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Here we evaluated the performance of a large set of serum biomarkers for the prediction of rapid progression of chronic kidney disease (CKD) in patients with type 2 diabetes. We used a case-control design nested within a prospective cohort of patients with baseline eGFR 30-60 ml/min per 1.73 m(2). Within a 3.5-year period of Go-DARTS study patients, 154 had over a 40% eGFR decline and 153 controls maintained over 95% of baseline eGFR. A total of 207 serum biomarkers were measured and logistic regression was used with forward selection to choose a subset that were maximized on top of clinical variables including age, gender, hemoglobin A1c, eGFR, and albuminuria. Nested cross-validation determined the best number of biomarkers to retain and evaluate for predictive performance. Ultimately, 30 biomarkers showed significant associations with rapid progression and adjusted for clinical characteristics. A panel of 14 biomarkers increased the area under the ROC curve from 0.706 (clinical data alone) to 0.868. Biomarkers selected included fibroblast growth factor-21, the symmetric to asymmetric dimethylarginine ratio, β2-microglobulin, C16-acylcarnitine, and kidney injury molecule-1. Use of more extensive clinical data including prebaseline eGFR slope improved prediction but to a lesser extent than biomarkers (area under the ROC curve of 0.793). Thus we identified several novel associations of biomarkers with CKD progression and the utility of a small panel of biomarkers to improve prediction.

BackgroundValidated prediction scores are required to assess the risks of end-stage renal disease (ESRD) and death in individuals with chronic kidney disease (CKD).Study DesignProspective cohort study with validation in a separate cohort.Setting & ParticipantsCox regression was used to assess the relevance of baseline characteristics to risk of ESRD (mean follow-up, 4.1 years) and death (mean follow-up, 6.0 years) in 382 patients with stages 3-5 CKD not initially on dialysis therapy in the Chronic Renal Impairment in Birmingham (CRIB) Study. Resultant risk prediction equations were tested in a separate cohort of 213 patients with CKD (the East Kent cohort).Factors44 baseline characteristics (including 30 blood and urine assays).OutcomesESRD and all-cause mortality.ResultsIn the CRIB cohort, 190 patients reached ESRD (12.1%/y) and 150 died (6.5%/y). Each 30% lower baseline estimated glomerular filtration rate was associated with a 3-fold higher ESRD rate and a 1.3-fold higher death rate. After adjustment for each other, only baseline creatinine level, serum phosphate level, urinary albumin-creatinine ratio, and female sex remained strongly (P < 0.01) predictive of ESRD. For death, age, N-terminal pro-brain natriuretic peptide, troponin T level, and cigarette smoking remained strongly predictive of risk. Using these factors to predict outcomes in the East Kent cohort yielded an area under the receiver operating characteristic curve (ie, C statistic) of 0.91 (95% CI, 0.87-0.96) for ESRD and 0.82 (95% CI, 0.75-0.89) for death.LimitationsOther important factors may have been missed because of limited study power.ConclusionsSimple laboratory measures of kidney and cardiac function plus age, sex, and smoking history can be used to help identify patients with CKD at highest risk of ESRD and death. Larger cohort studies are required to further validate these results.

Glomerular hyperfiltration is associated with puberty and increasing ACR levels and is predictive of MA independent of HbA1c. This suggests that factors other than poor glycemic control may be involved in the pathogenesis of early diabetic nephropathy and early intervention with medical therapy to reduce GFR may be beneficial even before onset of MA.

The use of an ACE inhibitor and a statin did not change the albumin-to-creatinine ratio over time. (Funded by the Juvenile Diabetes Research Foundation and others; AdDIT ClinicalTrials.gov number, NCT01581476 .).

Previous studies suggest reduced hepatic endothelial nitric oxide synthase activity contributes to increased intrahepatic resistance. Asymmetric dimethylarginine (ADMA), an endogenous nitric oxide synthase inhibitor, undergoes hepatic metabolism via dimethylargininedimethylamino-hydrolase, and is derived by the action of protein-arginine-methyltransferases. Our study assessed whether ADMA, and its stereo-isomer symmetric dimethylarginine (SDMA), are increased in alcoholic hepatitis patients, and determined any relationship with severity of portal hypertension (hepatic venous pressure gradient measurement) and outcome. Fifty-two patients with decompensated alcoholic cirrhosis were studied, 27 with acute alcoholic hepatitis and cirrhosis, in whom hepatic venous pressure gradient was higher (P ‫؍‬ 0.001) than cirrhosis alone, and correlated with ADMA measurement. Plasma ADMA and SDMA were significantly higher in alcoholic hepatitis patients and in nonsurvivors. Dimethylarginine-dimethylaminohydrolase protein expression was reduced and protein-arginine-methyltransferase-1 increased in alcoholic hepatitis livers. ADMA, SDMA and their combined sum, which we termed a dimethylarginine score, were better predictors of outcome compared with Pugh score, MELD and Maddrey's discriminant-function. Conclusion: Alcoholic hepatitis patients have higher portal pressures associated with increased ADMA, which may result from both decreased breakdown (decreased hepatic dimethylarginine-dimethylamino-hydrolase) and/or increased production. Elevated dimethylarginines may serve as important biological markers of deleterious outcome in alcoholic hepatitis. (HEPATOLOGY 2007;45:62-71.)A lcoholic hepatitis (AH) is a severe presentation of alcoholic liver disease associated with high mortality. 1 Patients present with acute hepatic decompensation on the background of cirrhosis, related to complications associated with portal hypertension. A potential link between changes in portal blood flow and poor outcome in severe AH has been suggested. 2 Furthermore, elevated portal pressures in patients with decompensated cirrhosis independently predicts survival 3 although the pathophysiological mechanisms behind these haemodynamic disturbances are incompletely defined.Factors modulating intrahepatic resistance, an important component in the severity of portal hypertension include liver ultrastructural changes secondary to cirrhosis, in addition to variable components such as myofibroblastic stellate cell activity and vaso-active mediators such as nitric oxide (NO). 4 Data from animal studies strongly support the notion that in portal hypertension, there is a deficiency of intrahepatic NO resulting from a reduction in the activity of endothelial NO synthase (eNOS). 5,6 Hepatic NO delivery in these models reduces the severity of portal hypertension through a reduction in intrahepatic resistance. 7 .

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Compensated assays that account for non-creatinine chromogen interference produce significantly higher estimates of GFR when using the original MDRD equation. Use of the ID-MS-traceable MDRD equation ameliorates this effect. There is good agreement between estimated GFR derived from the original MDRD equation using Beckman Astra CX3 data and estimated GFR derived from the new ID-MS-traceable MDRD equation using a local ID-MS creatinine assay. This suggests that the ID-MS-traceable MDRD equation may be reliably used with both ID-MS and true ID-MS-traceable creatinine assays without the requirement for standardization to the MDRD laboratory.