inquadramento diagnostico della nefropatia diabetica giuseppe.pdf · dichiarazione esplicita di...

Giuseppe PennoDipartimento di Medicina Clinica e SperimentaleUniversit di Pisa

La nefropatia diabetica

Inquadramento diagnostico della nefropatia diabetica

Dichiarazione esplicita di trasparenza delle fonti di finanziamentoe dei rapporti con soggetti portatori di interessi commerciali

Il sottoscritto Dr. Giuseppe Penno

in qualit diModeratore Relatore

ai sensi dellart. 3.3 sul Conflitto di Interessi, pag. 17 del Reg. Applicativo dellAccordo Stato-Regione del 5 novembre 2009,

dichiarache 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

Diagnostic parameters: albuminuria, eGFR and the clinical course of DKD

Key points

Albuminuria is a key marker ofkidney 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:

*Note that KDIGO 2012 guidelines recommend avoiding the terms microalbuminuria and macroalbuminuriaUACR, urine albumin-to-creatinine ratio

UACR (mg/g)24-hour UAE (mg/24 h)

Macroalbuminuria/severely increased*

>300>300A3

Microalbuminuria/moderately increased*

3030030300

A2

Normal to mildly increased

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:

Kidney Disease: Improving Global Outcomes (KDIGO) CKD Work Group. Kidney Int Suppl 2013;3:1

Kidney failure

KDIGO, Kidney Int Suppl 3: 1-150, 2013

Low riskModerate riskHigh riskVery 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.

Kidney Disease: Improving Global Outcomes (KDIGO) classification



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).

Low riskModerate riskHigh riskVery high risk

l Diagnostic parameters: albuminuria, eGFR and the clinical course of DKD

l Albuminuria and eGFR: clinicalcourse (and epidemiology) of DKD

Key points

Schematic presentation of the different clinical courses of diabetic kidney disease (DKD)

Boger CA et al., PLOS Genetics, 8: e1002989, 2012 (modified)

Normoalbuminuria

Normal GFR

Normoalbuminuria

Normal GFR

0 5 10 15 20Duration of diabetes (years)

Increased GFR (hyperfiltration)

Reduced GFR ESRD

crosstalk between the two channels

Normoalbuminuria

Microalbuminuria

Macroalbuminuria

Normal GFR

30-59 ml/min/1.73 m217.1%Normo 73.1%

Micro22.2%

Macro4.7%

60-89 ml/min/1.73 m251.7%

90 ml/min/1.73 m229.6%

62.5%12.0%

6.7%

17.1%

1.7%

No CKD

CKD stage 1

CKD stage 2

CKD stage 3

CKD stages 4/5

Approximately 40% of patientswith T2DM show signs of CKD (stages 1-5)

Approximately 20% of patientswith T2DM show signs of renalfailure (eGFR

Severe(A3)

Mild(A2)

Normal(A1)

15-29

30-44

45-59

60-89

>90

Albuminuria

Stage 2

Stage 1Stage 0(no CKD)

62.5%

Stage 3

Stage 4

Stage 5

Stage 1-2albuminuric phenotype

18.7%

Penno G et al. J Hypertens 29: 1802-1809, 2011

Renal dysfunction is common in patients with T2DMThe RIACE Study: 15,773 patients with T2DM

eGFRml/min/1.73 m2

Distribution of markers of CKD in RIACE and in NHANES participants with DM, hypertension, self-reported cardiovascular disease, & obesity, 20112014

Data Source: National Health and Nutrition Examination Survey (NHANES), 20112014 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 - 2016 Annual Data Report, Vol 1, CKD, Ch 1

10.6%

8.2%

18.7%

RIACE, Italy

De Cosmo S, et al., The AMD-Annals Study Group. Nephrol Dial Transplant, 29: 657-662, 2014

Kidney dysfunction and related cardiovascular risk factorsamong 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

10.6% 18.7% 8.2%62.5%

Diabetic Kidney Disease (DKD)

Thomas MC et al., Nature Reviews / Disease Primers, 1: 1-19, 2015

The prevalence of CKD in different populations with type 2 diabetes

*Adjusted for age, sex, and race/ethnicity. p-values are for trendUACR, urine albumin-to-creatinine ratio

Prevalent cases of diabetic kidney disease in the United States accounting for persistence

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

p=0.39 p

p=0.001 p=0.15p



l Albuminuria and eGFR in the KDIGO guidelines

Key points

Matsushita K et al, JAMA 307: 1941-1951, 2012

Distribution of estimated GFRData from 1.1 million adults from 25 general population cohorts,

7 high-risk cohorts (of vascular disease), and 13 CKD cohorts

Comparison of risk prediction using the CKD-EPI Equation and the MDRD Study Equation for Estimated Glomerular FiltrationRate


Reclassification across estimated GFR categories



Net reclassification improvements for all-cause mortality, cardiovascular mortality, and ESRD





l Albuminuria and eGFR for DKD monitoring

Key points

Normal AERn. 2,729 (75%)

Micro-albuminurian. 438 (12%)

Macro-albuminurian. 475 (13%)

Regressedn. 102

Persistentn. 336

Persistentn. 364

Regressedn. 111

23.3% 23.4%

The Finnish Diabetic Nephropathy Study

Study subjects (n. 3,642)

Men: 50.7%; Age: 37.4 11.9; BMI: 25.1 3.5

6.9 years follow-up

Jansson F et al., EASD, September 2016



0%

10%

20%

30%

40%

50%

0 5 10 15

Incidence of first ever CVD event by albuminuria status (n=3,449)

Time (years)

NORMO

MICRO

MACRO

HR = 1 (reference)

HR = 2.28 (1.68-3.10)

HR = 4.46 (3.46-5.77)



0%

10%

20%

30%

40%

50%

0 5 10 15

MACRO -> MICRO/NORMO

MICRO -> NORMO

HR = 1 (reference)

HR = 1.15 (0.61-2.19)

HR = 2.28 (1.68-3.10)

HR = 2.70 (1.73-4.24)

HR = 4.46 (3.46-5.77)

Time (years)

Incidence of first ever CVD event by albuminuria status (n=3,449)

NORMO

MICRO

MACRO



MACRO -> MICRO/NORMO

MICRO -> NORMO

HR = 1 (reference)NORMO

MICRO

MACRO

0%

10%

20%

30%

40%

0 5 10 15

Total mortality

Time (years)

HR = 1.19 (0.58-2.43)

HR = 2.65 (1.94-3.63)

HR = 3.54 (2.33-5.36)

HR = 6.32 (4.91-8.13)




l Albuminuria and eGFR and DKD monitoring

l What the diagnosis of DKD implies

Key points


The strong association between DKD and increased incidence and prevalence of other diabetic complications

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

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.

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: 217-232, 2018

In type 2 diabetes with CVD and kidney disease, empagliflozin reduced mortality and hospitalization

Wanner C et al., Circulation 137: 119-129, 2018


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

Key points

0

10

20

30

40

50

CKD stages 1-2

n. 2,949

No CKD

n. 9,865

Maj

or C

VD e

vent

s, %

794(26.9%)

1,756(17.8%)

Any CVD event by CKD phenotype

Chi square, p

Kidney Disease and Increased Mortality in Type 2 Diabetes

Distribuzione dellEURODIAB PCS risk score in base ai fenotipi di CKD

64.9

28.3

11.8

0

26.0

37.7

23.5

8.39.1

34.0

64.7

91.7

0

20

40

60

80

100

No CKD CKD stadi1-2

n. 53

CKD stadi 3Alb-n. 17

CKD stadi 3Alb+n. 12

Rischio basso Rischio alto

1-2n. 692

p

Sopr

avvi

venz

a cu

mul

ativ

a

Follow-up, anni

K-M: Log Rank test p

HR 4.58(1.69-12.42)

p=0.003

HR 2.77(0.97-7.94)

p=0.058

Sopr

avvi

venz

a cu

mul

ativ

a

Follow-up, anni

Ref

HR 2.57(1.11-5.94)

p=0.027

HR 95%CI p

Sesso (M) 1.52 0.77-3.01 0.225

EURODIAB risk scoreRischio bassoRischio intermedioRischio alto

13.35

11.74

---1.20-9.32

4.44-31.04


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

Key points


Glomerulopathy in diabetes

Morphological and functional alterations to renal glomeruli are one of the hallmarks of diabetic kidney disease

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.

Indicazioni alla biopsia renale

Le indicazioni legate alla presentazione atipica del danno renale sono le seguenti:

SID. Position Statement sullAppropriatezza nella Prescrizione degli Esami Strumentali in Diabetologia; Esami strumentali per lo Screening della Nefropatia Diabetica

- 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

CKD in diabetes: diabetic kidney disease versusnondiabetic kidney disease

Anders HJ et al., Nature Review / Nephrology, 14: 361-377, 2018

Causes of CKD in patients with diabetes mellitus and the pathophysiology of DKD

Presumed site of origin of commonly associated biomarkers predictive of DKD

Colhoun HM and Marcovecchio L, Diabetologia, Online, 8 march 2018

Thank for your attention!

Diapositiva numero 1Diapositiva numero 2Diapositiva numero 3Albuminuria is a key marker ofkidney damageEstimated glomerular filtration rate is the most commonly used index of renal function Diapositiva numero 6Diapositiva numero 7Diapositiva numero 8Diapositiva numero 9Diapositiva numero 10Diapositiva numero 11Diapositiva numero 12Diapositiva numero 13Diapositiva numero 14Diapositiva numero 15Diapositiva numero 16Diapositiva numero 17Diapositiva numero 18Diapositiva numero 19Diapositiva numero 20Diapositiva numero 21Diapositiva numero 22Diapositiva numero 23Diapositiva numero 24Diapositiva numero 25Diapositiva numero 26 Diapositiva numero 30Diapositiva numero 31Diapositiva numero 32Glycemic control of type 2 diabetes mellitus across stages of renal impairment: information for primary care providersGlycemic control of type 2 diabetes mellitus across stages of renal impairment: information for primary care providersDiapositiva numero 35Diapositiva numero 36Diapositiva numero 37Diapositiva numero 38Diapositiva numero 39Diapositiva numero 40Diapositiva numero 41Diapositiva numero 42Diapositiva numero 43Diapositiva numero 44Diapositiva numero 45Diapositiva numero 46Diapositiva numero 47Diapositiva numero 48Diapositiva numero 49

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