23-Jun-15. Albuminuria Renal and Cardiovascular Consequences A history of progress since ,490,000. Kidney Center, UMC Groningen

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1 Kidney function (egfr in ml/min) Albuminuria (mg/hr) Incidentie ESRD (%) 3-Jun- Number of patients worldwide that receives kidney replacement therapy Albuminuria Renal and Cardiovascular Consequences A history of progress since 997,9,,, Prof. Ron T. Gansevoort Dept. Nephology University Medical Center Groningen Netherlands NASHKO Curacao June 9 -, 6, Lysaght, J Am Soc Nephrol Predicted How effective is renoprotective treatment? How to prevent progression towards ESRD? Kidney function (egfr) 3 p=. 6% Control Losartan Early intervention N= N= Follow-up (months) Brenner et al, N Eng J Med RENAAL Study, n=3, overt DM nephropathy Start % RRT % Follow-up (years) Late intervention The natural course of diabetic nephropathy Hyperfiltration Normal renal function 997 The importance of albuminuria in non-diabetics. All inhabitants of the city Groningen, age - 7 years, invited for participation 7 Overt nephropathy 6 Positive response - Short questionnaire - First morning void urine sample per post to a central lab Macro-albuminuria Micro-albuminuria Inclusion criteria: - All with urinary albumin concentration > mg/l - Random sample with UAC < mg/l Exclusion criteria: - Known diabetes mellitus 3 Duration since start of diabetes (years) Normo-albuminuria 9 Screening in an outpatient clinic (once per 3 year) Albuminuria, egfr, RR, glucose, morbidity, mortality etc

2 for ESRD Life expectancy (years) Change in egfr (ml/min/.73m ) Decline in egfr (ml/min/.73m per year) CV mortaliteit (leeftijd en geslacht gecorrigeerd RR) 3-Jun- Classical renal risk markers Which one predicts egfr decline the best? Micro-albuminuria vs. egfr decline Also in the non-diabetic population >3 = N = Albuminuria (mg/d) Impaired kidney function (n=3) -, Crude General population (n=.7) Erythrocyturia (n=) -, -,6 -, Adjusted for age and gender Adjusted for age, gender, RR, glucose, CVD history - - Macro-albuminuria (n=3) - -, -, - -,6 - -, Follow-up (jr) Halbesma et al, JASN 6 General population, no diabetes Study, N=,9 - Van de Velde et al, JASN 9 General population, no diabetes Study, N=6,9 Albuminuria predicts ESRD incidence years of follow-up in the general population Albuminuria predicts CV mortality years of follow-up in the general population 3 Normal Micro-albuminuria Macro-albuminuria Hallan et al, JASN 9. 3 Albuminuria (mg/mmol) General population HUNT- study, Norway, n=69 HR for ESRD adjusted for age, gender and CV risk factors Hillege et al Circulation Normaal Micro-albuminurie Macro-albuminurie UAC (mg/l) General population study, n=6 HR for CV mortality adjusted for age and gender Albuminuria and life expectancy Microalbuminuria versus underlying cause in the general population Gansevoort et al Lancet 3 3 3, 3, 3,,7, 9, Age (years) Normo-albuminuria Micro-albuminuria Macro-albuminuria n=99.9 Observational cohort, Canada PIs: Hemmelgarn en Tonelli Prevalence of MA: 7.% Ozyilmaz et al NDT Newly discovered diabetes % Known hypertension 9% Newly discovered hypertension 37% Known diabetes 6% Healthy 36% 9 subjects with micro-albuminuria in the GP (= 3-3 mg/hr) Known with HT / DM defined as using medication and/or diet

3 CV morbidity and mortality (%) 3-Jun- Isolated albuminuria Effect of ACEi on cardiovascular events IT The old classification of CKD for renal and CV risk stratification Placebo ACEi (fosinopril) P=.9 3 Follow-up (months) Risk Reduction % NNT 3 In persons with UAE > mg/d NNT 9* Stage GFR (ml/min//73 m ) Additional signs of CKD i.e. albuminuria Estimated prevalence USA* Estimated prevalence ** > 9 Necessary 3.3 %.3 % 6-9 Necessary 3. % 3. % Not necessary.3 %.3 % - 9 Not necessary. %. % < of RRT Not necessary. %. % Total. %.6 % Asselbergs et al Circulation Double-blind RCT, ACEi vs placebo N= with isolated albuminuria (-3 mg/d) K/DOQI Guidelines Am J Kidney Dis 3 *Coresh et al; Am J Kidney Dis **De Zeeuw et al; Kidney Int The Mission and organisation The Selecting the cohorts Mission Perform meta-analyses to obtain an Evidence Based rationale for a new CKD classification based on prognosis, and especially to investigate the added value of albuminuria Organisation Steering committee Coresh (USA), Gansevoort (Nl), Hemmelgarn (Can), de Jong (Nl), Levey (USA), Levin (Can), Wen (Taiwan) Data analysis teams Hopkins, USA: Coresh, Matsushita, Astor, Wang, Woodward Groningen, the Netherlands: Gansevoort, de Jong Matsushita, Gansevoort et al Int J Epidemiol 3. Identification of eligible cohorts: PubMed search and expert panel. Selection criteria for inclusion: Prospective cohort studies Information available on: - Baseline egfr and albuminuria - Age, gender, race and CV risk factors - Mortality and/or renal outcomes during follow-up subjects per cohort, events per cohort per outcome 3. Result: general population, high risk and CKD cohorts, together > million participants. Data collected centrally. Matsushita, Gansevoort et al Int J Epidemiol 3 egfr and ACR versus ESRD risk (adjusted for each other and for CV RFs) CKD Prognsis egfr and albuminuria vs CVD Is diabetes status of importance? Adjusted relative risk for CV mortality,, Gansevoort et al for the CKD PC Kidney Int 9 GP and HR cohorts, n=..7 participants Fox et al for the CKD PC Lancet Meta-analysis of 3 cohort studies Diabetes n=, non-diabetes n=96.7 3

4 ESRD event rate (% per year) PKD Expertise Center, UMC Groningen 3-Jun- A fundamental difference between micro- and macro-albuminuria as risk predictors? egfr and albuminuria vs. risk Summary of Summary of Relative Risks adjusted Relative from Risks from continuous Continuous meta-analyses Meta-Analysis 6 All-Cause Mortality egfr, ml/min/.73m^ 6 Cardiovascular Mortality egfr, ml/min/.73m^,,, Albuminuria (mg/hr) Adapted from Lambers Heerspink et al, Am J Nephol ADVANCE AASK RENAAL IDNT REIN General population High risk population AA + hypertension DM DM Primary renal diseases End Stage Renal Disease egfr, ml/min/.73m^ Matsushita et al, NEJM Gansevoort et al, Kidney Int Van de Velde et al, Kidney Int 6 6 Acute Kidney Injury Adjusted OR egfr, ml/min/.73m^ Progressive CKD egfr, ml/min/.73m^ Based on meta-analyses of cohorts with million individuals en endpoints An integrated approach for a new classification of CKD An integrated approach for a new classification of CKD Summary of adjusted Relative Risks from categorical meta-analyses Prognosis of CKD based on GFR en Albuminuria categories: KDIGO No CKD (%) Mild risk (9,%) Moderate risk (,%) High risk (<%) Levey, Eckardt, Gansevoort et al, KI Based on meta-analyses of cohorts with million individuals en endpoints KDIGO Guidelines for Diagnosis, Staging and Management of CKD, Kidney Int 3 Based on meta-analyses of cohorts with million individuals en endpoints An integrated approach for a new classification of CKD Screening for early CKD is inadequate Diagnosis GFR stages (ml/min/.73m ) Diabetes : >9 Hypertension : 6-9 IgA nefropathy 3a: -9. 3b: 3- Transplantation : -9 Unknown : < Albuminuria stages (mg/d) : <3 : 3-3 3: >3 Urinary protein loss Kidney function Both tests Example: Diabetic nephropathy CKD stage G A3 Levey, Eckardt, Gansevoort et al, KI Report of the US Renal Database System

5 Incidende per per million of the population PKD Expertise Center, UMC Groningen PKD Expertise Center, UMC Groningen 3-Jun- Conclusions Albuminuria predicts CV and renal outcomes, independent of kidney function and CV risk factors Predictive value of albuminuria is not limited to the proteinuria / macro-albuminuria range Predictive value of albuminuria is not limited to patients with known diabetes and/or hypertension ADDITIONAL SLIDES On a population level is attention for micro-albuminuria more important than only focusing on macro-albuminuria, because it allows early prevention. This has led to a new classification of CKD that is 3 dimensional, based on diagnosis, egfr AND albuminuria Micro-albuminuria has grown to be of importance Can End-Stage Renal Disease be prevented? Can prevention of End-Stage Renal Disease be achieved? Number of patients starting renal replacement therapy in Europe 3 Incidence of RRT overall Incidence of RRT by age group Diabetes Hypertension Primary kidney diseases Urological problems Polycystic kidney disease Year Kramer, Gansevoort, Jager ERA-EDTA Registry data 3 Data of countries ( miljoen inwoners, 3. start RRT) Corrected for age and gender to the EU7 population Gansevoort et al Ned Tijdschr Geneesk Based on RENINE data, the Dutch registry for renalreplacement therapy Albuminuria: Mechanisms leading to disease progression Patient awareness of early CKD is low More than 3% function no symptoms Less than 3% function symptoms Fatigue Itching Nausea Loss of appetite Weight loss Less than % function life threatening Roscioni, Lambers Heerspink et al, Kidney Int Inflammation, fibrosis, mesangial expansion, high uric acid, hypertension, hyperlipidemia Progressive renale and cardiovascular damage

6 3-Jun- Albuminuria vs CV mortality Does age matter? egfr and albuminuria vs CVD Is hypertension status of importance? Adjusted relative risk for CV mortality Absolute risk for CV mortality Adjusted relative risk for CV mortality,, Halan et al for the CKD PC JAMA 3 Meta-analysis of 33 GP and 3 CKD cohort studies In total,. participants, with mean follow-up. years Mahmoodi et al for the CKD PC Lancet Meta-analysis of cohort studies Hypertension n=36.3, no hypertension n=