Background: There is strong biologic plausibility to support change in albuminuria as a surrogate endpoint for progression of chronic kidney disease (CKD), but empirical evidence to supports its validity in epidemiologic studies is lacking. Methods: We analyzed 28 cohorts including 693,816 individuals (80% with diabetes) and 7,461 end-stage kidney disease (ESKD) events, defined as initiation of kidney replacement therapy. Percent change in albuminuria was quantified during a baseline period of 1, 2 and 3 years using linear regression. Associations with subsequent ESKD were quantified using Cox regression in Coresh et al.

; for the Chronic Kidney Disease Prognosis Consortium ‡ Background: Although measuring albuminuria is the preferred method for defining and staging chronic kidney disease (CKD), total urine protein or dipstick protein is often measured instead. Objective: To develop equations for converting urine proteincreatinine ratio (PCR) and dipstick protein to urine albumincreatinine ratio (ACR) and to test their diagnostic accuracy in CKD screening and staging. Design: Individual participant-based meta-analysis. Setting: 12 research and 21 clinical cohorts. Participants: 919 383 adults with same-day measures of ACR and PCR or dipstick protein. Measurements: Equations to convert urine PCR and dipstick protein to ACR were developed and tested for purposes of CKD screening (ACR, ≥30 mg/g) and staging (stage A2: ACR, 30 to 299 mg/g; stage A3: ACR, ≥300 mg/g). Results: Median ACR was 14 mg/g (25th to 75th percentile of cohorts, 5 to 25 mg/g). The association between PCR and ACR was inconsistent for PCR values less than 50 mg/g. For higher PCR values, the PCR conversion equations demonstrated moderate sensitivity (91%, 75%, and 87%) and specificity (87%, 89%, and 98%) for screening (ACR, >30 mg/g) and classification into stages A2 and A3, respectively. Urine dipstick categories of trace or greater, trace to +, and ++ for screening for ACR values greater than 30 mg/g and classification into stages A2 and A3, respectively, had moderate sensitivity (62%, 36%, and 78%) and high specificity (88%, 88%, and 98%). For individual risk prediction, the estimated 2-year 4-variable kidney failure risk equation using predicted ACR from PCR had discrimination similar to that of using observed ACR. Limitation: Diverse methods of ACR and PCR quantification were used; measurements were not always performed in the same urine sample. Conclusion: Urine ACR is the preferred measure of albuminuria; however, if ACR is not available, predicted ACR from PCR or urine dipstick protein may help in CKD screening, staging, and prognosis.

Cardiovascular disease is more common in patients with chronic kidney disease (CKD), and traditional risk factors do not adequately predict those at risk for cardiovascular (CV) events. Recent evidence suggests elevated trimethylamine N-oxide (TMAO), created by gut microflora from dietary L-carnitine and choline, is associated with CV events. We investigated the relationship of TMAO levels in patients with stages 3b and 4 CKD to ischemic CV events using the CanPREDDICT cohort, a Canada-wide observational study with prospective 3-year follow-up of adjudicated CV events. Baseline samples were obtained for 2529 CKD patients. TMAO, choline, and L-carnitine levels were measured using tandem mass spectrometry. Baseline median TMAO level was high for the whole cohort (20.41 μM; interquartile range [IQR]: 12.82-32.70 μM). TMAO was independently associated with CV events (hazard ratio 1.23; 95% confidence interval: 1.06-1.42 / 1 SD lnTMAO) after adjusting for all potential CV risk factors. Those in the highest TMAO quartile had significantly higher risk of CV events (adjusted hazard ratio 1.59; 95% confidence interval: 1.04-2.43; P = 0.0351) in the analysis of recurring ischemic events. Among those with stage 3b CKD (hazard ratio 1.45; 95% confidence interval: 1.12-1.87 / 1 SD lnTMAO), independent of kidney function, TMAO levels identified those at highest risk for events. Our results suggest that TMAO may represent a new potentially modifiable CV risk factor for CKD patients. Further studies are needed to determine sources of variability and if lowering of TMAO reduces CV risk in CKD.

Background Some evidence suggests that chronic kidney disease is a risk factor for lower-extremity peripheral artery disease. We aimed to quantify the independent and joint associations of two measures of chronic kidney disease (estimated glomerular filtration rate [eGFR] and albuminuria) with the incidence of peripheral artery disease. Methods In this collaborative meta-analysis of international cohorts included in the Chronic Kidney Disease Prognosis Consortium (baseline measurements obtained between 1972 and 2014) with baseline measurements of eGFR and albuminuria, at least 1000 participants (this criterion not applied to cohorts exclusively enrolling patients with chronic kidney disease), and at least 50 peripheral artery disease events, we analysed adult participants without peripheral artery disease at baseline at the individual patient level with Cox proportional hazards models to quantify associations of creatinine-based eGFR, urine albumin-to-creatinine ratio (ACR), and dipstick proteinuria with the incidence of peripheral artery disease (including hospitalisation with a diagnosis of peripheral artery disease, intermittent claudication, leg revascularisation, and leg amputation). We assessed discrimination improvement through c-statistics. Findings We analysed 817 084 individuals without a history of peripheral artery disease at baseline from 21 cohorts. 18 261 cases of peripheral artery disease were recorded during follow-up across cohorts (median follow-up was 7·4 years [IQR 5·7–8·9], range 2·0–15·8 years across cohorts). Both chronic kidney disease measures were independently associated with the incidence of peripheral artery disease. Compared with an eGFR of 95 mL/min per 1·73 m2, adjusted hazard ratios (HRs) for incident study-specific peripheral artery disease was 1·22 (95% CI 1·14–1·30) at an eGFR of 45 mL/min per 1·73 m2 and 2·06 (1·70–2·48) at an eGFR of 15 mL/min per 1·73 m2. Compared with an ACR of 5 mg/g, the adjusted HR for incident study-specific peripheral artery disease was 1·50 (1·41–1·59) at an ACR of 30 mg/g and 2·28 (2·12–2·44) at an ACR of 300 mg/g. The adjusted HR at an ACR of 300 mg/g versus 5 mg/g was 3·68 (95% CI 3·00–4·52) for leg amputation. eGFR and albuminuria contributed multiplicatively (eg, adjusted HR 5·76 [4·90–6·77] for incident peripheral artery disease and 10·61 [5·70–19·77] for amputation in eGFR <30 mL/min per 1·73 m2 plus ACR ≥300 mg/g or dipstick proteinuria 2+ or higher vs eGFR ≥90 mL/min per 1·73 m2 plus ACR <10 mg/g or dipstick proteinuria negative). Both eGFR and ACR significantly improved peripheral artery disease risk discrimination beyond traditional predictors, with a substantial improvement prediction of amputation with ACR (difference in c-statistic 0·058, 95% CI 0·045–0·070). Patterns were consistent across clinical subgroups. Interpretation Even mild-to-moderate chronic kidney disease conferred increased risk of incident peripheral artery disease, with a strong association between albuminuria and amputation. Clinical attention should be paid to...