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the term scr was coined in a study of serial protocol biopsies in 1995 when immunosuppressive treatment consisted of cyclosporine , azathioprine , and prednisone . in this pioneering study ,
the prevalence of scr at different time points during the first year was over 50% .
accordingly , different studies evaluated whether scr was associated with outcome . in serial protocol biopsy studies , the presence of scr in a first biopsy was associated with progression of if / ta , impairment of glomerular adaptation , and progression of glomerulosclerosis in the second one , suggesting that early inflammation favors progression of chronic lesions . during the 90s ,
an association between the presence of if / ta and graft survival was consistently described in protocol biopsy studies .
similarly , in 2005 , an association between scr in 2-week protocol biopsies and graft survival was also documented .
more recently , it has been further described that the association of inflammation and if / ta in protocol biopsies implies a poorer outcome than if / ta or scr alone .
altogether , these observations suggest an association between scr and poor graft outcome , and raise the question whether treatment of scr may improve outcome .
the potential benefit of scr treatment was explored in a randomized trial in patients receiving cyclosporine , azathioprine , and prednisone . in the study group
, patients were biopsied at 1 , 2 , and 3 months and treated with steroid boluses , whereas the control group was not biopsied and accordingly not treated . if / ta at 6 months and serum creatinine at 2 years were lower in the treatment group , suggesting that treatment of scr may improve graft outcome .
however , introduction of tacrolimus and mycophenolate reduced the prevalence of scr to 10% , showing that scr can be prevented with more efficient immunosuppression . in a study of serial protocol biopsies
, it was observed that reduction of scr with tacrolimus and mycophenolate was also associated with a lower prevalence of if / ta at 1 year , in comparison with cyclosporine - based regimens .
moreover , in a randomized study comparing a calcineurin - based regimen , either associated with mycophenolate mofetil or associated with sirolimus , the sirolimus groups displayed a lower prevalence of acute rejection and scr during the first year and a lower prevalence of if / ta at 5 years .
altogether , these data suggest that scr prevention with more efficient immunosuppression may improve graft outcome .
the close association between immunosuppressive treatment and prevalence of scr has favored the assumption that it represents , at the histological level , the balance between alloimmune response and efficiency of immunosuppressive treatment . from the epidemiological point of view
, it has been described that the degree of sensitization and clinical episodes of acute rejection preceding the protocol biopsy constitute a risk factor for scr , further reinforcing the notion that scr represents the intensity of the immune response .
however , non - immune factors are also associated with scr , such as donor age .
kidneys from older donors are more susceptible to insult and have reduced capacity for tissue regeneration .
thus , it is tempting to speculate that scr may not only reflect alloimmune response but also may reflect the inflammatory response associated with tissue injury and repair .
innate immunity constitutes the first line of defense against infection and has a major role in tissue repair .
few highly conserved structures on microorganisms , that is , pathogen - associated molecular patterns , are recognized by pattern recognition receptors that are expressed on effector cells of the innate immune system , such as macrophages , dendritic cells , or b cells .
this pattern recognition receptors can be divided into three types : endocytic , signaling , and secreted .
probably , the best - known secreted pattern recognition receptors molecule is mannose - binding lectin ( mbl ) that activates complement by the lectin pathway and favors inflammation and phagocytosis at the site of infection .
cellular necrosis or apoptosis that follows tissue injury is characterized by the secretion of danger signals known as alarmins , which are sensed by the innate immune system .
recognition of alarmins triggers inflammation and favors phagocytosis of necrotic and apoptotic cells . once necrotic and apoptotic cells have been cleared , inflammation fades and tissue regeneration leads to injury healing . as the response to infection and tissue damage is similar , pathogen - associated molecular patterns and alarmins are also termed as danger - associated molecular patterns .
alterations of the innate immune response are associated with inefficient tissue healing , chronic inflammation , and autoimmune disease due to exposure of intracellular antigens and inefficient necrotic and apoptotic cell phagocytosis .
different polymorphisms of the mbl gene have been described and all of them are associated with decreased mbl levels and impaired mbl function .
whereas low serum mbl levels are associated with an increased prevalence of infection , autoimmunity , diabetes , and cardiovascular disease , high serum mbl levels are associated with a poorer outcome of certain autoimmune diseases .
an example is that low serum mbl level is associated with higher risk for diabetes , whereas in patients with diabetes , high serum mbl level is associated with more severe renal damage .
furthermore , in acute tissue injury after renal ischemia reperfusion injury , high serum mbl level is associated with more severe functional deterioration .
in renal transplantation , an association between mbl polymorphisms or low serum mbl levels and increased susceptibility to cytomegalovirus , bacterial , or fungal infections has been reported in some , but not in all , studies . despite the higher incidence of infection in low serum mbl patients , no association between mbl levels and mortality has been described . on the contrary ,
an association between high mbl serum levels and decreased death - censored renal allograft survival has been observed .
the incidence of acute rejection was not associated with serum mbl levels , but acute rejection was more often the cause for graft failure in patients with high serum mbl levels , suggesting that high mbl levels may be associated with severe forms of acute rejection .
in contrast , in heart transplantation , low mbl levels were associated with an increased prevalence of acute rejection and transplant - associated coronary artery disease . taking all these data together
a difference between kidney and heart transplants is that protocol biopsies are usually used to monitor heart histology and , only in few centers , to monitor renal allografts .
furthermore , transplant vasculopathy is actively monitored in the heart by means of coronariography or intravascular ultrasounds . until now
, no studies have analyzed the association between histological damage in protocol renal allograft biopsies and serum mbl levels . in a recent study , we measured serum mbl levels after transplantation in a cohort of consecutive renal transplants and classified mbl as low or high according to tertile distribution .
the first tertile was considered as the low mbl group and the two higher tertiles were considered as the high mbl group . despite the fact that donor and recipient characteristics were similar between groups , and that the prevalence of delayed graft function or acute rejection was not different between groups , we observed that patients with low mbl levels displayed more severe low - grade inflammation before transplantation as measured by serum levels of soluble tumor necrosis factor receptor 2 , suffered a higher incidence of bacterial or fungal infections , and showed an increased prevalence of new - onset diabetes after transplantation . in the above - mentioned study ,
< 200  mol / l and without significant proteinuria ( < 1  g / day ) after obtaining informed consent .
histological examination of these biopsies according to the banff criteria led to the diagnosis of scr in 7 of 18 ( 38.9% ) low mbl patients and in 3 of 42 ( 7.1% ) high mbl patients ( p=0.0054 ) .
induction and maintenance immunosuppression was not different in patients with low and high mbl levels ( table 1 ) .
this observation suggests that innate immune alterations such as mbl deficiency may contribute to the degree of inflammation of the renal allograft ( figure 1 ) .
thus , it is tempting to speculate that patients with low mbl levels may have an impaired capacity for tissue repair leading to more severe and prolonged inflammation .
innate immune alterations modulate different comorbidities in renal transplant patients and may influence graft outcome . despite this association ,
mechanisms linking innate immunity and graft damage have not been clearly elucidated . in one hand , it has been suggested that patients with high mbl levels may suffer from more severe episodes of rejection , whereas in other studies low mbl levels have been associated with a higher prevalence of subclinical or clinical rejection .
surveillance biopsies have contributed to the understanding of the natural history of renal allograft lesions . 
 subclinical rejection , defined as the presence of histological lesions , indistinguishable from acute rejection in stable grafts , is associated with progression of interstitial fibrosis and tubular atrophy . 
 the prevalence of subclinical rejection has decreased as more powerful immunosuppressive treatments have been introduced , suggesting that subclinical rejection represents the degree of control of the alloimmune response . however , non - immune factors such as donor age are also associated with the prevalence of subclinical rejection , suggesting that kidneys from older donors are more susceptible to insult and have a reduced capacity for tissue regeneration . 
 innate immunity has a crucial role in the modulation of the inflammatory response during infection and tissue damage . 
 mannose - binding lectin ( mbl ) is an innate immune protein , the polymorphisms of which are associated with infection , low - grade inflammation , diabetes , and cardiovascular disease . however , the relationship between mbl and disease is complex . 
 for example , low mbl level is associated with higher risk for diabetes , whereas in patients with diabetes , high mbl level is associated with more severe renal damage . in renal transplant patients , 
 low mbl levels are associated with an increased prevalence of infection and diabetes , whereas high mbl levels are associated with shortened graft survival . 
 although mbl is not clearly associated with prevalence of acute rejection , surveillance biopsy studies have shown that low mbl levels are associated with subclinical rejection in kidney and the heart , suggesting that mbl modulates the injury  repair process of the allograft .