Urinary kidney biomarkers identified RIFLE-negative patients with high-risk subclinical AKI as well as a higher risk subgroup of patients among RIFLE-AKI-positive patients. These findings support the concept that urinary biomarkers define subclinical AKI and higher risk subpopulations with worse long-term prognosis among standard patients with AKI.

COMT genotype may associate with different patterns of renal functional changes and tubular stress biomarker release response after open heart surgery.

Aim: Aim of this study was to investigate the association of genetic variants of functional polymorphisms of matrix metalloproteinase and Cubilin (CUBN) with diabetic nephropathy (DN), end-stage renal disease (ESRD), and risk of cardiovascular disease (CVD) in Caucasian type 2 diabetes (T2D) patients. Methods: 472 T2D-patients were genotyped for 3 single-nucleotide polymorphisms (SNPs; MMP-2 [rs2285053], MMP-9 [rs17576] and CUBN [rs1801239]). Genotyping was carried out by allelic discrimination using TaqMan SNP-genotyping-assay. Results: MMP-9 (Gln279Arg) AA-genotype (OR 0.17 [0.04–0.62, p = 0.008]) and the time elapsed since diagnosis of T2D without onset of proteinuria (OR 0.87 [0.79–0.97, p = 0.008]) were found to be independently associated with reduced risk of susceptibility to DN. On the contrary higher stages of chronic kidney disease (OR 1.93 [1.15–3.23], p = 0.012) and the presence of MMP-9 GG-genotype were independently associated with DN (OR 6.07 [1.60–22.99], p = 0.008). The CUBN CC or C-risk-allele of rs1801239 was associated with ESRD (OR 2.04 [1.07–3.87], p = 0.03) and peripheral artery disease (OR 2.08 [1.12–3.88], p = 0.021). We could not find an association with MMP-2, MMP-9, or CUBN with CVD in a composite clinical endpoint model. Conclusions: This study highlights that MMP-9 or CUBN-SNPs may exert effects on risk of susceptibility to DN or ESRD. We provide novel evidence on genetic susceptibility for macroangiopathy in patients with a missense variant of CUBN (Ile2984Val) in patients with T2D.

BACKGROUND: Acute kidney injury requiring renal replacement therapy (AKI-RRT) is strongly associated with mortality after cardiac surgery; however, options for early identification of patients at high risk for AKI-RRT are extremely limited. Early after cardiac surgery, the predictive ability for AKI-RRT even of one of the most extensively evaluated novel urinary biomarkers, neutrophil gelatinase–associated lipocalin (NGAL), appears to be only moderate. We aimed to determine whether the NGAL/hepcidin-25 ratio (urinary concentrations of NGAL divided by that of hepcidin-25) early after surgery may compare favorably to NGAL for identification of high-risk patients after cardiac surgery. METHODS: This is a prospective substudy of the BICARBONATE trial, a multicenter parallel-randomized controlled trial comparing perioperative bicarbonate infusion for AKI prevention to usual patient care. At a tertiary referral center, 198 patients at increased kidney risk undergoing cardiac surgery with cardiopulmonary bypass were included into the present study. The primary outcome measure was defined as AKI-RRT. Secondary outcomes were in-hospital mortality and long-term mortality. We compared area under the curve of the receiver operating characteristic (AUC-ROC) of urinary NGAL with that of the urinary NGAL/hepcidin-25 ratio within 60 minutes after end of surgery. We compared adjusted AUC and performed cross-validated reclassification statistics of the (logarithmic) urinary NGAL/hepcidin-25 ratio adjusted to Cleveland risk score/EuroScore, cross-clamp time, age, volume of packed red blood cells, and (logarithmic) urinary NGAL concentration. The association of the NGAL/hepcidin-25 ratio with long-term patient survival was assessed using Cox proportional hazard regression analysis adjusting for EuroScore, aortic cross-clamp time, packed red blood cells and urinary NGAL. RESULTS: Patients with AKI-RRT (n = 13) had 13.7-times higher NGAL and 3.3-times lower hepcidin-25 concentrations resulting in 46.9-times higher NGAL/hepcidin-25 ratio early after surgery compared to patients without AKI-RRT. The NGAL/hepcidin-25 ratio had higher AUC-ROC compared with NGAL for risk of AKI-RRT and in-hospital mortality (unadjusted AUC-ROC difference 0.087, 95% confidence interval [CI], 0.036–0.138, P < .001; 0.082, 95% CI, 0.018–0.146, P = .012). For AKI-RRT, the NGAL/hepcidin-25 ratio increased adjusted category-free net reclassification improvement (cfNRI; 0.952, 95% CI, 0.437–1.468; P < .001) and integrated discrimination improvement (IDI; 0.040, 95% CI, 0.008–0.073; P = .016) but not AUC difference. For in-hospital mortality, the ratio improved AUC of the reference model (AUC difference 0.056, 95% CI, 0.003–0.108; P = .037) and cfNRI but not IDI. The urinary NGAL/hepcidin-25 ratio remained significantly associated with long-term mortality after adjusting for the model covariates. CONCLUSIONS: The urinary NGAL/hepcidin-25 ratio appears to early identify high-risk patients and outperform NGAL after cardiac surgery. Confirmation of our findings in other cardiac surgery centers is now needed.

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