The lectin pathway of the complement system has been shown to considerably contribute to tissue damage during ischemia/reperfusion injury of several organs, including the kidneys [14
]. This is the first study to assess the importance of serum MBL with respect to the development of CIN in a clinical trial. MBL deficiency did not influence the occurrence of CIN as defined by a commonly quoted serum creatinine increment. However, it was associated with a limited increase in Cystatin C after the administration of CM.
To our knowledge the role of MBL has not been investigated in a rodent model of CIN. However, the fact that local ischemia and reperfusion is at least in part responsible for the development of CIN [4
], and that MBL aggravates tissue damage during I/R injury [9
], suggests a role of MBL in the pathogenesis of contrast-induced acute kidney injury.
With regard to the primary endpoint, the incidence of creatinine-based CIN, several reasons might account for the absent effect of MBL deficiency in this study. According to the baseline characteristics, the study cohort included only a rather small percentage of very high-risk patients (as reflected by 29/246 (11.7%) with GFR <30
, 52/246 (21.1%) with coronary angiography and ad hoc PCI, 69/246 (28.0%) with contrast media volume ≥140
], 90/246 (36.6%) with diabetes mellitus, and the exclusion of patients with advanced congestive heart failure), and CIN was diagnosed infrequently, especially in the sodium chloride prevention group (incidence 1.2%). Due to the latter fact the analysis of smaller differences between MBL sufficient and deficient patients is limited. Furthermore, in this study cohort low to moderate CM-induced damage is probably not reflected by a decline in kidney function as measured by the serum creatinine concentration, a parameter with limited sensitivity to detect an acute deterioration in renal function within 48
]. Besides underestimating the true change in GFR, the increase in serum creatinine after CM exposure is delayed achieving a maximum two to five days after CM exposure as compared to cystatin C, a more sensitive marker, which was shown to rise earlier, to peak as early as 24
hours after CM administration, and to detect even subtle changes in GFR after acute kidney injury including CIN [19
]. Indeed, when we analyzed the influence of MBL deficiency on the cystatin C course after CM exposure we observed a remarkable association: As compared to patients with MBL levels >500
ng/mL subjects with MBL deficiency were almost two-times less likely to develop a cystatin C increase ≥10% after administration of CM, a cut-off that has recently been proposed as an independent diagnostic and prognostic tool with respect to the occurrence of CIN and future adverse events [20
]. This suggests that deficiency of MBL might attenuate some of the detrimental effects of CM. Though being small in magnitude this increase in cystatin C of ≥10% might have important consequences for the patients as even apparently minor decreases in renal function have been shown to be associated with excessive mortality rates independent of other known risk factors [20
]. However, we were not able to demonstrate a consistent association of MBL deficiency with superior clinical outcomes, which the study was not powered for.
On the other hand, the importance of renal I/R injury in pathogenesis of CIN might be overestimated as several other factors (including direct toxic effect on renal tubular cells, increased urinary viscosity, and tubular obstruction) influence kidney function after exposure to CM [32
]. Moreover, I/R models that demonstrated a pivotal role of MBL in the context of renal ischemia (i.e. transient or permanent occlusion of a major renal artery) are most likely not comparable to the complex events occurring after administration of CM. The duration and extent of ischemia might be crucial as well. In a rodent model of renal I/R activation of the MBL-pathway was not induced by warm ischemia of less than 30
]. Data on the duration and significance of renal vasoconstriction and hypoxia after CM exposure in humans remain controversial [4
]. However, it has been demonstrated that MBL and its associated protease mannose-binding protein-associated serine protease 2 are strongly upregulated in the post-procedural urinary proteome profiles after application of CM, and that urine levels of MBL significantly increase in patients who developed CIN whereas MBL levels remain stable in non-CIN patients [17
]. Finally, the alternative pathway has been implicated in experimental renal ischemia/reperfusion injury and might play a dominant role in humans as compared to the MBL pathway [33
Despite the randomized controlled trial design of the original study and the precisely characterized cohort the present study has important limitations including the post hoc analysis of MBL serum levels and the use of a surrogate marker as primary endpoint. Furthermore, limiting the measurement of serum creatinine to 48
hours after CM exposure might result in an underestimation of creatinine-based CIN. As genetic material was not available, analysis of MBL deficiency solely relied on MBL phenotype. However, MBL serum levels show little variation throughout life, and correlate well with the functional activity of the MBL pathway in vivo
]. As individuals with the same genotype may vary up to tenfold in MBL serum levels, measurement of MBL serum levels by ELISA might in fact represent a more reliable approach than determination of genotypes [35
]. MBL levels (as measured by sandwich ELISA) have been shown to be significantly increased in Asian pre-dialysis and dialysis patients compared to healthy controls [37
]. To the best of our knowledge comparable studies in a Caucasian population with moderate renal impairment (similar to our study patients) are lacking.