Abstract Reduced kidney functional reserve, KFR, predicts poor outcomes in kidney diseases. We compared plasma proenkephalin‐A, plasma cystatin C, and creatinine clearance for kidney functional reserve measurement. KFR was measured preoperatively in 40 patients undergoing cardiac surgery and 22 healthy participants, including 14 kidney donors. Plasma proenkephalin‐A, cystatin C, and creatinine levels were compared before and after a protein meal for KFR calculation. Baseline creatinine clearance correlated poorly with baseline estimated glomerular filtration rate measured by any method. Cystatin C and proenkephalin‐A nadir after protein occurred earlier. The proenkephalin‐A‐based KFR had a greater dynamic range than cystatin C‐ and creatinine clearance‐based KFR (median [IQR] fractional KFR: proenkephalin‐A 44.2% [35.5; 58.0]; cystatin C 10.5% [4.4; 16.2]; creatinine clearance 30.0% [8.4; 68.9], p < 0.0001). Measurements were more homogeneous with cystatin C‐ and proenkephalin‐A‐estimated glomerular filtration rate than creatinine clearance (higher intraclass correlation: 0.98 for cystatin C; 0.86 for proenkephalin‐A, and 0.63 for creatinine clearance). The median [IQR] absolute proenkephalin‐A‐ and cystatin C‐based KFR were higher in healthy participants (proenkephalin‐A‐KFR: 33.8 [26.6; 59.0], cystatin C‐KFR: 11.6 [6.6; 15.1] mL/min/1.73m2) than cardiac surgery patients (proenkephalin‐A‐reserve: 28.5 [19.9; 40.6], cystatin C‐reserve: 5.0 [0.3; 8.7] mL/min/1.73m2, p < 0.05). Creatinine clearance‐KFR did not differ between groups and mostly reflected tubular secretion of creatinine than change in glomerular filtration rate. In conclusion, proenkephalin‐A provided a brief, homogeneous measure of KFR with wide dynamic range, encouraging wider use of this kidney stress test.

BACKGROUND AND HYPOTHESIS:Although arteriovenous fistulas (AVF) are widely accepted as the gold standard form of dialysis access for haemodialysis patients, high AVF flow may impose significant haemodynamic stress, potentially contributing to adverse cardiovascular events, including heart failure (HF). We hypothesize that higher AVF flow is associated with adverse cardiovascular outcomes including an increased incidence of heart failure. We sought to clarify this relationship as understanding this association is crucial for improving patient care. METHODS:A comprehensive search of the PubMed, EMBASE, and Cochrane databases was used to identify observational studies and randomized controlled trials reporting an effect of AVF flow on cardiac outcomes (clinical, echocardiographic, and biomarker). Due to study heterogeneity, meta-analysis was not feasible. Synthesis without meta-analysis (SWiM) was performed using vote counting of direction of effect as the primary outcome. RESULTS:Higher AVF flow rates were consistently associated with increased incidence of HF and worsening HF symptoms. Cardiac imaging revealed left ventricular dilation and reduced left ventricular ejection fraction in patients with high-flow AVFs. Elevated biomarkers, such as natriuretic peptides, corroborated the adverse cardiovascular effects of high AVF flow. CONCLUSIONS:This systematic review and synthesis without meta-analysis showed a positive relationship between AVF flow and clinical, echocardiographic, and biomarker cardiovascular outcomes. The methodological heterogeneity of studies highlights the need for well-designed prospective research with standardised definitions of high flow AVFs and measures for reporting of cardiovascular outcomes.

ABSTRACT Background Elevated plasma asymmetric and symmetric dimethylarginine (ADMA and SDMA) are risk factors for chronic kidney disease (CKD) and cardiovascular disease. Using plasma cystatin C (pCYSC)-based estimated glomerular filtration rate (eGFR) trajectories, we identified a cohort at high risk of poor kidney-related health outcomes amongst members of the Dunedin Multidisciplinary Health and Development Study (DMHDS). We therefore examined associations between methylarginine metabolites and kidney function in this cohort. Methods ADMA, SDMA, L-arginine and L-citrulline were measured in plasma samples from 45-year-olds in the DMHDS cohort by liquid chromatography–tandem mass spectrometry. Results In a healthy DMHDS subset (n = 376), mean concentrations were: ADMA (0.40 ± 0.06 µmol/L), SDMA (0.42 ± 0.06 µmol/L), L-arginine (93.5 ± 23.1 µmol/L) and L-citrulline (24.0 ± 5.4 µmol/L). In the total cohort (n = 857), SDMA correlated positively with serum creatinine (Pearson's r = 0.55) and pCYSC (r = 0.55), and negatively with eGFR (r = 0.52). A separate cohort of 38 patients with stage 3–4 CKD (eGFR 15–60 mL/min/1.73 m2) confirmed significantly higher mean ADMA (0.61 ± 0.11 µmol/L), SDMA (0.65 ± 0.25 µmol/L) and L-citrulline (42.7 ± 11.8 µmol/L) concentrations. DMHDS members classified as high-risk of poor kidney health outcomes had significantly higher mean concentrations of all four metabolites compared with individuals not at risk. ADMA and SDMA individually predicted high-risk of poor kidney health outcomes with areas under the ROC curves (AUCs) of 0.83 and 0.84, and together with an AUC of 0.90. Conclusions Plasma methylarginine concentrations facilitate stratification for risk of CKD progression.

Significant loss of kidney function is not easily identified by serum creatinine (sCr)-based measurements. In the presence of normal sCr, decreased kidney functional reserve (KFR) may identify a significant loss of function. We evaluated KFR in experimental subclinical chronic kidney disease (sCKD) before and after brief ischemia-reperfusion injury (IRI). Using fluorescein isothiocyanate-labeled sinistrin, glomerular filtration rate (GFR) was measured transcutaneously before and after adenine-induced sCKD, and 1 and 2 wk after brief IRI, and compared with urinary kidney damage biomarkers. sCKD reduced stimulated and unstimulated GFR by ∼20% while reducing KFR by 50%. IRI reduced unstimulated GFR for 14 days, but KFR remained relatively unchanged in sCKD and transiently increased in control kidneys at 7 days. sCr increased and creatinine clearance (CrCl) decreased only immediately after IRI; sCr and CrCl correlated poorly with measured GFR except on day 1 after IRI. Heterogeneity in sCr and CrCl resulted from variation in tubular creatinine secretion. The increase in damage biomarker concentrations persisted for up to 14 days after IRI, allowing retrospective detection of sCKD before AKI by urine clusterin/urine kidney injury molecule-1 with an area under the curve of 1.0. sCr and CrCl are unreliable unless sCr is acutely elevated. Measurement of KFR and urine damage biomarker excretion detected sCKD despite normal sCr and CrCl. After IRI, the urine clusterin-to-urine kidney injury molecule-1 ratio may identify prior sCKD.NEW & NOTEWORTHY Early kidney function loss is poorly identified by serum creatinine (sCr)-based measurements. Direct kidney functional reserve (KFR) measurement before kidney injury and elevated urinary biomarkers clusterin and kidney injury molecule-1 detect subclinical chronic kidney disease (sCKD) after kidney injury despite normal range sCr and creatinine clearance. Reliance on sCr masks underlying sCKD. Acute kidney injury risk evaluation requires direct glomerular filtration rate measurement and KFR, whereas kidney damage biomarkers facilitate identification of prior subclinical injury.