Inflammation-associated graft loss in renal transplant recipients

Dahle, Dag Olav; Mjøen, Geir; Öqvist, Björn; Scharnagl, Hubert; Weihrauch, Gisela; Grammer, Tanja B.; März, Winfried; Abedini, Sadollah; Norby, Gudrun E.; Holme, Ingar; Fellström, Bengt; Jardine, Alan G.; Holdaas, Hallvard

doi:10.1093/ndt/gfr163

Cited by 52 publications

(38 citation statements)

References 41 publications

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“…This link between CMV, inflammation (discussed earlier) cytotoxic CD4 + CD28 null cell expansion, endothelial injury, and allograft dysfunction may contribute to explaining the well-recognized but incompletely understood association between inflammation and graft outcome (30,31) and may even go toward explaining the "transplant paradox" by which improvements in acute rejection rates have not been mirrored by long-term improvement in graft survival (32).…”

Section: Increased Cd4mentioning

confidence: 97%

Cytomegalovirus-Associated CD4+CD28null Cells in NKG2D-Dependent Glomerular Endothelial Injury and Kidney Allograft Dysfunction

Shabir

Smith

Kaul

et al. 2016

American Journal of Transplantation

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Emerging data suggest that expansion of a circulating population of atypical, cytotoxic CD4 + T cells lacking costimulatory CD28 (CD4 + CD28 null cells) is associated with latent cytomegalovirus (CMV) infection. The purpose of the current study was to increase the understanding of the relevance of these cells in 100 unselected kidney transplant recipients followed prospectively for a median of 54 months. Multicolor flow cytometry of peripheral blood mononuclear cells before transplantation and serially posttransplantation was undertaken. CD4 + CD28 null cells were found predominantly in CMV-seropositive patients and expanded in the posttransplantation period. These cells were predominantly effector-memory phenotype and expressed markers of endothelial homing (CX3CR1) and cytotoxicity (NKG2D and perforin). Isolated CD4null cells proliferated in response to peripheral blood mononuclear cells previously exposed to CMV-derived (but not HLA-derived) antigens and following such priming incubation with glomerular endothelium resulted in signs of endothelial damage and apoptosis (release of fractalkine and von Willebrand factor; increased caspase 3 expression). This effect was mitigated by NKG2D-blocking antibody. Increased CD4 + CD28null cell frequencies were associated with delayed graft function and lower estimated glomerular filtration rate at end follow-up. This study suggests an important role for this atypical cytotoxic CD4 + CD28 null cell subset in kidney transplantation and points to strategies that may minimize the impact on clinical outcomes.

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Section: Increased Cd4mentioning

confidence: 97%

Cytomegalovirus-Associated CD4+CD28null Cells in NKG2D-Dependent Glomerular Endothelial Injury and Kidney Allograft Dysfunction

Shabir

Smith

Kaul

et al. 2016

American Journal of Transplantation

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“…High-sensitivity C-reactive protein (hsCRP) has been found to be independently associated with major CV events and allcause mortality in RTRs [135,136] , although this is not supported unanimously by all studies [137] . Those with a CRP > 5 have an increased mortality compared to patients below that threshold [138] and there is a Jshaped association between hsCRP and mortality suggesting that RTRs with very low hsCRP may also be at increased risk of death [139] .…”

Section: Inflammationmentioning

confidence: 98%

“…More novel markers such as asymmetric dimethylarginine, which is associated with endothelial dysfunction, are also associated with higher risk of mortality (HR = 2.18) and developing CVD (HR = 2.59) in ESRD [140] . Poorer graft outcomes are predicted by IL-6 [136,141] and elevated symmetric dimethylarginine [142] (HR = 5.51). TroponinT, usually used in the diagnosis of ACS, is a strong independent predictor of allcause mortality in stable RTRs [143] .…”

Section: Inflammationmentioning

confidence: 99%

Cardiovascular risk factors following renal transplant

Neale

Smith

2015

WJT

118

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Kidney transplantation is the gold-standard treatment for many patients with end-stage renal disease. Renal transplant recipients (RTRs) remain at an increased risk of fatal and non-fatal cardiovascular (CV) events compared to the general population, although rates are lower than those patients on maintenance haemodialysis. Death with a functioning graft is most commonly due to cardiovascular disease (CVD) and therefore this remains an important therapeutic target to prevent graft failure. Conventional CV risk factors such as diabetes, hypertension and renal dysfunction remain a major influence on CVD in RTRs. However it is now recognised that the morbidity and mortality from CVD are not entirely accounted for by these traditional risk-factors. Immunosuppression medications exert a deleterious effect on many of these well-recognised contributors to CVD and are known to exacerbate the probability of developing diabetes, graft dysfunction and hypertension which can all lead on to CVD. Nontraditional CV risk factors such as inflammation and anaemia have been strongly linked to increased CV events in RTRs and should be considered alongside those which are classified as conventional. This review summarises what is known about risk-factors for CVD in RTRs and how, through identification of those which are modifiable, outcomes can be improved. The overall CV risk in RTRs is likely to be multifactorial and a complex interaction between the multiple traditional and non-traditional factors; further studies are required to determine how these may be modified to enhance survival and quality of life in this unique population. Core tip: Cardiovascular disease (CVD) is the leading cause of death and disability in patients following a renal transplant. Identification of risk factors for CVD and strategies for their improvement are required in order to prevent graft failure in this complex patient

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“…Such factors as systolic BP, serum creatinine, diabetes mellitus, and smoking were included in the model as forced factors. The time to first occurrence of DSCGL was then analyzed by a stepwise Cox regression analysis that included the potential risk factors listed in Table 1, as well as risk factors for renal endpoints identified in previous analyses (7). A P value , 0.20 was used to select factors, and P,0.05 was the cutoff for final inclusion in the model.…”

Section: Statistical Analysesmentioning

confidence: 99%

“…We also analyzed death as a competing event, recognizing that death and graft failure share common risk factors, thus limiting the bias inherent in models that censor death in the analysis (5)(6)(7). For the marginal approach, we followed the method of Wei et al (8), which analyzes all recurrent events simultaneously, without conditioning for prior events.…”

Section: Introductionmentioning

confidence: 99%

Model Comparisons of Competing Risk and Recurrent Events for Graft Failure in Renal Transplant Recipients

Holme

Fellström

Jardine

et al. 2013

Clinical Journal of the American Society of Nephrology

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SummaryBackground and objectives Risk factor analysis of long-term graft survival in kidney transplant recipients is usually based on Cox regression models of time to first occurrence of doubling of serum creatinine or graft loss (DSCGL). However, death is a competing cause of failure, and censoring patients who die could bias estimates. We therefore compared estimates of time to first event versus estimates that included death as a competing risk and recurrent events.Design, setting, participants, & measurements A Cox regression analysis of 1997-2002 data from the Assessment of Lescol in Renal Transplant (ALERT) trial population identified an eight-factor risk model, by analyzing time to first occurrence of DSCGL. The same factors were re-analyzed, allowing for death as competing. The probability of survival free of DSCGL was estimated; and two recurrent models (marginal and conditional) were used for time to events.Results Creatinine, systolic BP, and HLA-DR mismatches lost 33%-46% of their strength of association with DSCGL when death was included as a competing risk. Small changes were observed if recurrent events were analyzed in the marginal model. ConclusionThe relationship between serum creatinine and DSCGL was attenuated when death was considered as a competing risk; inclusion of recurrent events had little effect. These findings have important implications for analysis and trial design in populations at high mortality risk.

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Inflammation-associated graft loss in renal transplant recipients

Abstract: The inflammation markers hsCRP and IL-6 are associated with long-term graft outcomes in renal transplant recipients.

Cited by 52 publications

References 41 publications

Cytomegalovirus-Associated CD4+CD28null Cells in NKG2D-Dependent Glomerular Endothelial Injury and Kidney Allograft Dysfunction

Cytomegalovirus-Associated CD4+CD28null Cells in NKG2D-Dependent Glomerular Endothelial Injury and Kidney Allograft Dysfunction

Cardiovascular risk factors following renal transplant

Model Comparisons of Competing Risk and Recurrent Events for Graft Failure in Renal Transplant Recipients

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