Background. The prognostic Kidney Donor Risk Index (KDRI)-developed and internally validated in the United States-is a widely used tool to predict transplant outcome of a deceased donor kidney. The... Show moreBackground. The prognostic Kidney Donor Risk Index (KDRI)-developed and internally validated in the United States-is a widely used tool to predict transplant outcome of a deceased donor kidney. The KDRI is currently used for longevity matching between donors and recipients in the United States. Methods. We aimed to externally validate the KDRIdonor-only and KDRIfull as proposed by Rao et al (2009). KDRIdonor-only consist of 10 donor factors, and KDRIfull with an additional 4 transplant factors. We used the Dutch Organ Transplantation Registry to include 3201 adult recipients transplanted from 2002 to 2012. Results. The median Dutch KDRI was 1.21 and comparable with the year 2012 in the United States (median of 1.24). The calibrationslope was 0.98 and 0.96 for the KDRIfull and KDRIdonor-only, respectively, indicating that predictions of graft failure were on average similar. The discriminative ability (Harrell C) of the KDRIfull and the KDRIdonor-only at 5 years was 0.63 (95% confidence interval [CI], 0.62-0.64), and 0.62 (95% CI, 0.61-0.63), respectively. We found misspecification of 3 KDRI factors: age (P = 0.002), weight (P = 0.017), and cold ischemia time (P < 0.001). Adding the use of inotropic drugs before donation (P = 0.040) and the interaction between circulatory-death donor kidneys and prolonged cold ischemic time (> 24 hours vs 12 hours; P = 0.059) could improve predictive ability. Conclusions. The KDRI performs equal in the Dutch population. Discriminative ability of the KDRI indicates limited clinical use for adequate individualized decisions. An updated KDRImay contribute to a standardized policymeeting the growing demand of donor kidneys in the Eurotransplant region. Show less
Ischemia/reperfusion injury (IRI) remains a major problem in renal transplantation. Clinical studies have identified that high serum levels of Mannan-binding lectin (MBL), the initiator of the... Show moreIschemia/reperfusion injury (IRI) remains a major problem in renal transplantation. Clinical studies have identified that high serum levels of Mannan-binding lectin (MBL), the initiator of the lectin pathway of complement activation, are associated with inferior renal allograft survival. Using a rat model, we identified an entirely novel role for MBL in mediating renal IRI. Therapeutic inhibition of MBL was protective against kidney dysfunction, tubular damage, neutrophil and macrophage accumulation, and expression of proinflammatory cytokines and chemokines. Following reperfusion, exposure of tubular epithelial cells to circulation-derived MBL resulted in internalization of MBL followed by the rapid induction of tubular epithelial cell death. Interestingly, this MBL-mediated tubular injury was completely independent of complement activation since attenuation of complement activation was not protective against renal IRI. Our identification that MBL-mediated cell death precedes complement activation strongly suggests that exposure of epithelial cells to MBL immediately following reperfusion is the primary culprit of tubular injury. In addition, also human tubular epithelial cells in vitro were shown to be susceptible to the cytotoxic effect of human MBL. Taken together, these data reveal a crucial role for MBL in the early pathophysiology of renal IRI and identify MBL as a novel therapeutic target in kidney transplantation. Show less
Pol, P. van der; Roos, A.; Berger, S.P.; Bajema, I.M.; Stahl, G.L.; Schlagwein, N.; ... ; Kooten, C. van 2011
Purpose of review Over the past decade, the role of the complement system in solid organ transplantation has received increased attention. A number of experimental and epidemiological studies have... Show morePurpose of review Over the past decade, the role of the complement system in solid organ transplantation has received increased attention. A number of experimental and epidemiological studies have suggested that the lectin pathway plays a role in infectious complications, rejection and long-term outcome after transplantation. This review discusses recent data on the role of the lectin pathway in solid organ transplantation. Recent findings Studies on the role of mannose-binding lectin (MBL) in organ transplantation have shown an association of MBL-deficient states with an increased risk of infection after liver and simultaneous pancreas-kidney transplantation. On the contrary, a high MBL status in the recipient has been associated with poorer organ survival and increased rejection associated damage in various transplant settings. Experimental data points towards a role for MBL in ischemia-reperfusion damage in various organs. Several lines of evidence suggest that MBL may contribute to immunoglobulin-mediated complement activation in both ischemia-reperfusion and rejection. The interaction of MBL with IgM may be of particular importance in this setting. Summary We review recent epidemiological data on the role of MBL in solid organ transplantation. We relate these findings to the emerging experimental data and attempt to explain some of the conflicting results on beneficial and harmful effects of the lectin pathway. Show less
Chavele et al. studied the role of the mannose receptor (MR) in crescentic nephritis [1]. The accelerated nephrotoxic model of glomerulonephritis was induced on both wild-type (WT) and MR-deficient... Show moreChavele et al. studied the role of the mannose receptor (MR) in crescentic nephritis [1]. The accelerated nephrotoxic model of glomerulonephritis was induced on both wild-type (WT) and MR-deficient mice. The mice lacking the MR showed a markedly altered phenotype. They were largely protected against the development of glomerulonephritis with less affected glomeruli, less proteinuria and much better renal function when compared to the WT mice. Whilst more infiltrating macrophages were present in the WT animals, there was no difference in the deposition of sheep and mouse immunoglobulins. To elucidate the mechanism of MR-mediated damage, the authors additionally performed a series of in vitro experiments. They show that the Fab portion of sheep immunoglobulins binds to MR binding domains. Interestingly, the MR seems to interact with FcR-mediated cellular reactions. When MR-deficient macrophages and mesangial cells were treated with immune complexes, the macrophages showed a significantly poorer oxygen burst when compared with WT cells. In line with this possible interaction between Fc-receptors and MR, co-localization of Fca-receptors and MR was demonstrated on macrophages. Additionally, the authors observed that MR-deficient mesangial cells in culture proliferated more abundantly and showed a markedly increased rate of spontaneous apoptosis compared with WT cells. These findings led the authors to test whether this increased apoptosis could play a role in the suppression of glomerular inflammation. Indeed, TNF-a production by LPS-stimulated macrophages was markedly reduced in the presence or apoptotic cells. The anti-inflammatory effect of apoptotic mesangial cells was increased when MR-deficient macrophages were used instead of WT cells (Figure 1). Show less
Pol, P. van der; Roos, A.; Berger, S.P.; Bajema, I.M.; Stahl, G.L.; Gijlswijk, D.J.; ... ; Kooten, C. van 2010
C4d+ antibody-mediated rejection following pancreas transplantation has not been well characterized. Therefore, we assessed the outcomes of 27 pancreas transplantation patients (28 biopsies), with... Show moreC4d+ antibody-mediated rejection following pancreas transplantation has not been well characterized. Therefore, we assessed the outcomes of 27 pancreas transplantation patients (28 biopsies), with both C4d staining and donor-specific antibodies (DSA) determined, from a cohort of 257 patients. The median follow-up was 50 (interquartile range [IQR] 8-118) months. Patients were categorized into 3 groups: group 1, patients with minimal or no C4d staining and no DSA (n = 13); group 2, patients with either DSA present but no C4d, diffuse C4d+ and no DSA or focal C4d+ and DSA (n = 6); group 3, patients with diffuse C4d+ staining and DSA (n = 9). Active septal inflammation, acinar inflammation and acinar cell injury/necrosis were significantly more abundant in group 3 than in group 2 (respective p-values: 0.009; 0.033; 0.025) and in group 1 (respective p-values: 0.034; 0.009; 0.002). The overall uncensored pancreas graft survival rate for groups 1, 2 and 3 were 53.3%, 66.7% and 34.6%, respectively (p = 0.044). In conclusion, recipients of pancreas transplants with no C4d or DSA had excellent long-term graft survival in comparison with patients with both C4d+ and DSA present. Hence, C4d should be used as an additional marker in combination with DSA in the evaluation of pancreas transplant biopsies. Show less
Background. Proteinuria predicts progressive renal failure. Next to being a progression marker, non-selective proteinuria itself is thought to be toxic to the tubulointerstitium. In proteinuric... Show moreBackground. Proteinuria predicts progressive renal failure. Next to being a progression marker, non-selective proteinuria itself is thought to be toxic to the tubulointerstitium. In proteinuric states, activation of filtered or locally produced complement is toxic for renal tubular cells and likely contributes to the progression of renal failure. Recent experimental evidence suggests an important role for properdin in promoting intrarenal complement activation. We measured properdin in proteinuric urine and assessed its relation with urinary SC5b-9 levels, the soluble form of the effector phase of complement activation. Methods. Seventy patients with renal disease of different origin but all with a protein excretion of at least 1 g/day were studied. Urinary properdin and SC5b-9 levels were measured using an ELISA technique. Results. Properdin was detectable in the urine of 37 patients (53%). These subjects had higher urinary SC5b-9 levels {median 0.50 U/ml [interquartile range (IQR) 0.13-1.81] versus 0.049 U/ml (IQR 0.024-0.089), P < 0.001}. When adjusted for proteinuria and renal function, properdin excretion was strongly associated with increased urinary SC5b-9 levels (odds ratio 16.2, 95% confidence interval 3.6-74.4). Properdin excretion was associated with worse renal function. Conclusion. Our results suggest that urinary properdin excretion enhances intrarenal complement activation and thus may contribute to the progression of renal damage in proteinuric states. Show less
