La nefropatia diabetica. Inquadramento diagnostico della nefropatia diabetica

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1 La nefropatia diabetica Inquadramento diagnostico della nefropatia diabetica Giuseppe Penno Dipartimento di Medicina Clinica e Sperimentale Università di Pisa

2 Dichiarazione esplicita di trasparenza delle fonti di finanziamento e dei rapporti con soggetti portatori di interessi commerciali Il sottoscritto Dr. Giuseppe Penno Moderatore in qualità di Relatore ai sensi dell art. 3.3 sul Conflitto di Interessi, pag. 17 del Reg. Applicativo dell Accordo Stato-Regione del 5 novembre 2009, dichiara che negli ultimi due anni ha avuto i seguenti rapporti anche di finanziamento con soggetti portatori di interessi commerciali in campo sanitario: AstraZeneca, Boerhinger Ingelheim, Eli-Lilly, Janssen, Merck Sharp & Dohme, Novo Nordisk, Takeda 2 ottobre 2015 NAPOLI, 9 GIUGNO 2018

3 Key points Diagnostic parameters: albuminuria, egfr and the clinical course of DKD

4 Albuminuria is a key marker of kidney damage Albuminuria indicates increased glomerular permeability Albuminuria can be categorised according to urine albumin-to-creatinine ratio or to 24-hour urine albumin excretion, as follows: Normal to mildly increased Microalbuminuria/ moderately increased* Macroalbuminuria/ severely increased* UACR (mg/g) 24-hour UAE (mg/24 h) <10 < A A2 >300 >300 A3 *Note that KDIGO 2012 guidelines recommend avoiding the terms microalbuminuria and macroalbuminuria UACR, urine albumin-to-creatinine ratio Kidney Disease: Improving Global Outcomes (KDIGO) CKD Work Group. Kidney Int Suppl 2013;3:1

5 Estimated glomerular filtration rate is the most commonly used index of renal function egfr is generally reduced after widespread structural damage to the kidney It is categorised as follows: Normal Mildly decreased Mildly-tomoderately decreased Moderatelyto-severely decreased Severely decreased Kidney failure 90 G G G3a G3b G4 <15 G5 egfr (ml/min/1.73 m 2 ) Kidney Disease: Improving Global Outcomes (KDIGO) CKD Work Group. Kidney Int Suppl 2013;3:1

Kidney Disease: Improving Global Outcomes (KDIGO) classification Low risk Moderate risk High risk Very high risk Referral decision making by GFR and albuminuria.

6 Kidney Disease: Improving Global Outcomes (KDIGO) classification Low risk Moderate risk High risk Very high risk Referral decision making by GFR and albuminuria. *Referring clinicians may wish to discuss with their nephrology service depending on local arrangements regarding monitoring or referring. KDIGO, Kidney Int Suppl 3: 1-150, 2013

Kidney Disease: Improving Global Outcomes (KDIGO) classification Low risk Moderate risk High risk Very high risk GFR and albuminuria grid to reflect the risk of progression by intensity

7 Kidney Disease: Improving Global Outcomes (KDIGO) classification Low risk Moderate risk High risk Very high risk GFR and albuminuria grid to reflect the risk of progression by intensity of coloring (green, yellow, orange, red, deep red). The numbers in the boxes are a guide to the frequency of monitoring (number of times per year). KDIGO, Kidney Int Suppl 3: 1-150, 2013

8 l l Key points Diagnostic parameters: albuminuria, egfr and the clinical course of DKD Albuminuria and egfr: clinical course (and epidemiology) of DKD

Schematic presentation of the different clinical courses of diabetic kidney disease (DKD) Reduced GFR ESRD Increased GFR (hyperfiltration) Macroalbuminuria crosstalk between the two channels

9 Schematic presentation of the different clinical courses of diabetic kidney disease (DKD) Reduced GFR ESRD Increased GFR (hyperfiltration) Macroalbuminuria crosstalk between the two channels Microalbuminuria Normal GFR Normal GFR Normal GFR Normoalbuminuria Normoalbuminuria Normoalbuminuria Duration of diabetes (years) Boger CA et al., PLOS Genetics, 8: e , 2012 (modified)

10 Renal dysfunction is common in patients with T2DM The RIACE Study: 15,773 patients with T2DM Albuminuria strata 30% 20% (ml/min/1.73 m 2 ) egfr strata (ml/min/1.73 m 2 ) Micro 22.2% Macro 4.7% Normo 73.1% ml/min/1.73 m % <30 ml/min/1.73 m 2 1.7% 90 ml/min/1.73 m % ml/min/1.73 m % Penno G, et al., The RIACE Study Group. J Hypertens 29: , 2011

11 Renal dysfunction is common in patients with T2DM The RIACE Study: 15,773 patients with T2DM 17.1% 1.7% No CKD CKD stage 1 CKD stage 2 CKD stage 3 CKD stages 4/5 12.0% 6.7% 62.5% Approximately 40% of patients with T2DM show signs of CKD (stages 1-5) 40% Approximately 20% of patients with T2DM show signs of renal failure (egfr <60 ml/min/1.73 m 2 ) 20% Penno G, et al., The RIACE Study Group. J Hypertens 29: , 2011

12 Renal dysfunction is common in patients with T2DM The RIACE Study: 15,773 patients with T2DM Albuminuria Normal (A1) Mild (A2) Severe (A3) G1 G2 > Stage 0 (no CKD) 62.5% Stage Stage albuminuric phenotype 18.7% Stage 2 egfr ml/min/ 1.73 m 2 G3a G3b G Stage 3/5 Non albuminuric CKD Phenotype 10.6% Stage 3 Stages 3/5 Albuminuric CKD Phenotype Stage 4 8.2% G5 <15 Stage 5 Penno G et al. J Hypertens 29: , 2011

Distribution of markers of CKD in RIACE and in NHANES participants with DM,

13 Distribution of markers of CKD in RIACE and in NHANES participants with DM, hypertension, self-reported cardiovascular disease, & obesity, RIACE, Italy 18.7% 8.2% 10.6% Data Source: National Health and Nutrition Examination Survey (NHANES), participants age 20 & older. Single-sample estimates of egfr & ACR; egfr calculated using the CKD-EPI equation. Abbreviations: ACR, urine albumin/creatinine ratio; BMI, body mass index; CKD, chronic kidney disease; SR CVD, self-reported cardiovascular disease; egfr, estimated glomerular filtration rate; HTN, hypertension. USRDS Annual Data Report, Vol 1, CKD, Ch 1

Kidney dysfunction and related cardiovascular risk factors among patients with type 2 diabetes Clinical features of 120,903 patients with type 2 diabetes: whole sample and

14 Kidney dysfunction and related cardiovascular risk factors among patients with type 2 diabetes Clinical features of 120,903 patients with type 2 diabetes: whole sample and divided according to the presence/absence of albuminuria or low egfr 62.5% 10.6% 18.7% 8.2% De Cosmo S, et al., The AMD-Annals Study Group. Nephrol Dial Transplant, 29: , 2014

15 Diabetic Kidney Disease (DKD) The prevalence of CKD in different populations with type 2 diabetes Thomas MC et al., Nature Reviews / Disease Primers, 1: 1-19, 2015

Clinical manifestations of Kidney Disease among US Adults with Diabetes, 1988-2014 Prevalent cases of

001 40% 30% 20% *Adjusted for age, sex, and race/ethnicity.

16 Clinical manifestations of Kidney Disease among US Adults with Diabetes, Prevalent cases of diabetic kidney disease in the United States accounting for persistence p<0.001 p=0.39 p< % 30% 20% *Adjusted for age, sex, and race/ethnicity. p-values are for trend UACR, urine albumin-to-creatinine ratio Afkarian M et al., JAMA 316: , 2016 USRDS Annual Data Report, Vol 1, CKD, Ch 1

001 Adults aged <65 Adults aged 65 Adults aged <65 Adults aged 65 *Adjusted for age, sex, and

17 Clinical manifestations of Kidney Disease among US Adults with Diabetes, Prevalent cases of albuminuria and reduced egfr in the United States by age accounting for persistence p<0.001 p=0.001 p=0.15 p<0.001 Adults aged <65 Adults aged 65 Adults aged <65 Adults aged 65 *Adjusted for age, sex, and race/ethnicity. p-values are for trend UACR, urine albumin-to-creatinine ratio Afkarian M et al., JAMA 316: , 2016

18 l l l Key points Diagnostic parameters: albuminuria, egfr and the clinical course of DKD Albuminuria and egfr: clinical course (and epidemiology) of DKD Albuminuria and egfr in the KDIGO guidelines

19 Kidney Disease: Improving Global Outcomes (KDIGO) classification KDIGO, Kidney Int Suppl 3: 1-150, 2013

20 Kidney Disease: Improving Global Outcomes (KDIGO) classification KDIGO, Kidney Int Suppl 3: 1-150, 2013

21 Comparison of risk prediction using the CKD-EPI Equation and the MDRD Study Equation for Estimated Glomerular Filtration Rate Distribution of estimated GFR Data from 1.1 million adults from 25 general population cohorts, 7 high-risk cohorts (of vascular disease), and 13 CKD cohorts Matsushita K et al, JAMA 307: , 2012

22 Comparison of risk prediction using the CKD-EPI Equation and the MDRD Study Equation for Estimated Glomerular Filtration Rate Reclassification across estimated GFR categories Matsushita K et al, JAMA 307: , 2012

23 Comparison of risk prediction using the CKD-EPI Equation and the MDRD Study Equation for Estimated Glomerular Filtration Rate Net reclassification improvements for all-cause mortality, cardiovascular mortality, and ESRD Matsushita K et al, JAMA 307: , 2012

24 Kidney Disease: Improving Global Outcomes (KDIGO) classification KDIGO, Kidney Int Suppl 3: 1-150, 2013

25 l l l l Key points Diagnostic parameters: albuminuria, egfr and the clinical course of DKD Albuminuria and egfr: clinical course (and epidemiology) of DKD Albuminuria and egfr in the KDIGO guidelines Albuminuria and egfr for DKD monitoring

26 The Finnish Diabetic Nephropathy Study Study subjects (n. 3,642) Men: 50.7%; Age: 37.4 ± 11.9; BMI: 25.1 ± 3.5 Normal AER n. 2,729 (75%) Micro-albuminuria n. 438 (12%) Macro-albuminuria n. 475 (13%) 6.9 years follow-up Regressed n. 102 Persistent n. 336 Regressed n. 111 Persistent n % 23.4% Jansson F et al., EASD, September 2016

27 The Finnish Diabetic Nephropathy Study 50% 40% Incidence of first ever CVD event by albuminuria status (n=3,449) MACRO HR = 4.46 ( ) 30% 20% MICRO HR = 2.28 ( ) 10% 0% NORMO HR = 1 (reference) Time (years) Jansson F et al., EASD, September 2016

The Finnish Diabetic Nephropathy Study 50% 40% Incidence of first ever CVD event by albuminuria status (n=3,449) MACRO HR = 4.46 (3.46-5.77) 30% MACRO -> MICRO/NORMO HR = 2.

28 The Finnish Diabetic Nephropathy Study 50% 40% Incidence of first ever CVD event by albuminuria status (n=3,449) MACRO HR = 4.46 ( ) 30% MACRO -> MICRO/NORMO HR = 2.70 ( ) 20% 10% MICRO MICRO -> NORMO NORMO HR = 2.28 ( ) HR = 1.15 ( ) HR = 1 (reference) 0% Time (years) Jansson F et al., EASD, September 2016

The Finnish Diabetic Nephropathy Study 40% Total mortality MACRO HR = 6.32 (4.91-8.13) 30% MACRO -> MICRO/NORMO HR = 3.54 (2.33-5.

29 The Finnish Diabetic Nephropathy Study 40% Total mortality MACRO HR = 6.32 ( ) 30% MACRO -> MICRO/NORMO HR = 3.54 ( ) 20% MICRO HR = 2.65 ( ) 10% MICRO -> NORMO NORMO HR = 1.19 ( ) HR = 1 (reference) 0% Time (years) Jansson F et al., EASD, September 2016

30 l l l l l Key points Diagnostic parameters: albuminuria, egfr and the clinical course of DKD Albuminuria and egfr: clinical course (and epidemiology) of DKD Albuminuria and egfr in the KDIGO guidelines Albuminuria and egfr and DKD monitoring What the diagnosis of DKD implies

31 The strong association between DKD and increased incidence and prevalence of other diabetic complications Thomas MC et al., Nature Reviews / Disease Primers, 1: 1-19, 2015

32 Impact of DKD on EASD/ADA Treatment Algorithm (Two-Drug Combibnations)

33 Glycemic control of type 2 diabetes mellitus across stages of renal impairment: information for primary care providers Tong L and Adker S. Postgraduate Medicine Published online: 18 Apr 2018.

34 Glycemic control of type 2 diabetes mellitus across stages of renal impairment: information for primary care providers Tong L and Adker S. Postgraduate Medicine Published online: 18 Apr 2018.

35 Role of lipids, glucose and BP on CVD and DKD. Solid blue lines = strong clinical evidence linking the treatment to end-organ benefit Blue dotted lines = inadequate evidence to support a clear benefit on CV or DKD Maqbool M et al., Seminars in Nephrology 38: , 2018

36 In type 2 diabetes with CVD and kidney disease, empagliflozin reduced mortality and hospitalization Wanner C et al., Circulation 137: , 2018

37 Key points Diagnostic parameters: albuminuria, egfr and the clinical course of DKD Albuminuria and egfr: clinical course (and epidemiology) of DKD Albuminuria and egfr in the KDIGO guidelines Albuminuria and egfr and DKD monitoring What the diagnosis of DKD implies What the stratification by DKD phenotypes implies

38 The RIACE (Renal Insufficiency and Cardiovascular Events) Italian Multicenter Study Any CVD event by CKD phenotype Chi square, p< (44.8%) Major CVD events, % ,756 (17.8%) 794 (26.9%) 528 (31.6%) 0 No CKD n. 9,865 CKD stages 1-2 n. 2,949 CKD stages 3-5 nonalbuminuric n. 1,673 CKD stages 3-5 albuminuric n. 1,286 Solini A. et al, The RIACE Study Group. Diabetes Care 35: , 2012

39 Kidney Disease and Increased Mortality in Type 2 Diabetes

40 Albuminuric and non-albuminuric chronic kidney disease in type 1 diabetes: association with major vascular outcomes risk and all-cause mortality Distribuzione dell EURODIAB PCS risk score in base ai fenotipi di CKD Rischio basso Rischio intermedio Rischio alto 100 p< No CKD CKD stadi CKD stadi CKD stadi n n. 53 Albn. 17 Alb+ n. 12 Garofolo M et al., J Diabetes Complications 32: , 2018

41 Albuminuric and non-albuminuric chronic kidney disease in type 1 diabetes: association with major vascular outcomes risk and all-cause mortality Mortalità per tutte le cause e fenotipi di DKD 3.0% (n. 21); Ref 3.56 x 1000/anno Sopravvivenza cumulativa No CKD CKD stadi 1-2 CKD stadi 3 Alb- CKD stadi 3 Alb+ K-M: Log Rank test p< % (n. 8) HR 4.50 ( ) x 1000/anno 29.4% (n. 5) HR 8.58 ( ) x 1000/anno 50.0% (n. 6) HR ( ) x 1000/anno 40 di % 6.26 x 1000/anno 774 pazienti con DMT1: follow-up 8.25±2.34 anni Follow-up, anni Garofolo M et al., J Diabetes Complications 32: , 2018

42 Albuminuric and non-albuminuric chronic kidney disease in type 1 diabetes: association with major vascular outcomes risk and all-cause mortality Mortalità per tutte le cause e fenotipi di DKD Ref HR 2.57 ( ) p=0.027 Sopravvivenza cumulativa No CKD CKD stadi 1-2 CKD stadi 3 Alb- CKD stadi 3 Alb+ p=0.008 Follow-up, anni HR 2.77 ( ) p=0.058 HR 4.58 ( ) p=0.003 HR 95%CI p Sesso (M) EURODIAB risk score Rischio basso Rischio intermedio Rischio alto < < Garofolo M et al., J Diabetes Complications 32: , 2018

Key points Diagnostic parameters: albuminuria, egfr and the clinical course of DKD Albuminuria and egfr: clinical course (and epidemiology) of DKD Albuminuria and egfr in the

43 Key points Diagnostic parameters: albuminuria, egfr and the clinical course of DKD Albuminuria and egfr: clinical course (and epidemiology) of DKD Albuminuria and egfr in the KDIGO guidelines Albuminuria and egfr and DKD monitoring What the diagnosis of DKD implies What the stratification by DKD phenotypes implies The kidney biopsy and the biomarkers

44 Glomerulopathy in diabetes Morphological and functional alterations to renal glomeruli are one of the hallmarks of diabetic kidney disease Thomas MC et al., Nature Reviews / Disease Primers, 1: 1-19, 2015

45 Indicazioni alla biopsia renale Indicata in pazienti con diabete nei quali esiste il sospetto della presenza di DKD differenti dalla nefropatia diabetica Permette di classificare la DKD in tre categorie associate a diverse prospettive prognostiche: 1. nefropatia diabetica (ND) 2. malattia renale non diabetica (NDRD, non-diabetic renal disease) 3. condizione mista caratterizzata da NDRD sovrapposta a ND.

46 Indicazioni alla biopsia renale Le indicazioni legate alla presentazione atipica del danno renale sono le seguenti: - proteinuria in range nefrosico o riduzione del GFR in assenza di RD - proteinuria in range nefrosico o riduzione del GFR in soggetti con durata del diabete inferiore a 5 anni - ematuria (microscopica) isolata o presenza di sedimento urinario attivo; - insufficienza renale acuta (AKI) - sospetto di nefropatia associata ad altre malattie sistemiche (basso complemento, ANCA, ANA, dsdna, anticorpi anticardiolipina, ASLO, HIV, M- Spike suggestivi di malattie monoclonali, crioglobuline, HCV) - mancanza della caratteristica cronologia della DKD (comparsa rapida di proteinuria senza progressione da micro- a macroalbuminuria, presentazione con sindrome nefrosica, progressivo rapido declino del GFR in pazienti con funzione renale precedentemente stabile) - significativa riduzione del GFR (>30%) dopo trattamento con bloccanti del RAS SID. Position Statement sull Appropriatezza nella Prescrizione degli Esami Strumentali in Diabetologia; Esami strumentali per lo Screening della Nefropatia Diabetica

47 CKD in diabetes: diabetic kidney disease versus nondiabetic kidney disease Causes of CKD in patients with diabetes mellitus and the pathophysiology of DKD Anders HJ et al., Nature Review / Nephrology, 14: , 2018

48 Presumed site of origin of commonly associated biomarkers predictive of DKD Colhoun HM and Marcovecchio L, Diabetologia, Online, 8 march 2018

49 Thank for your attention!

Farmaci innovativi e terapie di associazione: quali opportunità? Giuseppe Penno Dipartimento di Medicina Clinica e Sperimentale

Farmaci innovativi e terapie di associazione: quali opportunità? Giuseppe Penno Dipartimento di Medicina Clinica e Sperimentale Dichiarazione esplicita di trasparenza delle fonti di finanziamento e dei