1. Predicting Progression in Diabetic Nephropathy: New Biomarker: sTNFR1* Circulating soluble Tumor Necrosis Factor Receptor 1

2. Diabetic Nephropathy: The Facts  Diabetic nephropathy is the leading cause of End Stage Renal Disease (ESRD) worldwide  40% of diabetic patients will develop symptoms of diabetic nephropathy  >90% of these will not progress to ESRD, but we are not yet able to predict which patients will progress and which patients will not.  Average life expectancy for a patient on Dialysis is < 5yrs Reference: USRDS 2013

3. What is soluble Tumor Necrosis Factor Receptor 1 (TNFR1)?  TNFα:  Cytokine TNFα is a transmembrane protein generated by many cells, including endothelial cells and leukocytes  Implicated in the pathogenesis of diabetic kidney disease  The receptors TNFR1 (and TNFR2) binds TNFα to mediate activate inflammatory and stress response pathways

4. sTNFR1 improves risk prediction in Diabetic Nephropathy (leading to ESRD)  sTNFR1 provides additional information on risk in the same way Cholesterol provides information on CVD risk Current TestsShortcomings Albuminuria (Micro / Marco) Poor prognostic value Renal decline predates albuminuria Unstable and highly variable Glomerular Filtration Rate (estimated GFR)

5. Niewczas et al Circulating TNF Receptors 1 and 2 Predict ESRD in Type 2 Diabetes.pdf sTNFR1 predicts ESRD within 3-12 years in type 2 diabetes patients with proteinuria (>300mg/day) “For patients with sTNFR1 levels > 2000pg/ml, the risk of progression to ESRD was nearly 80% in 12 years”

6. sTNFR1 predicts ESRD over 10- 12 years of follow up in type 2 diabetes patients without proteinuria. “For patients without proteinuria, C-Index for sTNFR1 was 0.93 whereas that for albumin excretion rate was only 0.78 (P=0.048)” Niewczas et al Circulating TNF Receptors 1 and 2 Predict ESRD in Type 2 Diabetes.pdf

7. sTNFR1 prediction of ESRD replicated in independent cohort for type 2 diabetics with CKD Survival Distribution Function Q1 Q2 Q3 Q4 Follow up period (months) “The risk of renal event was greater in those people from the fourth quartile compared with those in the first to third quartiles, even after multiple adjustments” Reproduced from oral presentations of: Reproduced from oral presentations of: Association of Serum Concentration of TNFR1 With All- Cause Mortality (and Renal Decline) in Patients With Type 2 Diabetes and Chronic Kidney Disease: Follow-up of the SURDIAGENE Cohort.pdf

8. Conclusions  Diabetic nephropathy is leading cause of End Stage Renal Disease (ESRD), but we can’t predict which patients will progress or not progress to ESRD  sTNFR1 identify which T2DM patients are at highest risk of ESRD  Combining sTNFR1 and urine Albumin Creatinine Ratios gives best predictive value  European Association for the Study of Diabetes algorithms suggest Multimodal therapy combining hypoglycaemic agents, statins & ACE inhibitors for patients with diabetic kidney disease

9. References YearTitleReference 2012Circulating TNF Receptors 1 and 2 predict ESRD in Type 2 Diabetes JASN Niewczas et al. 2014Association of Serum Concentration of TNFR1 With All- Cause Mortality (and Renal Decline) in Patients With Type 2 Diabetes and Chronic Kidney Disease: Follow-up of the SURDIAGENE Cohort Diabetes Care Saulnier et al. 2012Circulating TNF receptors 1 and 2 predict stage 3 CKD in Type 1 Diabetes JASN Ghoda et al. 2014Added Value of Soluble Tumor Necrosis Factor Alpha Receptor-1 as a Biomarker of ESRD Risk in Patients With Type 1 Diabetes Diabetes Care Forsblom et al.