Prediabetes Experience from the Troms Study The Renal

Prediabetes – Experience from the Tromsø Study The Renal Iohexol Clearance Survey (RENIS) Toralf Melsom, Associate Prof, Nephrologist University Hospital of North Norway

The RENIS – A study of agerelated GFR decline in the general population. Disclosure: The RENIS-Follow Up was funded by the North Norway Health Authority and by a grant from Boehringer Ingelheim.

Age-related GFR decline CKD prevalence by age Normal ageing or a disease? ? AJKD, Vol 39, Feb. 2002 (NHANES) Coresh et al. JAMA 2007.

GFR and risk of ESRD and Death HR of ESRD, by age HR of mortality, by age Risk factors for accelerated GFR decline Hallan et. al. JAMA 2012. 2 mill people – 33 cohorts gen pop + high risk pop.

Hyperglycemia and risk of GFR decline • Large prop Dia CKD – Even with optimal treatment (Rossing KI, 2011) – Accounts 20 -50% ESRD Prediabetes X 2 (Tabak, Lancet 2012) = 800 millions • 50% of Prediabetic diabetes in 10 year (Tabak, Lancet 2012) Window of opportunity. . • Definition • IGT: 2 h, 7. 8 – 11 mmol/L • IFG: 6. 1 – 6. 9 (WHO) 5. 6 – 6. 9 (ADA)

Prediabetes and risk of CKD • Unknown: Prediabetes CKD? ? • Cross-sectional studies: • Low-grade albuminuria (Plantinga, CJASN 2010) • Reduced GFR • A few longitudinal studies – mixed results • Does renal dysfunction in hyperglycemia start in prediabes? ?

Hyperfiltration: a risk factor for CKD? Prediabetes? Ruggenenti 02. 12. 2020 Int. 2006 and Remuzzi, Kidney 7

GFR and Mortality risk N= 106 000, 7 years follow-up e. GFRcrea General population (Lancet 2010) Confounding Chronic illnes – lower muscles mass e. GFR Outcome

Population studies of normal GFR and hyperfiltration • Estimated GFR – Lack precision – Biased by non-GFR related factors (Mathisen et. al. JASN 2011, Rule KI 2013, Schei CJASN 2016) • • • Poggio, E. , JASN 2005 02. 12. 2020 9 Muscle mass Obesity Smoking Inflammation CVD risk factors.

Aims Measure GFR -general population Hyperfiltration GFR decline. . Mortality. .

The Tromsø Study – population survey Approximately 80 000 TROMSO, NORTHERN NORWAY inhabitants, mainly Caucasians

The Tromsø population based surveys Invited Attended (%) Tromso 1 (1974) 8 866 6 595 (83) Tromso 2 (1979 -80) 21 439 16 620 (85) Tromso 6 (2007 -2008) 19 762 12 984 (66%)

The Renal Iohexol Clearance Survey of Tromso 6 (RENIS-T 6) 2007 -2009 Attended Tromsø-6 and between 50 -62 years 3564 739 reported CVD, CKD or Diabetes Positive resp: 2107 (74%) 02. 12. 2020 Included in RENIS-T 6 cohort: 1627 13

Method • Plasma iohexol clearance. Fasting, 8 -10 am. – Validated vs inulin clearance (Gaspari, JASN 1995, Bird, AJKD, 2009)

Persons without diabetes

Association of fasting glucose and m. GFR in persons without diabetes. Does this represent hyperfiltration ? ? Multivariable adjustment: Age, sex, height, weight, smoking, BP and antihypertensive med. Melsom et al Diabetes Care 2011

Definition of hyperfiltration in population studies • • No consensus – define HF at a whole-kidney level Most previous studies: absolute cut off > 120 -160 ml/min/1. 73 sqm Why is this problematic? ? Normal Values for GFR in Men and Women. Inulin Clearance

To illustrate: EMPA-REG. Acute reduction in GFR by reducing glucose using a SGLT 2 -i Reduction in GFR within the normal range…. . treatment of hyperfiltration? ? ? Wanner et al. NEJM, 2016

Definition of hyperfiltration • Whole kidney GFR vs Single Nephron GFR Poggio, E. , JASN 2005 1600 kidney donors, Denic A et al. JASN 2016 When whole kidney GFR decrease – SNGFR remains stable, Denic A, NEJM 2017

70 000 glom per decade (7 -8%) 280 000 per 10 cm height Average per kidney Luyckx V. Review Lancet 2013

Age adjusted Definition of Hyperfiltration 662 DM 2 patients, Measured GFR Premaratne et al Diabetologia, 2005 Hyperfiltration: Age, sex, heigh, (weight) adjusted GFR above 90 percentile. (Melsom, et al. Diabetes Care, 2011, Stefansson BMJ Neph 2016) Closer to single nephron hyperfiltration

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Exercise with high intensity: Lower resting HR, higher HDL cholesterol, lower insulin resistance and lower albumin-to-creatinine ratio. Lower Odds Ratio of hyperfiltration in men. OR 0. 5 (0. 3 – 0. 8) 02. 12. 2020 24

Association of glucose with GFR, by physical exercise. . . Possibly, a protective effect of exercise Cross-sectional data. . 02. 12. 2020 25 (Melsom et. al, CJASN 2012)

2008 -2009 The RENIS-T 6 cohort N=1627 N=7 Possible adverse reaction to iohexol ≈1. 5% Dead RENIS Follow-UP Inclusion of subjects N=1620 (100%) 1324 (83%): Investigated 2014 -2015 RENIS Follow-Up Day-to-day mean CV 4. 2% (3. 4 – 4. 9%) ≈5%: Repeated iohexolclearance measurement N=88 Random sampling

Change in GFR from baseline to follow-up (5. 6 years) Mean GFR decline rate 0. 95 (2. 23) ml/min/year Hypertension, obesity, prediabetes NOT associated with faster decline (Eriksen, Melsom, KI, AJKD, CJASN) Increased weight Fasting glucose Blood Pressure Measurement error

Prediabetes at baseline and risk of hyperfiltration at follow-up Am J Kidney Dis, Dec 2015

Definition of hyperfiltration Alternative longitudinal definition : – Longitudinal change in GFR >= 0 – Increased GFR Hyperfiltration in at least a proportion of nephrons. 02. 12. 2020 29

Association of increasing GFR with albuminuria 334 (27%) persons had increased GFR (ΔGFR>0 m. L/min) after 5, 6 years of follow up CJASN 2017

Is high GFR a risk factor for subsequent rapid GFR decline? ?

Does high GFR predict subsequent rapid decline? ? Mixed model regression. Separates the error term – day-to-day variation in GFR -- key factor that causes regression to the mean. Then assess the correlation between random intercept (baseline GFR) and random slope (GFR decline rate)

HIGH GFR predicts subsequent steeper GFR decline during 5, 6 years

Conclusions • Prediabetes – Associated with hyperfiltration– years before diabetes – Exercise may attenuate the effect of glucose on HF – Incident low-grade albuminuri • Increasing GFR – indicating hypefiltration increasing ACR in non-diabetics • High GFR, or hyperfiltration, is associated with steeper GFR decline in the general non-diabetic population.

– RENIS 3 - 2018/2019 (3 rd m. GFR, 11 years followup) – Non linear trajectory of GFR – Prediabetes and long-term GFR decline. . – Hyperfiltration, GFR and mortality

Thanks • PI RENIS, Bjørn Odvar Eriksen • Staff at the clinical research unit. • Northern Norway Health Authority.

KI 2014 Adjusted for age, sex, traditional CV risk factors, ACR and fasting glucose

Interaction with sex, stronger effect in females

Does high GFR predict subsequent rapid decline? ? Median follow-up Almost 6 and 10 years, resp.

RENIS> Mathisen et al. JASN, 2011 Mean GFR 10 % lower in Women. . Mean GFR 10% lower per decade. . Same as difference in nephron number. .

Patophysiology AGE, oxidativ stress, endothelial dysfunction, growth factors (Heptinstall, 2007) Glomerular growth Diabetes Obesity Prediabetes? Hyperfiltration Sodium-Glucose reaborption, Renin. Angiotensin System, inflammation, oxidative stress (Persson, Act Physiol, 2010) REDUCED NEPRHON NUMB PODOCYT DAMAGE (Wiggins, JASN, 2005) Proteinuria, Glom. sclerosis GFR decline

Histopathology Typical: • Enlarged glomeruli • Thickening of the GBM • Mesangial growth Obesity related glomerulopathy Diabetes Nephropathy

Prediabetes Diabetes Federation Diabetes Atlas 2011: Diabetes x 2 500 million people by 2030, increasing • Definition – IGT: 2 h postload, 7. 8 – 11 mmol/L – IFG: 6. 1 – 6. 9 (WHO), 5. 6 – 6. 9 (ADA)

Estimated GFR 02. 12. 2020 47

Ruggenenti 2012: 600 DM 2 and HT, no MA. FU 4 years. 4 GFRs using iohexol cl