Plasma NGAL levels in stable kidney transplant recipients and the risk of allograft loss

BACKGROUND: The object of this study was to investigate the utility of Neutrophil gelatinase-associated lipocalin (NGAL) and Calprotectin (CPT) to predict long-term graft survival in stable kidney transplant recipients (KTR). METHODS: 709 stable outpatient KTR were enrolled >2 months post-transplant. The utility of plasma and urinary NGAL (pNGAL, uNGAL) and plasma and urinary CPT at enrollment to predict death-censored graft loss (GL) was evaluated during a 58-month follow-up. RESULTS: Among biomarkers, pNGAL showed best predictive ability for graft loss and was the only biomarker with an AUC > 0.7 for GL within 5 years. Patients with GL within 5 years (n=49) had a median pNGAL of 304[IQR 235-358] versus 182[IQR 128 -246]ng/ml with surviving grafts (p<0.001). Time-dependent Receiver operating characteristic analyses at 58 months indicated an Area-Under-the-Curve (AUC) for pNGAL of 0.795, serum creatinine (sCr) based estimated glomerular filtration rate (eGFR) CKD EPI had an AUC of 0.866. pNGAL added to a model based on conventional risk factors for GL with death as competing risk (age, transplant age, presence of donor specific antibodies, presence of proteinuria, history of delayed graft function) had a strong independent association with GL (subdistribution Hazard ratio (sHR) for binary log transfomed pNGAL (log2 (pNGAL)) (3.4 95% CI 2.24-5.15), p<0.0001). This association was substantially attenuated when eGFR was added to the model (sHR for log2 (pNGAL) 1.63 95% CI 0.92-2.88, p=0.095). Category-free net reclassification improvement of a risk model including log2(pNGAL) additionally to conventional risk factors and eGFR was 54.3% (95% CI 9.2 to 99.3%) but C-statistic did not improve significantly. CONCLUSIONS: pNGAL was an independent predictor of renal allograft loss in stable KTR from one transplant center but did not show consistent added value when compared to baseline predictors including the conventional marker eGFR. Future studies in larger cohorts are warranted

Serum creatinine and cystatin C-based estimates of glomerular filtration rate are misleading in acute heart failure

AIMS: We aimed to test whether the endogenous filtration markers serum creatinine or cystatin C and equation-based estimates of glomerular filtration rate (GFR) based on these markers appropriately reflect changes of measured GFR in patients with acute heart failure. METHODS: In this prospective cohort study of 50 hospitalized acute heart failure patients undergoing decongestive therapy, we applied an intravenous visible fluorescent injectate (VFI), consisting of a low molecular weight component to measure GFR and a high molecular weight component to correct for measured plasma volume. Thirty-eight patients had two sequential GFR measurements 48 h apart. The co-primary endpoints of the study were safety of VFI and plasma stability of the high molecular weight component. A key secondary endpoint was to compare changes in measured GFR (mGFR) to changes of serum creatinine, cystatin C and estimated GFR. RESULTS: VFI-based GFR measurements were safe and consistent with plasma stability of the high molecular weight component and glomerular filtration of the low molecular weight component. Filtration marker-based point estimates of GFR, when compared with mGFR, provided only moderate correlation (Pearson's r, range 0.80-0.88, depending on equation used), precision (r(2) , range 0.65-0.78) and accuracy (56%-74% of estimates scored within 30% of mGFR). Correlations of 48-h changes GFR estimates and changes of mGFR were significant (P 15% decrease in mGFR. CONCLUSIONS: In patients hospitalized for acute heart failure, serum creatinine- and cystatin C-based predictions performed poorly in detecting actual changes of GFR. These data challenge current clinical strategies to evaluate dynamics of kidney function in acute heart failure

Discordance between estimated and measured changes in plasma volume among patients with acute heart failure

AIMS: In acute heart failure (AHF), changes of venous haemoglobin (Hb) concentrations, haematocrit (Hct), and estimated plasma volume (ePV) have been proposed as surrogates of decongestion. These estimates are based on the theoretical assumptions that changes of Hb concentrations and Hct are driven by the intravascular volume status and that the intravascular Hb pool remains stable. The objective of this study was to assess the relationship of changes of measured plasma volume (mPV) with changes of Hb, Hct, and ePV in AHF. METHODS AND RESULTS: We studied 36 AHF patients, who received two sequential assessments of mPV, measured red cell volume (mRCV) and measured total blood volume (mTBV) (48 h apart), during the course of diuretic therapy using a novel visible fluorescent injectate (VFI) technique based on the indicator dilution principle. Changes of ePV were calculated based on the Kaplan–Hakim or Strauss formula. AHF patients receiving diuretics (median intravenous furosemide equivalent 160 mg/48 h) displayed a wide range of changes of mPV (−25.4% to +37.0%). Changes in mPV were not significantly correlated with changes of Hb concentration [Pearson's r (r) = −0.241, P = 0.157], Hct (r = −0.307, P = 0.069), ePVKaplan–Hakim (r = 0.228, P = 0.182), or ePVStrauss (r = 0.237, P = 0.163). In contrast to theoretical assumptions, changes of mTBV were poorly correlated with changes of Hb concentrations and some patients displayed unanticipated variability of mRCV, suggesting an unstable intravascular red cell pool. CONCLUSIONS: Changes of Hb or Hct were not reflective of directly measured changes of intravascular volume status in AHF patients. Basing clinical assessment of decongestion on changes of Hb or Hct may misguide clinical decision-making on an individual patient level

Serum creatinine and cystatin C‐based estimates of glomerular filtration rate are misleading in acute heart failure

AIMS: We aimed to test whether the endogenous filtration markers serum creatinine or cystatin C and equation-based estimates of glomerular filtration rate (GFR) based on these markers appropriately reflect changes of measured GFR in patients with acute heart failure. METHODS: In this prospective cohort study of 50 hospitalized acute heart failure patients undergoing decongestive therapy, we applied an intravenous visible fluorescent injectate (VFI), consisting of a low molecular weight component to measure GFR and a high molecular weight component to correct for measured plasma volume. Thirty-eight patients had two sequential GFR measurements 48 h apart. The co-primary endpoints of the study were safety of VFI and plasma stability of the high molecular weight component. A key secondary endpoint was to compare changes in measured GFR (mGFR) to changes of serum creatinine, cystatin C and estimated GFR. RESULTS: VFI-based GFR measurements were safe and consistent with plasma stability of the high molecular weight component and glomerular filtration of the low molecular weight component. Filtration marker-based point estimates of GFR, when compared with mGFR, provided only moderate correlation (Pearson's r, range 0.80-0.88, depending on equation used), precision (r(2) , range 0.65-0.78) and accuracy (56%-74% of estimates scored within 30% of mGFR). Correlations of 48-h changes GFR estimates and changes of mGFR were significant (P 15% decrease in mGFR. CONCLUSIONS: In patients hospitalized for acute heart failure, serum creatinine- and cystatin C-based predictions performed poorly in detecting actual changes of GFR. These data challenge current clinical strategies to evaluate dynamics of kidney function in acute heart failure