition might be prevented by not exposing patients with chronic kidney disease to gadolinium. Future studies should be directed toward understanding the molecular mechanism by which fibrosis occurs following gadolinium exposure in patients with underlying chronic kidney disease and targeting that mechanism with specific therapies that will prevent development of and reverse fibrosis.

• #52

  https://www.slideshare.net/slideshow/nsf/96272

  Nephrogenic systemic fibrosis is a rare fibrosing disorder seen exclusively in patients with severe renal failure. It is associated with exposure to gadolinium-based contrast agents used for MRI. While the exact pathogenesis is unclear, gadolinium deposition in tissues is thought to play a key role. […] Pathogenesis Not well understood Contributors to exaggerated tissue fibrosis Activation of TGF-beta-1 pathway Increase in circulating fibrocytes. […] Nephrogenic systemic fibrosis (NSF) is a severe skin condition seen in patients with kidney failure exposed to gadolinium-based contrast agents. […] Nephrogenic Systemic Fibrosis Etiology Nephrogenic Systemic Fibrosis Gadolinium Non tissue specific Non ionic Hyperosmolal (650mosmol/kg) Contrast used for MR studies Excreted exclusively by the kidneys.

• #53

  https://www.slideshare.net/slideshow/nsf/96272

  Pathology Deep biopsy needed (extends to subcutaneous tissue) Subtle proliferation of dermal fibrocytes Marked thickening of dermis a/w histiocytes and satellite factor XIIIa+ dermal dendritic cells Thick collagen bundles with surrounding clefts (prominent findings) Variable increase in dermal mucin and elastic fibers on special stains. […] The dermis demonstrates haphazardly arranged collagen bundles and a strikingly increased number of spindled and plump fibroblast-like cells. […] Pathogenesis Not well understood Contributors to exaggerated tissue fibrosis Activation of TGF-beta-1 pathway Increase in circulating fibrocytes.

• #54

  https://www.slideshare.net/slideshow/nsf/96272

  Pathology Deep biopsy needed (extends to subcutaneous tissue) Subtle proliferation of dermal fibrocytes Marked thickening of dermis a/w histiocytes and satellite factor XIIIa+ dermal dendritic cells Thick collagen bundles with surrounding clefts (prominent findings) Variable increase in dermal mucin and elastic fibers on special stains. […] The dermis demonstrates haphazardly arranged collagen bundles and a strikingly increased number of spindled and plump fibroblast-like cells. […] Pathogenesis Not well understood Contributors to exaggerated tissue fibrosis Activation of TGF-beta-1 pathway Increase in circulating fibrocytes.

• #55 What Causes Nephrogenic Systemic Fibrosis? – The Rheumatologist

  https://www.the-rheumatologist.org/article/what-causes-nephrogenic-systemic-fibrosis/?singlepage=1

  Although NSF most notably involves the skin, tissue obtained during surgery and at autopsy has revealed systemic involvement. Examination of striated and cardiac muscles has demonstrated muscle fiber atrophy, perimysial and endomysial fibrosis, calcium deposition, scattered interstitial chronic inflammation, and endomysial deposition of collagen fibrils. In the lungs, mild interstitial fibrosis, thickening of the adventitia of small- and medium-size arterioles, and fibrosis of the pleura and diaphragm have been observed. Cardiac involvement also occurs, with fibrosis of the pericardium, great vessels, left ventricle, and interventricular septum. Fibrotic changes of the genitourinary tract and of the dura mater also have been observed. […] The strong association between NSF and prior exposure to gadolinium-containing contrast agents suggests that this condition might be prevented by not exposing patients with chronic kidney disease to gadolinium. Future studies should be directed toward understanding the molecular mechanism by which fibrosis occurs following gadolinium exposure in patients with underlying chronic kidney disease and targeting that mechanism with specific therapies that will prevent development of and reverse fibrosis.

• #56 SciELO Brazil – Nephrogenic systemic fibrosis: concepts and perspectives Nephrogenic systemic fibrosis: concepts and perspectives

  https://www.scielo.br/j/abd/a/YRrkNwbg8vdYmP5SR85wmcG/?lang=en

  Direct toxic effects are suggested by the presence of Gd deposits in the skin of individuals who develop NSF. […] An increase in serum iron (Fe) concentration can induce in vivo transmetallation of Gd, a phenomenon whereby free Gd is released from the chelate and subsequent binds to endogenous ions. […] Increased expression and activation of transglutaminases in NSF were documented, but with no exact role in the pathogenesis of the disease. […] Procoagulant states, recent surgery (especially vascular), deep vein thrombosis, newly transplanted-kidney failure and sudden-onset kidney disease with significant swelling of the extremities may be associated with NSF. […] The injured vessels allow the dissociated Gd prompt penetration in the interstitial space and tissues. […] The presence of Gd deposits can be seen via spectrometry, but their intensity does not correlate with the extent of clinical involvement.

• #57 Nephrogenic Systemic Fibrosis, Moh’d sharshir | PPT

  https://www.slideshare.net/slideshow/nephrogenic-systemic-fibrosis/101723380

  The pathogenesis of NSF is not fully understood. The resemblance of NSF to a tissue injury reaction and the presence of myofibroblasts in the tissue specimens suggest that fibrogenic cytokines may be important, possibly resulting in a cascade of events similar to wound healing. Two proposed contributors to the exaggerated tissue fibrosis are: 1. Activation of the transforming growth factor (TGF)-beta-1 pathway. 2. An increase in circulating fibrocytes. […] Skin disease in NSF typically presents as symmetrical, bilateral, fibrotic, indurated papules, plaques, or subcutaneous nodules that may or may not be erythematous. […] The major preventive measure for NSF that can be currently recommended to patients with advanced kidney failure is the avoidance of gadolinium. […] There is no proven medical therapy for NSF other than recovery of renal function. […] Several treatments and combinations of treatments have been evaluated, but none have shown consistent benefit.

• #58 Nephrogenic systemic fibrosis (NSF) – implications for radiology

  https://inis.iaea.org/records/k9bkv-gt196

  Nephrogenic systemic fibrosis (NSF) is a systemic disease with a 5% mortality which was first described in 1997 and which only occurs in patients with severely impaired renal function (GFR 30 ml/min per 1.73 m2) and for which an association with previous administration of several Gd-chelates has been observed. […] Even though the pathogenesis is not completely understood at this time, the European Pharmacovigilance Working Party has decided that gadodiamide and gadopentetate dimeglumine must not be used in high-risk patients. […] Wenngleich der genaue Pathomechanismus der NSF-Entstehung bisher noch nicht bekannt ist, hat die europaeische Pharmakovigilanz-Arbeitsgruppe dennoch entschieden, dass Gadodiamid und Gadopentetat-Dimeglumine bei bestimmten Risikopatienten nicht mehr eingesetzt werden duerfen.

• #59 Nephrogenic systemic fibrosis (NSF) and gadolinium-based contrast media | Ngoya | South African Journal of Radiology

  https://sajr.org.za/index.php/sajr/article/view/277/354

  More than 300 cases of NSF in patients with severe chronic renal insufficiency, acute renal failure or in those undergoing dialysis have been reported in peer-reviewed literature, with an overwhelming majority occurring within weeks to months after injection of a GBCA. […] Because there is no consistently effective treatment for NSF, prevention is important. […] The most up-to-date assessment and guidelines were reported by Thomsen et al. in 2012. […] Based on the evidence presented in this review, the ESUR CMSCs new guidelines are summarised below, with their strength of evidence and recommendation ratings. […] If two different Gd-CMs have been injected, it is impossible to determine with certainty which agent triggered the development of NSF, and the situation is described as confounded.

• #60 Nephrogenic systemic fibrosis – Symptoms and causes – Mayo Clinic

  https://www.mayoclinic.org/diseases-conditions/nephrogenic-systemic-fibrosis/symptoms-causes/syc-20352299

  Nephrogenic systemic fibrosis is a rare disease that occurs mainly in people with advanced kidney failure with or without dialysis. […] For some people with advanced kidney disease, being exposed to older gadolinium-based contrast agents (group 1) during magnetic resonance imaging (MRI) and other imaging studies has been identified as a trigger for development of this disease. […] The exact cause of nephrogenic systemic fibrosis isn’t fully understood. Fibrous connective tissue forms in the skin and connective tissues, resulting in scarring of tissue throughout the body, most commonly the skin and subcutaneous tissues. […] Exposure to older gadolinium-based contrast agents (group 1) during magnetic resonance imaging (MRI) has been identified as a trigger for development of this disease in people with kidney disease. This increased risk is thought to be related to the kidneys’ reduced ability to remove the contrast agent from the bloodstream. […] Avoidance of older gadolinium-based contrast agents (group 1) is key to preventing nephrogenic systemic fibrosis, as newer gadolinium-based contrast agents (group 2) are safer and are not associated with increased risk.

• #61 Nephrogenic systemic fibrosis: pathogenesis, diagnosis, and therapy – PubMed

  https://pubmed.ncbi.nlm.nih.gov/19406336/

  Nephrogenic systemic fibrosis (NSF) is a newly recognized disorder occurring exclusively in patients with renal failure. Exposure to gadolinium-based magnetic resonance (MR) contrast media has been associated with subsequent development of NSF. Nephrogenic systemic fibrosis is characterized by skin induration preferentially affecting the extremities. […] The main therapeutic goal is restoration of renal function. To reduce the risk of NSF, renal function must be determined before exposure to gadolinium-containing MR contrast agents. Gadolinium-based MR contrast media should be avoided in the presence of advanced renal failure with estimated glomerular filtration rate below 30 ml/min/1.73 m2, unless the diagnostic information is essential and not available with noncontrast magnetic resonance imaging techniques. […] In addition, a sufficient period of time for elimination of the contrast agent from the body should be allowed before readministration of the contrast agent.

• #62 Nephrogenic Systemic Fibrosis as a Complication after Gadolinium-Containing Contrast Agents: A Rapid Review

  https://www.mdpi.com/1660-4601/18/6/3000

  Nephrogenic systemic fibrosis (NFS) is a generalized disorder occurring in people with kidney failure. This new disease entity can lead to significant disability or even death. Gadolinium-associated systemic fibrosis is related to exposure to contrast agents used for magnetic resonance imaging. The first to hypothesize that gadolinium-based contrast agents are involved in the pathogenesis of NSF was Grobner. The most commonly used magnetic contrast agents for magnetic resonance imaging (MRI) are gadolinium chelates. Their excretion from the body takes place through the kidneys. The prolonged exposure time results in the dissociation of ions from the paramagnetic particles and their accumulation as deposits in the lymph nodes, bones, brain and liver. In addition, the presence of Gd3+ causes the activation of dendritic cells. These cells, producing transforming growth factor beta 1, initiate fibrosis and mobilize other dendritic cells. This may lead to an intensification of the fibrosis process. Another mechanism that may initiate fibrosis is related to the phagocytosis of Gd3+ by macrophages. By releasing proinflammatory cytokines, these cells attract circulating fibrocytes, which then transform in the dermis into fibroblasts and initiate fibrosis. An additional causative factor, especially in patients with renal failure, may be the transmetalation process. This process releases gadolinium by replacing Gd3+ in chelate molecules with systemic cations such as iron, zinc and copper. The process of the release of free Gd3+ ions varies depending on the structure of the compound, which is part of the contrast agents. There are two structural forms of chelates: linear and cyclic. A higher probability of the release of Gd3+ ions from chelate compounds is with linear contrast media, as opposed to cyclic chelate compounds, in which gadolinium is trapped inside. Since 2006, data have been collected on the basis of studies that confirm the relationship between NSF occurrence after exposure to contrast mediums containing gadodiamide and gadopentetate dimeglumine. Most of the described cases were exposed to linear gadolinium chelates during magnetic resonance imaging. These were gadodiamide (Omniscan) and gadopentetate dimeglumine (Magnevist). The authors of five studies have pointed out other variables that occurred in patients with NSF, which may also be a factor increasing the development of the disease. In one study, all patients who developed NSF had metabolic acidosis, while healthy patients showed normal pH values. Others noted elevated inflammatory values during contrast administration in patients who developed NSF. Marckmann et al., suggest that the risk of NSF increases during therapy with higher doses of erythropoietin and higher serum concentrations of calcium and phosphorus in patients at the time of exposure to contrast agents. The hypothesis that gadolinium contrast agents are related to the development of NSF was put forward for the first time by Grobner et al., in 2006. The common feature of all patients with NSF is renal failure. Many authors emphasized that the highest risk of NSF exists in patients with a GFR < 15 mL/min/1.73 m² (i.e., chronic kidney disease at stage 5). In patients with kidney failure, the period of the elimination of the contrast medium from the body can be extended up to over 30 h. The role of dialysis in preventing NSF is unclear. Currently, it is assumed that the risk of developing NSF may decrease when patients undergo immediate dialysis (<24 h) after contrast medium administration. However, Saitoh et al., pointed out that one dialysis treatment is not sufficient to remove all gadolinium. In a study by Perez-Rodrigue et al., seven patients underwent dialysis within 24 h of contrast medium exposure and continued to develop NSF. Some authors suggest that it might be acceptable to give some additional dialysis sessions to patients already undergoing renal replacement therapy. It would, at least, limit the potential Gd3+ toxicities. Metabolic acidosis, ongoing inflammatory process, treatment with erythropoietin and high serum concentrations of calcium and phosphorus have been reported as factors contributing to the development of NSF. In the Grobner et al. study, all patients affected by NSF had metabolic acidosis. Their mean pH was 7.29 ± 0.04 (mean actual bicarbonate value 19.5 ± 1.7 mmol/L), while the mean pH of healthy individuals was 7.39 ± 0.01 (mean actual bicarbonate value: 22.95 ± 0.58 mmol/L). Marckmann et al., did not confirm this hypothesis. In their clinical–control study, no significant difference in serum bicarbonate concentration between patients with NSF and the control group was found. However, the researchers pointed out the difference in treatment with erythropoietin. Ultimately, the hypothesis that NSF may be induced by analogs of erythropoietin was rejected because three of their subjects have never been treated with such drugs. However, there was a tendency to use higher doses of erythropoietin in people with NSF than in the control group. Higher doses of erythropoietin were used in people with a severe course of NSF. Of note, a series of cases described by Othersen et al., did not support this hypothesis—two patients received a small dose of erythropoietin, and two did not take it while exposed to gadolinium. The researchers suggest that in the case of erythropoietin treatment, the relationship with NSF is unlikely to be causative. In a study by Marckmann et al., it was noted that all NSF cases had significantly higher concentrations of phosphate and ionized calcium in serum during exposure to contrast media. This confirms the chemical theory that higher levels of ionized calcium and phosphates lead to a process of transmetallation and a greater risk of Gd3+ ion retention outside the contrast agent complex. This leads to the retention of Gd3+ ion, which is toxic to the body, and its penetration through membranes to other cells. A significant relationship between NSF and infection was confirmed by Golding et al. Precisely 6.7% of NSF cases were with an infection. It has been estimated that infection in patients with renal failure increases the risk of NSF 25-fold.

• #63 Nephrogenic Systemic Fibrosis in Patients with Chronic Kidney Disease after the Use of Gadolinium-Based Contrast Agents: A Review for the Cardiovascular Imager

  https://www.mdpi.com/2075-4418/12/8/1816

  Gadolinium-enhanced cardiac magnetic resonance has revolutionized cardiac imaging in the last two decades and has emerged as an essential and powerful tool for the characterization and treatment guidance of a wide range of cardiovascular diseases. However, due to the high prevalence of chronic renal dysfunction in patients with cardiovascular conditions, the risk of nephrogenic systemic fibrosis (NSF) after gadolinium exposure has been a permanent concern. […] The pathophysiology and molecular mechanism of NSF are still a matter of debate. It is believed that the intravenous administration of some GBCAs causes a limited chelate instability that plays an essential role in the release of free Gd. […] After de-chelation (by transmetalation), free Gd binds with endogenous anions, creating an insoluble precipitate that penetrates the interstitial tissue of the lung, esophagus, liver, and kidneys. In vitro studies have shown that Gd-anion complexes are highly immunogenic, binding to toll-like receptors (TLRs) on professional antigen-presenting cells (such as macrophages and dendritic cells) and leading to the release of pro-inflammatory and pro-fibrotic cytokines.

• #64 Nephrogenic systemic fibrosis (NSF) – Questions and Answers ​in MRI

  https://mriquestions.com/what-is-nsf.html

  The strong association with renal insufficiency most likely relates to the prolonged biological half-life due to prolonged excretion of gadolinium. However, other factors have been imputed, including metabolic acidosis; elevated iron and phosphate levels; erythropoietin therapy; vasculopathy; and infectious/inflammatory mediators. […] The pathogenesis of NSF is believed to begin with the displacement of the Gd ion from its chelate by another metallic cation (Fe+3, Zn+2, or Ca+2) through a so-called transmetalation reaction: (Metal ion) + Gd-Chelate Metal-Chelate + Gd+3. The free Gd ion is then deposited in the skin and other soft tissues. There it is engulfed by CD163+ iron-recycling and other macrophages creating an inflammatory response and cytokine release. Circulating fibrocytes (immunologically unique CD-34 positive cells derived from bone marrow) deposit in tissue, transforming into spindle cells that proliferate and become the hallmark of the disease. Following recognition of this disorder and its association with gadolinium in patients with renal insufficiency, the worldwide radiology community responded immediately to put an end to this iatrogenic disease. Today, NSF has been nearly completely eliminated due to these measures. In more recent times, however, gadolinium-induced plaques have been reported in the extremities not meeting the full criteria for NSF. The story of NSF is sad one that we radiologists created. It should serve as a lesson that even drugs which appear to be extraordinarily safe may not be infinitely safe for all patients. Sometimes adverse effects may be subtle, disguised, or appear at long time intervals following administration. NSF is thus a call and reminder to be forever vigilant.

• #65 Nephrogenic Systemic Fibrosis After Gadolinium-Contrast MRIlogo-32logo-40logo-60NEJM Journal WatchnejmJW_1L_RGB-b

  https://www.jwatch.org/na51867/2020/06/30/nephrogenic-systemic-fibrosis-after-gadolinium-contrast

  Nephrogenic systemic fibrosis (NSF) — a severe and often fatal condition caused by collagen deposition in soft tissues and organs — occurs (rarely) in patients after receiving gadolinium-based contrast agents (GBCAs) for magnetic resonance imaging. […] Newer gadolinium agents might pose less risk than older ones. […] However, interpreting the latter finding is problematic, because three of those four NSF patients had previous GBCA exposure outside the study setting. […] Unfortunately, the number of patients with renal disease who were evaluated after use of newer gadolinium agents was relatively low and likely insufficient to allow definitive assessment of their risk. […] Although some authorities suggest that NSF cases are nonexistent after newer gadolinium agents are used, this comprehensive analysis suggests that cases might occur occasionally. Prudent use of gadolinium among patients with severely limited renal function is advisable.

• #66 What Causes Nephrogenic Systemic Fibrosis? – Page 5 of 6 – The Rheumatologist

  https://www.the-rheumatologist.org/article/what-causes-nephrogenic-systemic-fibrosis/5/

  Other institutions, such as mine, have adopted similar policies for all gadolinium-containing contrast agents. […] Future studies should be directed toward understanding the molecular mechanism by which fibrosis occurs following gadolinium exposure in patients with underlying chronic kidney disease and targeting that mechanism with specific therapies that will prevent development of and reverse fibrosis. […] Toll-like receptors appear to play an important role in the pathogenesis of fibrotic disorders including nephrogenic systemic fibrosis and systemic sclerosis.

• #67 What Causes Nephrogenic Systemic Fibrosis? – The Rheumatologist

  https://www.the-rheumatologist.org/article/what-causes-nephrogenic-systemic-fibrosis/?singlepage=1

  Although NSF most notably involves the skin, tissue obtained during surgery and at autopsy has revealed systemic involvement. Examination of striated and cardiac muscles has demonstrated muscle fiber atrophy, perimysial and endomysial fibrosis, calcium deposition, scattered interstitial chronic inflammation, and endomysial deposition of collagen fibrils. In the lungs, mild interstitial fibrosis, thickening of the adventitia of small- and medium-size arterioles, and fibrosis of the pleura and diaphragm have been observed. Cardiac involvement also occurs, with fibrosis of the pericardium, great vessels, left ventricle, and interventricular septum. Fibrotic changes of the genitourinary tract and of the dura mater also have been observed. […] The strong association between NSF and prior exposure to gadolinium-containing contrast agents suggests that this condition might be prevented by not exposing patients with chronic kidney disease to gadolinium. Future studies should be directed toward understanding the molecular mechanism by which fibrosis occurs following gadolinium exposure in patients with underlying chronic kidney disease and targeting that mechanism with specific therapies that will prevent development of and reverse fibrosis.

• #68 Nephrogenic systemic fibrosis (NSF) – Questions and Answers ​in MRI

  https://mriquestions.com/what-is-nsf.html

  The strong association with renal insufficiency most likely relates to the prolonged biological half-life due to prolonged excretion of gadolinium. However, other factors have been imputed, including metabolic acidosis; elevated iron and phosphate levels; erythropoietin therapy; vasculopathy; and infectious/inflammatory mediators. […] The pathogenesis of NSF is believed to begin with the displacement of the Gd ion from its chelate by another metallic cation (Fe+3, Zn+2, or Ca+2) through a so-called transmetalation reaction: (Metal ion) + Gd-Chelate Metal-Chelate + Gd+3. The free Gd ion is then deposited in the skin and other soft tissues. There it is engulfed by CD163+ iron-recycling and other macrophages creating an inflammatory response and cytokine release. Circulating fibrocytes (immunologically unique CD-34 positive cells derived from bone marrow) deposit in tissue, transforming into spindle cells that proliferate and become the hallmark of the disease. Following recognition of this disorder and its association with gadolinium in patients with renal insufficiency, the worldwide radiology community responded immediately to put an end to this iatrogenic disease. Today, NSF has been nearly completely eliminated due to these measures. In more recent times, however, gadolinium-induced plaques have been reported in the extremities not meeting the full criteria for NSF. The story of NSF is sad one that we radiologists created. It should serve as a lesson that even drugs which appear to be extraordinarily safe may not be infinitely safe for all patients. Sometimes adverse effects may be subtle, disguised, or appear at long time intervals following administration. NSF is thus a call and reminder to be forever vigilant.

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